1 00:00:05,000 --> 00:00:09,200 WELCOME TO OUR MONTHLY 2 00:00:09,200 --> 00:00:11,160 BIOMEDICAL ENGINEERING 3 00:00:11,160 --> 00:00:12,560 SCIENTIFIC INTEREST GROUP 4 00:00:12,560 --> 00:00:14,600 SEMINAR SERIES AND TODAY WE HAVE 5 00:00:14,600 --> 00:00:17,240 Dr. PAULA HAMMOND FROM MIT 6 00:00:17,240 --> 00:00:19,960 SHE IS THE 7 00:00:19,960 --> 00:00:22,480 INSTITUTE PROFESSOR AT THE KOCH 8 00:00:22,480 --> 00:00:25,360 INSTITUTE FOR INTEGRATIVE CANCER 9 00:00:25,360 --> 00:00:26,720 RESEARCH AND THE HEAD OF THE 10 00:00:26,720 --> 00:00:27,120 DEPARTMENT OF CHEMICAL 11 00:00:27,120 --> 00:00:28,120 ENGINEERING AT MIT. 12 00:00:28,120 --> 00:00:32,120 Dr. HAMMOND'S ACHIEVEMENTSES 13 00:00:32,120 --> 00:00:34,560 ARE NUMEROUS BEING NAMED THE 14 00:00:34,560 --> 00:00:36,840 NATIONAL SCIENCE ENGINEERING AND 15 00:00:36,840 --> 00:00:38,160 MEDICINE AND SHE'S CURRENTLY 16 00:00:38,160 --> 00:00:39,320 SERVING ON PRESIDENT JOE BIDEN'S 17 00:00:39,320 --> 00:00:41,280 COUNCIL ADVISERS ON SCIENCE AND 18 00:00:41,280 --> 00:00:42,400 TECHNOLOGY AND HER TALK TODAY 19 00:00:42,400 --> 00:00:45,360 WILL BE ON ELECTRO STATIC 20 00:00:45,360 --> 00:00:48,080 ASSEMBLY OF LAYER BY LAYER IN 21 00:00:48,080 --> 00:00:48,640 BIO MEDICINE. 22 00:00:48,640 --> 00:00:50,680 TAKE IT AWAY. 23 00:00:50,680 --> 00:00:51,920 >> THANK YOU SO MUCH. 24 00:00:51,920 --> 00:00:53,480 I'M EXCITED TO HAVE A CHANCE TO 25 00:00:53,480 --> 00:00:54,880 TALK TO THIS GROUP TODAY. 26 00:00:54,880 --> 00:00:57,000 WE HAVE BEEN FOCUSING ON THE USE 27 00:00:57,000 --> 00:00:59,680 OF THE ELECTRO STATIC ASSEMBLY 28 00:00:59,680 --> 00:01:01,240 METHODS TO GENERATE SYSTEMS THAT 29 00:01:01,240 --> 00:01:02,840 CAN BE USED FOR DRUG DELIVERY 30 00:01:02,840 --> 00:01:11,880 AND HOPEFULLY, WE CAN TALK IN AND 31 00:01:11,880 --> 00:01:12,600 HAVE DISCUSSION. 32 00:01:12,600 --> 00:01:14,600 ONE IS NANO PARTICLES FOR 33 00:01:14,600 --> 00:01:18,120 DELIVERY TO TUMORS BUT THE OTHER 34 00:01:18,120 --> 00:01:21,800 IS CHARGED POLYMERIC SYSTEMS FOR 35 00:01:21,800 --> 00:01:23,720 DELIVERY OF ARTHRITIS. 36 00:01:23,720 --> 00:01:26,120 SO, OUR WORK THAT IS FOCUSED ON 37 00:01:26,120 --> 00:01:27,480 CANCER, TAKES ADVANTAGE OF A 38 00:01:27,480 --> 00:01:29,040 TECHNIQUE THAT WE'VE BEEN USING 39 00:01:29,040 --> 00:01:31,280 FOR SEVERAL YEARS IN OUR LAB 40 00:01:31,280 --> 00:01:33,800 WHICH INVOLVES THAL TERNE 41 00:01:33,800 --> 00:01:35,320 NATURING POSITIVELY AND NEGATIVE 42 00:01:35,320 --> 00:01:39,640 LOW CHARGED POLYMERIC SPECIES TO 43 00:01:39,640 --> 00:01:43,000 CREATE CO'S I HAVE NANO SCALE IN 44 00:01:43,000 --> 00:01:44,680 NATURE AND WE FOUND THAT WE CAN 45 00:01:44,680 --> 00:01:48,320 ACTUALLY APPLY THESE SYSTEMS TO 46 00:01:48,320 --> 00:01:50,120 A RANGE OF DIFFERENT SURFACES 47 00:01:50,120 --> 00:01:54,920 FROM THE SURFACES OF DRESSINGS 48 00:01:54,920 --> 00:01:56,440 FOR WOUND HEALING AND TO 49 00:01:56,440 --> 00:01:59,160 APPLYING THEM ON SURFACES THAT 50 00:01:59,160 --> 00:02:02,800 CAN HELP PROMOTE THE GENERATION 51 00:02:02,800 --> 00:02:03,480 OF BALM. 52 00:02:03,480 --> 00:02:04,840 HOWEVER, IN THIS CASE, WE'VE 53 00:02:04,840 --> 00:02:10,600 BEEN TAKING LYPOSOME S&P LGA 54 00:02:10,600 --> 00:02:12,640 THAT CAN BE LOADED WITH A 55 00:02:12,640 --> 00:02:14,200 CHEMOTHERAPY DRUG IN THE CORE 56 00:02:14,200 --> 00:02:17,880 AND USING THOSE PARTICLES AS 57 00:02:17,880 --> 00:02:19,280 SURFACES THAT CAN ESSENTIALLY 58 00:02:19,280 --> 00:02:21,840 SUPPORT THE GENERATION OF MULTI 59 00:02:21,840 --> 00:02:22,200 LAYERS. 60 00:02:22,200 --> 00:02:24,520 AND IN THESE LAYERS, WE 61 00:02:24,520 --> 00:02:26,880 INCORPORATE A POSITIVELY-CHARGED 62 00:02:26,880 --> 00:02:28,480 POLYMER ON TOP OF THE NEGATIVELY 63 00:02:28,480 --> 00:02:30,400 CHARGED NANO PARTICLE AND THEN 64 00:02:30,400 --> 00:02:41,920 WE CAN INCORPORATE A NEWCLEIC 65 00:02:41,920 --> 00:02:45,960 AND THE HEAVILY CHARGED ACID IS 66 00:02:45,960 --> 00:02:47,680 GOING TO HAVE A NICE PROTECTIVE 67 00:02:47,680 --> 00:02:49,480 LAYER ON TOP OF IT, WHICH IS 68 00:02:49,480 --> 00:02:51,160 ANOTHER POSITIVELY-CHARGED 69 00:02:51,160 --> 00:02:51,520 LAYER. 70 00:02:51,520 --> 00:02:56,040 SO NOW WE'VE COMPACTED OUR 71 00:02:56,040 --> 00:02:59,800 NEUCLEIC ACID INTO A THIN FOAM. 72 00:02:59,800 --> 00:03:00,960 OUR INITIAL GOAL IN THIS WORK 73 00:03:00,960 --> 00:03:03,480 WAS TO CREATE COMBINATION 74 00:03:03,480 --> 00:03:06,120 SYSTEMS AND THE IDEA WAS TO 75 00:03:06,120 --> 00:03:09,200 ADDRESS CANCERS THAT HAVE A 76 00:03:09,200 --> 00:03:12,080 NUMBER OF DIFFERENT GENETIC 77 00:03:12,080 --> 00:03:13,960 MODIFICATIONS THAT WHEN SILENCES 78 00:03:13,960 --> 00:03:15,680 WOULD ALLOW THE CHEMOTHERAPY TO 79 00:03:15,680 --> 00:03:16,760 BE MUCH MORE EFFECTIVE. 80 00:03:16,760 --> 00:03:18,760 SO IN OTHER WORDS, SILENCING THE 81 00:03:18,760 --> 00:03:20,120 TUMOR DEFENSE MECHANISMS THAT 82 00:03:20,120 --> 00:03:21,800 ARE PREVALENT IN A NUMBER OF 83 00:03:21,800 --> 00:03:22,960 TUMOR TYPES AND I'LL GIVE ONE 84 00:03:22,960 --> 00:03:23,880 EXAMPLE OF THAT. 85 00:03:23,880 --> 00:03:25,720 HOWEVER, WE WERE MORE AND MORE 86 00:03:25,720 --> 00:03:27,240 INTERESTED IN THIS FINAL LAYER, 87 00:03:27,240 --> 00:03:29,120 WHICH IS THE LAST LAYER WE PUT 88 00:03:29,120 --> 00:03:30,680 DOWN, THIS IS A NEGATIVELY 89 00:03:30,680 --> 00:03:34,160 CHARGED OUTER LAYER. 90 00:03:34,160 --> 00:03:35,520 WE NEED THE NEGATIVE CHARGE SO 91 00:03:35,520 --> 00:03:41,360 THE NOW PARTICLE IS POSITIVITY 92 00:03:41,360 --> 00:03:44,480 CHARGED AND GET OXYGENIZED AND 93 00:03:44,480 --> 00:03:46,080 GET ELIMINATED OR CLEARED ON THE 94 00:03:46,080 --> 00:03:49,280 BLOOD STREAM AND SO THIS IS PART 95 00:03:49,280 --> 00:03:51,120 OF THE REASON FOR THIS OUTER 96 00:03:51,120 --> 00:03:55,080 LAYER AND WE TAKE AND WE CAN USE 97 00:03:55,080 --> 00:03:57,080 POLYMERS THAT HAVE HUGE AMOUNTS 98 00:03:57,080 --> 00:03:58,360 OF HYDRATION AND ASSOCIATIONED 99 00:03:58,360 --> 00:04:00,840 WATER THAT PROVIDES US WITH A 100 00:04:00,840 --> 00:04:03,320 PENALTY FOR DISRUPTION OF THAT 101 00:04:03,320 --> 00:04:07,280 HYDRATION LAYER IF PROTEINS DO 102 00:04:07,280 --> 00:04:09,360 ABSORB ON THE SURFACE AND 103 00:04:09,360 --> 00:04:14,480 PROVIDE A LAYER THAT CAN EXIST 104 00:04:14,480 --> 00:04:15,720 FOR MORE TIMEFRAMES THAN WE 105 00:04:15,720 --> 00:04:18,120 MIGHT TYPICALLY EXPECT FROM A 106 00:04:18,120 --> 00:04:21,200 NEUTRAL NANOPARTICLE. 107 00:04:21,200 --> 00:04:22,600 THIS SYSTEM A LOUSE A LARGE 108 00:04:22,600 --> 00:04:28,920 AMOUNT OF MODULARITY SO WE HAVE 109 00:04:28,920 --> 00:04:35,480 LAYERED LYPOSOMES WHICH ONLY 110 00:04:35,480 --> 00:04:37,520 INCREASE IN SIZE BY 10 OR 15 111 00:04:37,520 --> 00:04:42,640 NANO MEETERS IN THICKNESS AND WE 112 00:04:42,640 --> 00:04:45,320 CAN LAYER PARTICLES, GOLD 113 00:04:45,320 --> 00:04:46,880 NANOPARTICLES AND ANY SORT OF 114 00:04:46,880 --> 00:04:51,240 METAL NANO PARTICLE AND THIS CAN 115 00:04:51,240 --> 00:04:59,320 BE USED FOR IMAGING. 116 00:04:59,320 --> 00:05:02,560 THESE ARE CENTERING AND WE JUST 117 00:05:02,560 --> 00:05:04,600 ONE NEGATIVELY CHARGED FOLLOWED 118 00:05:04,600 --> 00:05:10,120 BY ONE POSITIVELY CHARGED BY ONE 119 00:05:10,120 --> 00:05:11,480 NEGATIVE LEON THE PARTICLES AND 120 00:05:11,480 --> 00:05:13,600 WE CAN SEE INTERESTING RESULTS. 121 00:05:13,600 --> 00:05:15,240 FOR EXAMPLE, HERE WE'RE LOOKING 122 00:05:15,240 --> 00:05:18,600 AT A POLY ELECTRO LIGHT BUY 123 00:05:18,600 --> 00:05:23,840 LAYER WHICH CONSISTS OF POLY LIE 124 00:05:23,840 --> 00:05:27,480 SING FOLLOWING BY HYDRO LONIC 125 00:05:27,480 --> 00:05:27,680 ACID. 126 00:05:27,680 --> 00:05:30,920 IF WE CONSTRUCT THIS ON TO A 127 00:05:30,920 --> 00:05:32,480 NANO PARTICLE AT ONE CONDITION 128 00:05:32,480 --> 00:05:35,840 WE CAN SEE THAT AT THAT PH, 4.7, 129 00:05:35,840 --> 00:05:38,080 WE HAVE A VERY STRONGLY 130 00:05:38,080 --> 00:05:42,520 NEGATIVELY CHARGED NANO PARTICLE 131 00:05:42,520 --> 00:05:45,040 AND THIS IS ABLE TO EXHIBIT NON 132 00:05:45,040 --> 00:05:47,080 HALF LIES AND IS ABLE TO 133 00:05:47,080 --> 00:05:47,880 ESSENTIALLY EXIST IN BLOOD 134 00:05:47,880 --> 00:05:49,280 STREAM FOR SOME TIME. 135 00:05:49,280 --> 00:05:51,800 HOWEVER, WHEN THE PH IS 136 00:05:51,800 --> 00:05:54,080 DECREASED SLIGHTLY, WE GET 137 00:05:54,080 --> 00:05:55,320 SWELLING OF THE BUY LAYER 138 00:05:55,320 --> 00:05:58,080 BECAUSE WE'RE BEGIN TO GO 139 00:05:58,080 --> 00:06:04,600 PROTEASOME NATURE THE ACIDS ON 140 00:06:04,600 --> 00:06:06,480 THE BACKBONE AND WE ARE ERASING 141 00:06:06,480 --> 00:06:08,840 THE ICONIC CROSS LINKS TO HOLD 142 00:06:08,840 --> 00:06:11,880 THAT TOGETHER AND THAT LEADS TO 143 00:06:11,880 --> 00:06:13,760 SWELLING AND THAT SWELLING CAN 144 00:06:13,760 --> 00:06:16,120 HELP FACILITATE THINGS AS SIRNA 145 00:06:16,120 --> 00:06:19,440 OR OTHER MOLECULES THAT MIGHT BE 146 00:06:19,440 --> 00:06:20,640 INCAPSULATED UNDER THESE LAYERS. 147 00:06:20,640 --> 00:06:22,280 WHAT WE CAN ALSO SEE IS A 148 00:06:22,280 --> 00:06:23,240 SIGNIFICANT SHIFT IN THE CHARGE 149 00:06:23,240 --> 00:06:26,160 OF THE NANO PARTICLE AS WE GO 150 00:06:26,160 --> 00:06:27,120 DOWN IN PH. 151 00:06:27,120 --> 00:06:32,680 EVEN AT A MODERATE SHIFT, WE CAN 152 00:06:32,680 --> 00:06:35,240 GET CHANGE IN THE ZETA POTENTIAL 153 00:06:35,240 --> 00:06:38,080 GIVING US A NEUTRAL NANO 154 00:06:38,080 --> 00:06:39,960 PARTICLE OR IN SOME CASES EVEN A 155 00:06:39,960 --> 00:06:43,880 SLIGHT POSITIVE CHARGE. 156 00:06:43,880 --> 00:06:47,400 IT GOES FROM STEALTHY MODE TO A 157 00:06:47,400 --> 00:06:48,600 STICKY MODE JUST THROUGH A MICRO 158 00:06:48,600 --> 00:06:51,760 ENVIRONMENT SHIFT AND THAT MEANS 159 00:06:51,760 --> 00:06:53,280 FOR THE NANO PARTICLES IN THIS 160 00:06:53,280 --> 00:06:54,600 FASHION WE CAN HAVE A SYSTEM 161 00:06:54,600 --> 00:06:56,960 THAT IS VERY STABLE AND DOESN'T 162 00:06:56,960 --> 00:06:58,040 INTERACT VERY MUCH WITH CELLS 163 00:06:58,040 --> 00:07:00,400 WHEN IT'S IN THE BLOOD STREAM 164 00:07:00,400 --> 00:07:04,120 AND IT GETS NO A TIME OR AND IT 165 00:07:04,120 --> 00:07:06,800 GETS INTO THE TUMOR COMPARTMENT 166 00:07:06,800 --> 00:07:08,480 AND WE CAN SEE OFTEN THE SHIFT 167 00:07:08,480 --> 00:07:12,400 IN THE PH DUE TO HYPOXIA IN THAT 168 00:07:12,400 --> 00:07:14,280 TUMOR LEADING TO THIS CHANGE IN 169 00:07:14,280 --> 00:07:17,320 THE NET CHARGE AND ESSENTIAL LOW 170 00:07:17,320 --> 00:07:23,200 THIS NANO PARTICLE IS SA IS A STICKIER 171 00:07:23,200 --> 00:07:24,720 NANO PARTICLE AND ONE CELLS 172 00:07:24,720 --> 00:07:26,560 INTERACT WITH AND WE SEE NON 173 00:07:26,560 --> 00:07:28,600 SPOKE UPTAKE. 174 00:07:28,600 --> 00:07:29,760 NON-SPECIFIC UPTAKE ASIDE, THIS 175 00:07:29,760 --> 00:07:31,080 IS AN INTERESTING MECHANISM, WE 176 00:07:31,080 --> 00:07:32,680 HAVE FOUND THAT THIS OUTER LAYER 177 00:07:32,680 --> 00:07:35,480 CAN BE VERY INTERESTING FOR A 178 00:07:35,480 --> 00:07:41,760 SPECIFIC INCOMPETENTER ACTIONS 179 00:07:41,760 --> 00:07:45,160 AND AND IT'S KNOWN TO BUY THE 180 00:07:45,160 --> 00:07:47,040 RECEPTORS AND IN A LARGE NUMBER 181 00:07:47,040 --> 00:07:51,240 OF THE SOLID EPITHELIAL TYPE 182 00:07:51,240 --> 00:07:54,680 TUMORS WE SEE HIGH OVER 183 00:07:54,680 --> 00:07:56,120 EXPRESSION OF THE RECEPTOR AND 184 00:07:56,120 --> 00:07:57,840 FOR THAT REASON WE CAN SEE VERY 185 00:07:57,840 --> 00:08:01,320 STRONG UPTAKE OF OUR NANO 186 00:08:01,320 --> 00:08:03,680 PARTICLE SHOWN IN RED BY TUMOR 187 00:08:03,680 --> 00:08:05,440 CELLS AND WE HAVE SEEN THIS WITH 188 00:08:05,440 --> 00:08:08,520 TRIPLE NEGATIVE BREAST CANCER, 189 00:08:08,520 --> 00:08:10,640 OVARIAN CANCER AND SOME FORMS OF 190 00:08:10,640 --> 00:08:13,560 GLEGLIOBLASTOMA AS WELL AS HIGH 191 00:08:13,560 --> 00:08:16,480 GRADE OVARIAN CANCER. 192 00:08:16,480 --> 00:08:18,960 HERE YOU CAN SEE A SECTION OF 193 00:08:18,960 --> 00:08:20,680 TUMOR TISSUE THAT WE STAINED 194 00:08:20,680 --> 00:08:23,440 FOLLOWING AN IB INJECTION AND 195 00:08:23,440 --> 00:08:25,920 THIS IS A FLANK TUMOR AND WE CAN 196 00:08:25,920 --> 00:08:29,360 SEE VERY NICE KIND OF LAYER OF 197 00:08:29,360 --> 00:08:29,800 CELLS. 198 00:08:29,800 --> 00:08:32,280 HOWEVER, WE CAN ALSO SEE THESE 199 00:08:32,280 --> 00:08:37,360 TUMOR CELLS THAT OVER PRESS CD44 200 00:08:37,360 --> 00:08:41,000 LABELED IN GREEN AND THE 201 00:08:41,000 --> 00:08:41,600 PARTICLES PENETRATE THE LAYER 202 00:08:41,600 --> 00:08:45,840 AND GET INTO THE TUMOR ITSELF. 203 00:08:45,840 --> 00:08:47,720 I MENTIONED NON SMALL CELL 204 00:08:47,720 --> 00:08:51,200 CANCER AND WE HAVE A GREAT 205 00:08:51,200 --> 00:08:52,000 COLLABORATORS HERE AT. 206 00:08:52,000 --> 00:08:52,680 >> Mitch: AND THE COKE INSTITUTE 207 00:08:52,680 --> 00:08:56,080 AND ONE OF OUR COLLABORATORS IS 208 00:08:56,080 --> 00:08:57,480 TYLER JACKS AND HE PROVIDED US 209 00:08:57,480 --> 00:09:01,640 WITH A MODEL OF CELLS THAT ARE 210 00:09:01,640 --> 00:09:03,120 ESSENTIALLY EXHIBITING TWO 211 00:09:03,120 --> 00:09:04,200 PHOTOGRAPHIC MUTATIONS IN NON 212 00:09:04,200 --> 00:09:06,240 SMALL HUNG CANCER WHICH MAKES IT 213 00:09:06,240 --> 00:09:07,680 PARTICULARLY AGGRESSIVE AND MORE 214 00:09:07,680 --> 00:09:11,000 RESISTANT TO TREATMENT. 215 00:09:11,000 --> 00:09:13,960 THESE TWO GENETIC MUTATIONS ARE 216 00:09:13,960 --> 00:09:18,680 THE PRESENCE OF KRAS, ACTUALLY 217 00:09:18,680 --> 00:09:23,680 ENABLES MUCH MORE AGGRESSIVE AND 218 00:09:23,680 --> 00:09:25,840 NET A STATIC TYPE AND IT'S 219 00:09:25,840 --> 00:09:28,880 UNDRUGABLE WITH SMALL MOLECULES. 220 00:09:28,880 --> 00:09:31,520 AND WE ALSO LOOK AT THE LOSS OF 221 00:09:31,520 --> 00:09:33,000 THE P53 GENE. 222 00:09:33,000 --> 00:09:35,240 THE P53 FUNCTION, WHICH 223 00:09:35,240 --> 00:09:37,120 ESSENTIALLY IS A GUARDIAN 224 00:09:37,120 --> 00:09:39,040 FUNCTION WHICH MANAGING DNA 225 00:09:39,040 --> 00:09:41,880 DAMAGE AND CAUSES A POP TOE SIS 226 00:09:41,880 --> 00:09:44,280 WHEN DNA DAMAGE GOES TOO FAR IN 227 00:09:44,280 --> 00:09:47,520 THESE CELLS, IS ABSENT IN THE 228 00:09:47,520 --> 00:09:50,000 NUMBER OF TUMORS OF INTEREST 229 00:09:50,000 --> 00:09:50,280 HERE. 230 00:09:50,280 --> 00:09:53,920 WE LOOK TO REPLACE THE LOSS OF 231 00:09:53,920 --> 00:09:55,480 P53 OR THE SINGLE POINT MUTATION 232 00:09:55,480 --> 00:09:59,600 OF IT, WITH A MICRO RNA WHICH IS 233 00:09:59,600 --> 00:10:05,320 KNOWN TOE REPLACE SOME OF THOSE 234 00:10:05,320 --> 00:10:07,960 AFFECT OR FUNCTIONS THAT P53 235 00:10:07,960 --> 00:10:08,240 PROVIDED. 236 00:10:08,240 --> 00:10:10,320 WE GET THE MONITORING BACK AND 237 00:10:10,320 --> 00:10:13,440 THAT ENABLES CELL APOPTOSIS. 238 00:10:13,440 --> 00:10:15,560 SO IN THIS CASE, WE LOOKED AT A 239 00:10:15,560 --> 00:10:28,240 COMBINATION THERAPY AND WE USE 240 00:10:28,240 --> 00:10:32,680 SIS PLATEN, WE DESIGN OUR 241 00:10:32,680 --> 00:10:35,080 LYPOSOME SO IT HAS NEGATIVELY 242 00:10:35,080 --> 00:10:36,280 CHARGED LIPIDS AND WE CAN BUILD 243 00:10:36,280 --> 00:10:38,720 OUR MULTI-LAYER AND HERE WE 244 00:10:38,720 --> 00:10:42,840 ABSORB A POLY BECAUSE WE FOUND 245 00:10:42,840 --> 00:10:46,040 THAT IT ACTUALLY FACILITATES 246 00:10:46,040 --> 00:10:48,640 ESCAPE VERY NICELY IN THESE 247 00:10:48,640 --> 00:10:49,120 SYSTEMS. 248 00:10:49,120 --> 00:10:51,360 WE THEN ABSORBED A COMBINATION 249 00:10:51,360 --> 00:10:56,880 OF KRAS SIRNA SO WE SILENCED THE 250 00:10:56,880 --> 00:11:01,280 SIRNA AND KRAS WITH AN SIRNA MOL 251 00:11:01,280 --> 00:11:02,480 ACTUAL AND THESE ARE ROUGHLY THE 252 00:11:02,480 --> 00:11:06,800 SAME SIZE, NEGATIVELY CHARGED 20 253 00:11:06,800 --> 00:11:08,880 TO 21 BASE PAIR MOLECULES THAT 254 00:11:08,880 --> 00:11:15,400 ABSORB NICELY INTO OUR LAYER. 255 00:11:15,400 --> 00:11:22,360 WE TOP OFF WITH HIGH LOR ONIC 256 00:11:22,360 --> 00:11:24,240 ACID WITH CD44 TARGETING. 257 00:11:24,240 --> 00:11:25,400 WHEN WE LOOK A LOT THE RELEASE 258 00:11:25,400 --> 00:11:26,840 OF THE COMPONENTS OF THE 259 00:11:26,840 --> 00:11:28,480 THEORIES IN OUR NANO PARTICLE, 260 00:11:28,480 --> 00:11:32,480 WE CAN SEE THE SIRNA, IN THE 261 00:11:32,480 --> 00:11:35,080 LAYERS IS RELEASED MORE RAPIDLY 262 00:11:35,080 --> 00:11:37,880 THAN THE SIS-PLATEN INCORPORATED 263 00:11:37,880 --> 00:11:40,280 IN THE CORE AND WE GET A TWO TO 264 00:11:40,280 --> 00:11:42,160 THROW TIMES MORE RAPID RELEASE 265 00:11:42,160 --> 00:11:45,120 OF THE SRNA ALLOWING US TO 266 00:11:45,120 --> 00:11:46,280 ESSENTIALLY REPROGRAM THE TUMOR 267 00:11:46,280 --> 00:11:48,280 CELLS THAT ARE PRESENT BEFORE 268 00:11:48,280 --> 00:11:51,560 THE SISPLATEN REACHES ITS PEAK 269 00:11:51,560 --> 00:11:54,480 ACCUMULATION IN THE CELL. 270 00:11:54,480 --> 00:11:56,840 WE LOOKED AT WHERE THESE NANO 271 00:11:56,840 --> 00:11:59,000 PARTICLES GO IN HEALTHY MICE AND 272 00:11:59,000 --> 00:12:01,160 IN MICE THAT EXHIBIT LUNG CANCER 273 00:12:01,160 --> 00:12:04,080 AND WE CAN SEE THE USUAL 274 00:12:04,080 --> 00:12:07,560 ESSENTIALLY ACCUMULATION AND THE 275 00:12:07,560 --> 00:12:08,280 EXCRETION THROUGH THE LIVER THAT 276 00:12:08,280 --> 00:12:09,680 WE SEE WITH NANO PARTICLES BUT 277 00:12:09,680 --> 00:12:12,480 THIS IS A COMMON THEME IN 278 00:12:12,480 --> 00:12:14,320 NANOMEDICINE AND OBSERVED 279 00:12:14,320 --> 00:12:16,080 BETWEEN THE 12 AND 24 HOUR 280 00:12:16,080 --> 00:12:16,280 POINT. 281 00:12:16,280 --> 00:12:19,160 THIS IS A 48-EIGHT HOUR POINT. 282 00:12:19,160 --> 00:12:20,920 HOWEVER, WE SEE NO ACCUMULATION 283 00:12:20,920 --> 00:12:23,320 IN LUNGS IN HEALTHY MICE AND A 284 00:12:23,320 --> 00:12:25,080 VERY SIGNIFICANT ACCUMULATION IN 285 00:12:25,080 --> 00:12:28,040 THE LUNGS OF TUMORRED MICE. 286 00:12:28,040 --> 00:12:31,240 40 TO 50 FOLD MEASUREMENTS 287 00:12:31,240 --> 00:12:31,680 DIFFERENCE. 288 00:12:31,680 --> 00:12:32,640 AND WHAT WE CAN SEE IS 289 00:12:32,640 --> 00:12:36,040 ESSENTIALLY THAT THE TUMOR ARE 290 00:12:36,040 --> 00:12:36,960 VERY HEAVILY STAINED WHEN WE 291 00:12:36,960 --> 00:12:39,480 LOOK FOR CD44. 292 00:12:39,480 --> 00:12:40,960 NOW, WHEN WE TAKE OUR NANO 293 00:12:40,960 --> 00:12:43,280 PARTICLE AND INCORPORATE THE 294 00:12:43,280 --> 00:12:46,680 DRUGS, ESSENTIALLY, THE PLATEN 295 00:12:46,680 --> 00:12:48,600 COMBINED WITH THE SIRNA AND 296 00:12:48,600 --> 00:12:51,080 MICRO RNA COMBINATION, WE CAN 297 00:12:51,080 --> 00:12:55,360 LOOK AT WHAT HAPPENS IN MICE AND 298 00:12:55,360 --> 00:12:58,760 IN THIS CASE, WE ESSENTIALLY ARE 299 00:12:58,760 --> 00:13:01,840 LOOKING AT THE KP MOUSE MODEL 300 00:13:01,840 --> 00:13:03,720 DEVELOPED BY THE TYPIER LAB. 301 00:13:03,720 --> 00:13:07,600 WHAT WE CAN FIND IS THAT FOR 302 00:13:07,600 --> 00:13:09,480 CONTROL WE SEE A NUMBER OF THESE 303 00:13:09,480 --> 00:13:11,280 TUMORS AND WE HAVE A LARGE TUMOR 304 00:13:11,280 --> 00:13:13,360 MASSES THAT ARE GROWING AND WHEN 305 00:13:13,360 --> 00:13:18,400 WE LOOK AT JUST RNA, OR JUST 306 00:13:18,400 --> 00:13:21,000 SISPLATIN ALONE, WE SEE A 307 00:13:21,000 --> 00:13:23,480 DECEASE BUT NOT SIGNIFICANT IN 308 00:13:23,480 --> 00:13:24,480 THESE ANIMALS AND THIS IS 309 00:13:24,480 --> 00:13:25,920 BECAUSE THIS IS A FAIRLY RESIST 310 00:13:25,920 --> 00:13:27,800 APARTMENT FORM OF THE CANCER. 311 00:13:27,800 --> 00:13:33,280 WE CAN SEE HERE, IN SURVIVAL, 312 00:13:33,280 --> 00:13:37,360 THE RNA DOESN'T DO MUCH ON ITS 313 00:13:37,360 --> 00:13:37,520 OWN. 314 00:13:37,520 --> 00:13:38,600 SIS PLAT INIS IMPROVED COMPARED 315 00:13:38,600 --> 00:13:58,680 TO THE CONTROL. 316 00:13:58,680 --> 00:14:00,160 OTHER OF OUR WORK, OTHER AREAS 317 00:14:00,160 --> 00:14:02,720 OF WORK, HAVE LOOKED AT 318 00:14:02,720 --> 00:14:03,920 INHIBITOR COMBINATIONS. 319 00:14:03,920 --> 00:14:07,160 WE BEGAN TO REALLY FOCUS ON 320 00:14:07,160 --> 00:14:07,960 OVARIAN CANCER. 321 00:14:07,960 --> 00:14:10,360 OUR INTEREST IN THIS IS TRYING 322 00:14:10,360 --> 00:14:14,320 TO ADDRESS SOME OF THE REAL 323 00:14:14,320 --> 00:14:15,960 DIFFICULTIES IN ESSENTIALLY 324 00:14:15,960 --> 00:14:18,920 TARGETING OVARIAN CANCER CELLS 325 00:14:18,920 --> 00:14:21,080 EFFECTIVELY AND DELIVERING 326 00:14:21,080 --> 00:14:22,960 THERAPIES THAT WILL ENABLE THE 327 00:14:22,960 --> 00:14:24,120 GREATER SURVIVAL AND WE'LL TALK 328 00:14:24,120 --> 00:14:25,880 ABOUT THAT IN A MINUTE. 329 00:14:25,880 --> 00:14:27,800 BUT TO DO THAT EFFECTIVELY, WE 330 00:14:27,800 --> 00:14:29,480 WANTED TO LOOK AT THE RANGE OF 331 00:14:29,480 --> 00:14:32,560 OUTER LAYERS THAT WE COULD 332 00:14:32,560 --> 00:14:32,920 EXPERIMENT WITH. 333 00:14:32,920 --> 00:14:34,640 LOOK AT AND UNDERSTAND IF WE CAN 334 00:14:34,640 --> 00:14:37,280 HAVE SYSTEMS THAT HAVE A NATIVE 335 00:14:37,280 --> 00:14:39,280 AFFINITY FOR OVARIAN CANCER 336 00:14:39,280 --> 00:14:39,480 CELLS. 337 00:14:39,480 --> 00:14:43,880 SO WE START BI STARTED BY MAKING A SMALL 338 00:14:43,880 --> 00:14:44,120 LIBRARY. 339 00:14:44,120 --> 00:14:46,640 THIS IS A WORK OF MY FORMER 340 00:14:46,640 --> 00:14:48,320 STUDENT, SANTEE KOREA WHO 341 00:14:48,320 --> 00:14:50,160 DESIGNED A NANOPARTICLE LIBRARY 342 00:14:50,160 --> 00:14:52,360 WHERE WE LOOKED AT A RANGE OF 343 00:14:52,360 --> 00:14:54,680 DIFFERENT NEGATIVE LOW CHARGED 344 00:14:54,680 --> 00:15:00,880 POLYMER, INCLUDING HIGHER ACID 345 00:15:00,880 --> 00:15:02,160 AND SULPHATED SURFACE CHEM IS 346 00:15:02,160 --> 00:15:04,680 TREES AND WE JUST STARTED TO 347 00:15:04,680 --> 00:15:06,360 ESSENTIALLY USE ROBOTICS TO 348 00:15:06,360 --> 00:15:09,160 GENERATE THESE NANO PARTICLES 349 00:15:09,160 --> 00:15:10,440 AND TEST THEM. 350 00:15:10,440 --> 00:15:13,280 THIS ALLOWED US TO ASK A SIMPLE 351 00:15:13,280 --> 00:15:14,680 QUESTION, ARE THERE SYSTEMS THAT 352 00:15:14,680 --> 00:15:17,880 HAVE A HIGHER AFFINITY FOR HIGH 353 00:15:17,880 --> 00:15:20,120 GRADE OVARIAN CANCER CELLS 354 00:15:20,120 --> 00:15:22,680 COMPARED TO HEALTHY CELLS. 355 00:15:22,680 --> 00:15:25,120 SO, IN THIS WORK, WE ACTUALLY 356 00:15:25,120 --> 00:15:27,040 LOOKED AT 10 DIFFERENT OVARIAN 357 00:15:27,040 --> 00:15:28,800 CANCER CELL LINES AS WELL AS 358 00:15:28,800 --> 00:15:30,920 SEVEN HEALTHY CELL LINES AND WE 359 00:15:30,920 --> 00:15:34,320 FOUND THAT THERE WERE SYSTEMS 360 00:15:34,320 --> 00:15:39,800 WHICH GAVE US A HIGH AMOUNT OF 361 00:15:39,800 --> 00:15:41,480 NANO PARTICLE ASSOCIATION USING 362 00:15:41,480 --> 00:15:44,680 CELL SORTING. 363 00:15:44,680 --> 00:15:48,520 SO, FROM THOSE EXPERIMENTS, WE 364 00:15:48,520 --> 00:15:51,680 NARROWED OUR STUDIES TO HIGH LER 365 00:15:51,680 --> 00:15:52,960 ON I CAN ACID AND WE RECOGNIZED 366 00:15:52,960 --> 00:15:54,080 THAT WAS GOING TO BE AN 367 00:15:54,080 --> 00:15:56,200 IMPORTANT OUTER LAYER AND WE 368 00:15:56,200 --> 00:16:02,280 ALSO FOUND THAT POLY LGLUTAMIC 369 00:16:02,280 --> 00:16:06,080 ACID AND POLY-L-ASPARTIC SHOWED 370 00:16:06,080 --> 00:16:10,000 A ASSOCIATION OF CELLS THAN OUR 371 00:16:10,000 --> 00:16:23,640 HIGH ALLURE ON I CAN ACID. 372 00:16:23,640 --> 00:16:24,800 WE LOOKED CLOSELY AT WHAT WAS 373 00:16:24,800 --> 00:16:30,640 GOING ON AND WE FOUND, WITH HIGH 374 00:16:30,640 --> 00:16:32,760 LURE ON I CAN ACID WE CAN SEE 375 00:16:32,760 --> 00:16:46,040 THESE NANO PARTICLES DO GET THIS IS 376 00:16:46,040 --> 00:16:49,520 NORTH WE ANTICIPATE FROM THE 377 00:16:49,520 --> 00:16:49,880 CD44. 378 00:16:49,880 --> 00:16:54,560 WITH POLY LGLUTAMIC ACID, THEY 379 00:16:54,560 --> 00:16:56,840 ASSOCIATED ON THE CELLS' OUTER 380 00:16:56,840 --> 00:16:57,080 SURFACE. 381 00:16:57,080 --> 00:16:59,560 SO WE HAVE SURFACE MEMBRANE 382 00:16:59,560 --> 00:16:59,920 ASSOCIATION. 383 00:16:59,920 --> 00:17:01,600 OVER LONG PERIODS OF TIME, VERY 384 00:17:01,600 --> 00:17:03,160 LITTLE UPTAKE IS OBSERVED. 385 00:17:03,160 --> 00:17:04,880 THIS IS INTERESTING TO US AND WE 386 00:17:04,880 --> 00:17:05,720 DIDN'T QUITE UNDERSTAND IF 387 00:17:05,720 --> 00:17:09,120 THERE'S A SPECIFIC RECEPTORS 388 00:17:09,120 --> 00:17:14,040 ASSOCIATED WITH IT. 389 00:17:14,040 --> 00:17:19,680 POLY LASPARTIC ACID WE SEE 390 00:17:19,680 --> 00:17:21,360 GRADUAL COMMUNICATION ON THE 391 00:17:21,360 --> 00:17:22,760 SURFACE MEMBRANE AND WE SEE 392 00:17:22,760 --> 00:17:24,640 THERE'S UPTAKE AND THAT UPTAKE, 393 00:17:24,640 --> 00:17:27,040 UNLIKE THE UPTAKE OF HA, 394 00:17:27,040 --> 00:17:33,160 DECORATED NANO PARTICLES IS 395 00:17:33,160 --> 00:17:34,520 CAVOLAR SO DIFFERENT PROTEINS 396 00:17:34,520 --> 00:17:36,360 ARE INVOLVED IN THE UPTAKE OF 397 00:17:36,360 --> 00:17:37,120 THESE NANO PARTICLES. 398 00:17:37,120 --> 00:17:39,600 WE'RE CONTINUING TO TRY TO 399 00:17:39,600 --> 00:17:42,200 UNDERSTAND THESE INTERACTIONS. 400 00:17:42,200 --> 00:17:47,240 IN THE MEANTIME, WE FOUND THAT 401 00:17:47,240 --> 00:17:50,480 THESE COULD BE ADVANTAGEOUS TO 402 00:17:50,480 --> 00:17:52,040 OUR APPROACH. 403 00:17:52,040 --> 00:17:53,480 HYALURONIC ACID IS INTERESTING 404 00:17:53,480 --> 00:17:54,560 FOR DELIVERING DRUGS THAT NEED 405 00:17:54,560 --> 00:17:55,480 TO GET INSIDE. 406 00:17:55,480 --> 00:17:58,760 THAT INCLUDES SIRNA AND 407 00:17:58,760 --> 00:17:59,520 DNA-DAMAGING DRUGS. 408 00:17:59,520 --> 00:18:02,680 HOWEVER, THE SURFACE BOUND 409 00:18:02,680 --> 00:18:04,680 ARRANGEMENT HERE, ALLOWS US TO 410 00:18:04,680 --> 00:18:06,680 THINK ABOUT NANO PARTICLES THAT 411 00:18:06,680 --> 00:18:08,000 CAN DELIVER SOMETHING THAT WE 412 00:18:08,000 --> 00:18:10,840 DON'T WANT TO HAVE IN THE 413 00:18:10,840 --> 00:18:12,040 TRAFFICKING MECHANISM BECAUSE WE 414 00:18:12,040 --> 00:18:14,760 DON'T WANT TO SEE DEGRADATION. 415 00:18:14,760 --> 00:18:16,520 THEREFORE, PROTEIN-RELATED DRUGS 416 00:18:16,520 --> 00:18:18,320 ARE GOING TO BE INTERESTING AND 417 00:18:18,320 --> 00:18:20,720 IN PARTICULAR, IF WE WANT TO 418 00:18:20,720 --> 00:18:23,040 RELEASE OUR DRUG TO NEIGHBORING 419 00:18:23,040 --> 00:18:24,440 CELLS, THIS WOULD BE A NICE WAY 420 00:18:24,440 --> 00:18:26,000 OF DOING IT. 421 00:18:26,000 --> 00:18:27,440 WHILE STILL HAVING HIGH 422 00:18:27,440 --> 00:18:31,040 ACCUMULATION IN THE TUMOR. 423 00:18:31,040 --> 00:18:32,880 I SHOULD MENTION, WE'RE THINKING 424 00:18:32,880 --> 00:18:35,200 ABOUT THESE MECHANISMS THAT SOME 425 00:18:35,200 --> 00:18:39,120 WORK THAT HAS BEEN GOING ON IN 426 00:18:39,120 --> 00:18:52,160 OUR LAB, HAS USED PRISM TO LOOK 427 00:18:52,160 --> 00:18:54,680 AT RAPID SCREENS TO UNDERSTAND 428 00:18:54,680 --> 00:18:56,920 NANO PARTICLE INTERACTIONS WITH 429 00:18:56,920 --> 00:19:00,680 SPECIFIC CELLS TYPES AND LOOK AT 430 00:19:00,680 --> 00:19:08,240 WHICH GENES AND IT ALSO LET'S US 431 00:19:08,240 --> 00:19:11,360 ASSOCIATE WHICH GENES ARE BEING 432 00:19:11,360 --> 00:19:13,640 EXPRESSED UNDER CERTAIN UPTAKE 433 00:19:13,640 --> 00:19:15,400 CONDITIONS AND IN THAT WORK, WE 434 00:19:15,400 --> 00:19:21,880 HE DID FIND IN DEED THAT POLY L 435 00:19:21,880 --> 00:19:24,200 ACID PARTICLES ACTUALLY THE 436 00:19:24,200 --> 00:19:27,640 UPTAKE IN THOSE CASES TEND TO BE 437 00:19:27,640 --> 00:19:29,880 ASSOCIATED WITH ENRICHMENTS IN 438 00:19:29,880 --> 00:19:31,560 GENE NETWORKS ASSOCIATED WITH 439 00:19:31,560 --> 00:19:34,760 INTER CELLULAR UPTAKE WHEREAS 440 00:19:34,760 --> 00:19:39,080 POLY LGLUTANIC ACID WAS ENRICHED 441 00:19:39,080 --> 00:19:42,680 IN CELL SURFACE BINDING 442 00:19:42,680 --> 00:19:44,640 INTERACTIONS IN THAT WORK SO 443 00:19:44,640 --> 00:19:46,880 WE'RE SEEING A CORRELATION AND 444 00:19:46,880 --> 00:19:51,000 WE'RE HOPING TO UNDERSTAND THE 445 00:19:51,000 --> 00:19:52,400 SYSTEMS BOYOLOGY OF THOSE 446 00:19:52,400 --> 00:19:52,880 SYSTEMS. 447 00:19:52,880 --> 00:19:54,040 HOWEVER, IN THE MEANTIME, WE 448 00:19:54,040 --> 00:19:57,480 WANT TO TAKE ADVANTAGE OF THIS 449 00:19:57,480 --> 00:20:01,720 POLY LGLUTANIC ACID'S TENDENCY 450 00:20:01,720 --> 00:20:04,880 TO ASSOCIATE WITH THE OUTSIDE OF 451 00:20:04,880 --> 00:20:06,960 OVARIAN CANCER CELLS AND IN 452 00:20:06,960 --> 00:20:12,240 COLLABORATION, WE GUN TO ASK THE 453 00:20:12,240 --> 00:20:13,760 QUESTION CAN WE DELIVER A 454 00:20:13,760 --> 00:20:15,680 CYTOKINE THAT CAN ACTIVATE THE 455 00:20:15,680 --> 00:20:17,880 IMMUNE SYSTEM IN OVARIAN CANCER. 456 00:20:17,880 --> 00:20:20,080 NOW, THIS IS GENERAL IDEA IS 457 00:20:20,080 --> 00:20:21,520 INTERESTING TO US BECAUSE 458 00:20:21,520 --> 00:20:25,800 OVARIAN CANCER TENDS TO BE A 459 00:20:25,800 --> 00:20:27,760 RELATIVELY COLD TUMOR. 460 00:20:27,760 --> 00:20:31,200 ESPECIALLY THE ADVANCED OVARIAN 461 00:20:31,200 --> 00:20:35,640 CANCER THAT LEADS TO AT LEAST 462 00:20:35,640 --> 00:20:36,000 70% RECURRENCE. 463 00:20:36,000 --> 00:20:39,040 WE CAN ACTUALLY ADDRESS SOME OF 464 00:20:39,040 --> 00:20:39,760 THIS RECURRENCE IF WE CAN 465 00:20:39,760 --> 00:20:42,920 STIMULATE A VERY EFFECTIVE 466 00:20:42,920 --> 00:20:45,320 IMMUNE RESPONSE AGAINST THE 467 00:20:45,320 --> 00:20:45,680 TUMOR. 468 00:20:45,680 --> 00:20:47,880 HOWEVER, THERE ARE TYPICALLY 469 00:20:47,880 --> 00:20:50,400 SMALLER NUMBERS OF IMMUNE CELLS 470 00:20:50,400 --> 00:20:52,960 PRESENT IN THESE TUMORS. 471 00:20:52,960 --> 00:20:56,080 ONE WAY OF CHANGING THAT IS TO 472 00:20:56,080 --> 00:20:57,680 INTRODUCE SOMETHING THAT CAN 473 00:20:57,680 --> 00:21:00,080 ACTUALLY STIMULATE THE IMMUNE 474 00:21:00,080 --> 00:21:01,360 ENVIRONMENT AND AN APPROACH IS 475 00:21:01,360 --> 00:21:04,880 TO USE IL12 OR SIMILAR CYTOKINE 476 00:21:04,880 --> 00:21:07,800 THAT CAN ACTUALLY TRIGGER SOME 477 00:21:07,800 --> 00:21:10,880 OF THESE IMMUNE PATHWAYS. 478 00:21:10,880 --> 00:21:15,400 IL-12 IS INTERESTING, BECAUSE IT 479 00:21:15,400 --> 00:21:20,520 LEADS TO THE INTER FEWER AN 480 00:21:20,520 --> 00:21:23,480 GAMMA AND IT LEADS TO SIGNALING 481 00:21:23,480 --> 00:21:27,080 THAT CAN ESSENTIALLY ACTIVATE 482 00:21:27,080 --> 00:21:29,880 CD4, POSITIVE AND CD8 POSITIVE T 483 00:21:29,880 --> 00:21:31,640 CELLS AND WHEN WE ARE ABLE TO 484 00:21:31,640 --> 00:21:33,280 ACTIVATE THESE 485 00:21:33,280 --> 00:21:34,080 ANTIGEN-PRESENTING CELLS. 486 00:21:34,080 --> 00:21:35,480 WHEN WE'RE DOING THIS IN THE 487 00:21:35,480 --> 00:21:39,520 TUMOR ENVIRONMENT, WE CAN GET 488 00:21:39,520 --> 00:21:40,840 ANTIGEN-SPECIFIC RESPONSES TO 489 00:21:40,840 --> 00:21:42,720 THE TUMOR. 490 00:21:42,720 --> 00:21:45,680 SO, THIS IS THE GENERAL IDEA. 491 00:21:45,680 --> 00:21:48,120 THE PROBLEM WITH IL-12 AND THE 492 00:21:48,120 --> 00:21:49,800 REASON WHY WE'RE NOT USING IT 493 00:21:49,800 --> 00:21:51,480 BROAD LOW, ALTHOUGH THERE HAVE 494 00:21:51,480 --> 00:21:53,200 BEEN ATTEMPTS IN THE PAST, IS 495 00:21:53,200 --> 00:21:55,080 BECAUSE IT'S VERY POTENT AND 496 00:21:55,080 --> 00:21:57,440 CYTOKINES HAS BEEN NON TO HAVE A 497 00:21:57,440 --> 00:21:59,680 NUMBER OF OFF-TARGET EFFECTS 498 00:21:59,680 --> 00:22:01,320 BEAUCE IT'S SUCH A POTENT 499 00:22:01,320 --> 00:22:03,320 STIMULATER OF INTERFERON KAMA 500 00:22:03,320 --> 00:22:06,880 AND OF COURSE SYSTEMIC 501 00:22:06,880 --> 00:22:10,920 STIMULATION OF INTER FEWER ON 502 00:22:10,920 --> 00:22:11,720 LEFT A LARGE SCALE HOST EFFECT 503 00:22:11,720 --> 00:22:14,800 SO WE'RE TRYING TO CONTROL WHERE 504 00:22:14,800 --> 00:22:16,280 IL-12 IS EXPOSED. 505 00:22:16,280 --> 00:22:20,120 IN OUR CASE, WE THINK THIS IS AN 506 00:22:20,120 --> 00:22:21,240 ABSOLUTE OPPORTUNITY TO 507 00:22:21,240 --> 00:22:23,080 INTRODUCE IP INJECTION OF OUR 508 00:22:23,080 --> 00:22:24,840 NANO PARTICLES WHICH THEN 509 00:22:24,840 --> 00:22:32,280 ASSOCIATE WITH THESE TUMOR CELLS 510 00:22:32,280 --> 00:22:33,960 AND THE QUESTION IS CAN WE USE 511 00:22:33,960 --> 00:22:36,520 OUR NANOPARTICLE TO DO THAT? 512 00:22:36,520 --> 00:22:38,680 WE LOOKED AT A NANOPARTICLE 513 00:22:38,680 --> 00:22:41,960 DESIGNS THAT BEGINS WITH A LIP 514 00:22:41,960 --> 00:22:48,280 OSEM BUT WE USE THE TAG THAT 515 00:22:48,280 --> 00:22:49,600 DARYL'S LAB HAD BEEN USING TO 516 00:22:49,600 --> 00:22:57,920 ATTACH THESE PROTEINS. 517 00:22:57,920 --> 00:23:03,360 WE HAVE A SCIL-12 AND IT'S 518 00:23:03,360 --> 00:23:03,640 ATTACHED. 519 00:23:03,640 --> 00:23:09,600 WE CAN LAYER ON TOP OF THAT, 520 00:23:09,600 --> 00:23:14,040 POLY-L-ARGINE AND A POLIAN TON 521 00:23:14,040 --> 00:23:17,080 AND IT WAS ON -- WE DID 522 00:23:17,080 --> 00:23:20,920 COMPARISONS WITH HYALURONIC 523 00:23:20,920 --> 00:23:21,200 ACID. 524 00:23:21,200 --> 00:23:24,840 WE USED UNDERSTANDING THE 525 00:23:24,840 --> 00:23:26,280 RELEASE KEN ET TICKS OF THIS 526 00:23:26,280 --> 00:23:28,880 SYSTEM BECAUSE THE IL-12 DOES 527 00:23:28,880 --> 00:23:30,360 GET TO BE PRE IN THE SYSTEMS 528 00:23:30,360 --> 00:23:33,200 THAT I'VE JUST DESCRIBED AND IN 529 00:23:33,200 --> 00:23:37,320 THIS STUDY, WE LABELED 530 00:23:37,320 --> 00:23:40,680 ESSENTIALLY FRET DYES FOR THE 531 00:23:40,680 --> 00:23:42,920 IL12 AND PLR TO SEE WHEN THESE 532 00:23:42,920 --> 00:23:44,800 SEPARATE FROM THE NANOPARTICLE 533 00:23:44,800 --> 00:23:50,080 AND WE CAN SEE THAT THE PLR IS 534 00:23:50,080 --> 00:23:50,720 ESSENTIALLY ESCAPING FIRST AND 535 00:23:50,720 --> 00:23:53,920 THEN WE SEE THE IL-12 ESCAPING 536 00:23:53,920 --> 00:24:00,280 SHORT LOSHORTLY AFTERWARDS. 537 00:24:00,280 --> 00:24:02,880 ONE OF THE MODELS IS THAT 538 00:24:02,880 --> 00:24:05,920 POTENTIALLY THE BUY LAYER GETS 539 00:24:05,920 --> 00:24:09,560 DIS RESULTED OR DESTABILIZED AND 540 00:24:09,560 --> 00:24:11,080 IT'S RELEASED WITH THE OUTER 541 00:24:11,080 --> 00:24:13,960 LAYER AND THE IL-12 RELEASED 542 00:24:13,960 --> 00:24:14,560 AFTERWARD. 543 00:24:14,560 --> 00:24:16,640 ANOTHER IS THERE'S JUST 544 00:24:16,640 --> 00:24:17,240 SIGNIFICANT SWELLING THAT CAN 545 00:24:17,240 --> 00:24:21,240 OCCUR WHICH ALLOWS THE IL-12 TO 546 00:24:21,240 --> 00:24:21,600 RELEASE. 547 00:24:21,600 --> 00:24:23,120 AND THE QUESTION OF WHETHER IT 548 00:24:23,120 --> 00:24:27,360 CAN WORK IN OVARIAN CANCER, WAS 549 00:24:27,360 --> 00:24:28,480 REALLY IMPORTANT TO US. 550 00:24:28,480 --> 00:24:30,800 WE DID SOME EARLY STUDIES 551 00:24:30,800 --> 00:24:32,040 LOOKING AT PROSTATE CANCER 552 00:24:32,040 --> 00:24:33,560 MODELS AND OTHER MODEL THAT'S 553 00:24:33,560 --> 00:24:35,160 WERE MORE COMMON AND MORE 554 00:24:35,160 --> 00:24:38,680 RESPONSIVE TO IMMUNOTHERAPY. 555 00:24:38,680 --> 00:24:41,040 OVARIAN CANCER WAS THE ULTIMATE 556 00:24:41,040 --> 00:24:47,320 GOAL AND IN THIS WORK, WE USED A 557 00:24:47,320 --> 00:24:49,120 MODEL AND A FAIRLY AGGRESSIVE 558 00:24:49,120 --> 00:24:54,600 ONE KNOWN AS HM-1 SOLVE IN THIS 559 00:24:54,600 --> 00:24:57,480 MODEL, WE CAN TRACK WHERE 560 00:24:57,480 --> 00:24:58,160 NANOPARTICLE GOES. 561 00:24:58,160 --> 00:25:01,480 WE LET THAT INTRAVENOUS 562 00:25:01,480 --> 00:25:02,880 INJECTION AND WHAT WE FOUND WAS 563 00:25:02,880 --> 00:25:07,640 THAT THERE'S ACCUMULATION IN 564 00:25:07,640 --> 00:25:08,640 BOTH CASES. 565 00:25:08,640 --> 00:25:11,960 IV GIVES US A NICE ACCUMULATION 566 00:25:11,960 --> 00:25:14,640 FOR INTERVENE YUS AND IT'S 567 00:25:14,640 --> 00:25:19,000 SOMEWHERE BETWEEN 8% AND 9% 568 00:25:19,000 --> 00:25:19,800 ACCUMULATION. 569 00:25:19,800 --> 00:25:23,440 HOWEVER, THE INJECTION GIVES US 570 00:25:23,440 --> 00:25:26,280 SOMETHING CLOSER TO AN 85% 571 00:25:26,280 --> 00:25:28,960 ASSOCIATION OF THE NANO PART CAL 572 00:25:28,960 --> 00:25:30,400 OF THE TUMOR AND WE THINK THIS 573 00:25:30,400 --> 00:25:32,080 IS THE ROUTE THAT EX SIGHTS US 574 00:25:32,080 --> 00:25:33,920 MOST, ALTHOUGH INTRAVENOUS IS 575 00:25:33,920 --> 00:25:35,480 SOMETHING THAT WE STUDY 576 00:25:35,480 --> 00:25:38,200 ALONGSIDE THIS WORK. 577 00:25:38,200 --> 00:25:41,000 SO, GOING WITH THIS IP INJECTION 578 00:25:41,000 --> 00:25:45,080 APPROACH, WE LOCKED AT 579 00:25:45,080 --> 00:25:45,680 ESSENTIALLY THE INTRODUCTION 580 00:25:45,680 --> 00:25:49,920 WITH IP INJECTIONS OF REASONABLY 581 00:25:49,920 --> 00:25:52,560 HIGH DOSE OF THE IL-12 AND WE 582 00:25:52,560 --> 00:25:55,880 LOOKED FIRST AT TOXICITY AND YOU 583 00:25:55,880 --> 00:25:58,000 CAN SEE THE WEIGHT OF ANIMALS 584 00:25:58,000 --> 00:26:01,800 AND HERE WE'RE LOOKING AT 585 00:26:01,800 --> 00:26:03,320 ESSENTIALLY THE DROP THAT WE 586 00:26:03,320 --> 00:26:05,720 EXPECT WHEN WE HAVE FREE IL-12 587 00:26:05,720 --> 00:26:07,160 COMPARED TO THE CONTROL ANIMALS 588 00:26:07,160 --> 00:26:10,760 WHICH IS VERY SIGNIFICANT. 589 00:26:10,760 --> 00:26:14,320 THE ARROWS ALSO INDICATE LOSS OF 590 00:26:14,320 --> 00:26:14,680 LIFE. 591 00:26:14,680 --> 00:26:17,240 WE LOSE SOME ANIMALS DUE TO THE 592 00:26:17,240 --> 00:26:19,520 TOXICITY, HOWEVER, WITH OUR 593 00:26:19,520 --> 00:26:23,320 IL-12 NANOPARTICLE, LAYERED WITH 594 00:26:23,320 --> 00:26:27,440 THE POLY GLUTAMIC ACID, WE SEE 595 00:26:27,440 --> 00:26:28,880 WE'RE ABLE TO PRESERVE THE 596 00:26:28,880 --> 00:26:30,760 WEIGHTS OF ANIMALS AND 597 00:26:30,760 --> 00:26:33,000 ESSENTIALLY RESCUE THAT 598 00:26:33,000 --> 00:26:33,280 TOXICITY. 599 00:26:33,280 --> 00:26:35,680 WITHOUT THE LAYERS ON THE 600 00:26:35,680 --> 00:26:38,520 NANOPARTICLE WE STILL SEE THAT 601 00:26:38,520 --> 00:26:41,680 THERE IS A NUMBER OF -- A 602 00:26:41,680 --> 00:26:42,520 SIGNIFICANT LOSS. 603 00:26:42,520 --> 00:26:43,840 SO, WE ARE EXCITED ABOUT THE 604 00:26:43,840 --> 00:26:46,440 FACT THAT THE LAYERS ARE ABLE TO 605 00:26:46,440 --> 00:26:49,600 PROTECT AND ALSO TO TARGET. 606 00:26:49,600 --> 00:26:52,760 WHEN WE LOOKED AT EFFICACY IN 607 00:26:52,760 --> 00:26:57,520 HM1 TUMORS, WE FOUND THERE WAS 608 00:26:57,520 --> 00:26:59,160 SIGNIFICANT ENHANCEMENT IN 609 00:26:59,160 --> 00:27:06,720 SURVIVAL IN THE IL-1 L-12PLE SYSTEM 610 00:27:06,720 --> 00:27:08,960 COMPARED TO OUR UNTARGETED 611 00:27:08,960 --> 00:27:09,200 SYSTEM. 612 00:27:09,200 --> 00:27:10,640 IT GOT US VERY EXCITED. 613 00:27:10,640 --> 00:27:12,040 WE'RE EXCITED ABOUT THE FACT WE 614 00:27:12,040 --> 00:27:16,280 WERE SEEING ABOUT A 30% SURVIVAL 615 00:27:16,280 --> 00:27:18,840 RATE WE LOOKED AT SERUM 616 00:27:18,840 --> 00:27:20,480 CYTOKINES IN THESE ANIMALS AND 617 00:27:20,480 --> 00:27:23,880 WE WERE PARTICULARLY INTERESTED 618 00:27:23,880 --> 00:27:25,920 IN WHETHER WE WERE GOING TO SEE 619 00:27:25,920 --> 00:27:29,160 ANY SORT OF ACCUMULATION OF 620 00:27:29,160 --> 00:27:30,080 INTER FEWER AN GAMMA AFTER 621 00:27:30,080 --> 00:27:33,200 INJECTION AND WE SEE THAT THE 622 00:27:33,200 --> 00:27:34,240 INTER FEWER ON GAMMA IS LOWER 623 00:27:34,240 --> 00:27:37,360 COMPARED TO THE FREE IL-12. 624 00:27:37,360 --> 00:27:40,560 IN THE HEALTHY MICE AND IN 625 00:27:40,560 --> 00:27:42,320 TUMOR-BEARING MICE, WE SEE IT'S 626 00:27:42,320 --> 00:27:46,040 EVEN MORE SIGNIFICANT. 627 00:27:46,040 --> 00:27:48,960 OF COURSE, WE DID DO A MUCH MORE 628 00:27:48,960 --> 00:27:51,240 DETAILED LOOK AT WHICH IMMUNE 629 00:27:51,240 --> 00:27:53,880 CELLS ARE PRESENT AFTER OUR 630 00:27:53,880 --> 00:27:54,320 TREATMENTS. 631 00:27:54,320 --> 00:27:56,880 THIS IS JUST A LITTLE BIT OF 632 00:27:56,880 --> 00:27:57,520 THAT DATA. 633 00:27:57,520 --> 00:27:59,880 HERE WE'RE LOOKING AT 634 00:27:59,880 --> 00:28:02,160 ESSENTIALLY, THE PRESENCE OF 635 00:28:02,160 --> 00:28:05,360 IMMUNE CELLS IN KT CELLS AND K 636 00:28:05,360 --> 00:28:07,880 CELLS AND C8 POSITIVE CELLS IN 637 00:28:07,880 --> 00:28:10,480 TUMORS AND WE'RE COMPARING THEM 638 00:28:10,480 --> 00:28:14,280 AGAINST THE PRE IL-12 WHICH WE 639 00:28:14,280 --> 00:28:16,280 ALSO ANTICIPATE SHOULD PRESENT 640 00:28:16,280 --> 00:28:18,920 THESE IMMUNE CELLS AN CELLS. 641 00:28:18,920 --> 00:28:22,880 IN ALL OF OUR CASES, NANO 12 642 00:28:22,880 --> 00:28:24,080 NANOPARTICLES CAN DO AS WELL AS 643 00:28:24,080 --> 00:28:27,120 THE FREE IL12 IF NOT BETTER. 644 00:28:27,120 --> 00:28:30,280 WHEN WE LOOK ELSEWHERE OUTSIDE 645 00:28:30,280 --> 00:28:31,520 OF THE TUMOR, WE SEE THAT 646 00:28:31,520 --> 00:28:35,920 THERE'S A RELATIVELY LOW 647 00:28:35,920 --> 00:28:38,080 PRESENCE IN A SIGH TEASE AND IN 648 00:28:38,080 --> 00:28:38,400 DISPLAYING. 649 00:28:38,400 --> 00:28:40,080 WE DON'T SEE THERE'S AN 650 00:28:40,080 --> 00:28:46,440 ENHANCEMENT AND THESE OTHER 651 00:28:46,440 --> 00:28:54,080 AREAS SO WE LOCKED AT HM1 MODEL 652 00:28:54,080 --> 00:28:54,280 BEFORE. 653 00:28:54,280 --> 00:28:55,680 I DIDN'T REALLY DESCRIBE IT IN 654 00:28:55,680 --> 00:28:59,080 MUCH DETAIL BUT THIS MODEL HAS 655 00:28:59,080 --> 00:29:01,200 MODERATE T-CELL PRESENCE AND IT 656 00:29:01,200 --> 00:29:03,200 HAS A HIGH AMOUNT OF 657 00:29:03,200 --> 00:29:04,880 INFILTRATION OF GRANULAR SITES 658 00:29:04,880 --> 00:29:07,240 AND IT'S RESPONSIVE TO DNA 659 00:29:07,240 --> 00:29:08,520 DAMAGING AGENTS BUT IT'S 660 00:29:08,520 --> 00:29:12,440 RESISTANT TO PD1 AND PDL-1 661 00:29:12,440 --> 00:29:12,680 BLOCKADES. 662 00:29:12,680 --> 00:29:15,400 WE LOOKED AT THE KPCA MODEL. 663 00:29:15,400 --> 00:29:17,160 THIS IS A COLD TUMOR. 664 00:29:17,160 --> 00:29:21,280 WITH MODERATE AMOUNTSES OF T 665 00:29:21,280 --> 00:29:23,880 REGULATORY CELLS SO IT'S 666 00:29:23,880 --> 00:29:25,560 RESPONSIBLE TO -- RESPONSIVE TO 667 00:29:25,560 --> 00:29:28,360 CHECKPOINT INHIBITORS. 668 00:29:28,360 --> 00:29:29,800 SO, THIS ON THE LEFT IS THE DATA 669 00:29:29,800 --> 00:29:33,200 YOU SAW BEFORE FOR THE HM1 670 00:29:33,200 --> 00:29:33,440 MODEL. 671 00:29:33,440 --> 00:29:36,040 WHEN WE LOOK AT THE KPCA MODEL 672 00:29:36,040 --> 00:29:38,960 THE NANOPARTICLE IS MORE 673 00:29:38,960 --> 00:29:41,040 RESPONSIVE THAN IT WAS IN THE 674 00:29:41,040 --> 00:29:41,480 HM1. 675 00:29:41,480 --> 00:29:45,120 THIS IS TRUE ALSO FOR THE FRO 676 00:29:45,120 --> 00:29:46,800 IL12 BUT WE'RE SEEING THIS 677 00:29:46,800 --> 00:29:49,040 EFFICACY ENHANCEMENT IS 678 00:29:49,040 --> 00:29:53,480 CONSISTENT ACROSS MODELS. 679 00:29:53,480 --> 00:29:55,280 WE CONTINUE TO DO THIS WORK, WE 680 00:29:55,280 --> 00:29:56,880 HAVE RECENT DATA THAT I HAVEN'T 681 00:29:56,880 --> 00:29:58,920 BEEN ABLE TO INCORPORATE IN THIS 682 00:29:58,920 --> 00:30:00,440 TALK YET BUT I HOPE I CAN TALK 683 00:30:00,440 --> 00:30:03,040 TO YOU ABOUT IT LATER. 684 00:30:03,040 --> 00:30:04,480 WHICH INCLUDES A DIFFERENT MEANS 685 00:30:04,480 --> 00:30:07,400 OF ATTACHING THE IL12 TO THE 686 00:30:07,400 --> 00:30:08,880 NANOPARTICLE WHICH SEEMS TO BE 687 00:30:08,880 --> 00:30:11,200 GIVING US A VERY SIGNIFICANT 688 00:30:11,200 --> 00:30:14,360 ENHANCEMENT IN THAT SURVIVAL 689 00:30:14,360 --> 00:30:14,720 NUMBER. 690 00:30:14,720 --> 00:30:16,040 SO WE'RE LOOKING AT THAT AND 691 00:30:16,040 --> 00:30:19,480 WE'RE ALSO TRYING TO UNDERSTAND 692 00:30:19,480 --> 00:30:21,040 THE MECHANISM FOR THAT AND 693 00:30:21,040 --> 00:30:22,480 HOPEFULLY WE CAN BRING MORE TO 694 00:30:22,480 --> 00:30:27,920 THE TABLE WITH RESPECT TO HOW TO 695 00:30:27,920 --> 00:30:40,480 CONTROL THE CYTOKYNK FOR MORE 696 00:30:40,480 --> 00:30:41,520 EXTENDED TIME PERIODS. 697 00:30:41,520 --> 00:30:42,600 BEFORE MOVING ON, I SHOULD 698 00:30:42,600 --> 00:30:43,800 MENTION WE HAVE LOOKED AT OTHER 699 00:30:43,800 --> 00:30:44,880 KINDS OF CANCERS. 700 00:30:44,880 --> 00:30:46,560 THIS IS AN EXAMPLE OF WORK IN 701 00:30:46,560 --> 00:30:49,560 WHICH WE TARGETED LYMPHOMA USING 702 00:30:49,560 --> 00:30:53,680 AN SIRNA AGAINST BCL. 703 00:30:53,680 --> 00:30:56,880 AND IN THIS CASE, WE'RE LOOKING 704 00:30:56,880 --> 00:30:59,000 AT AN ANTI BODY ATTACHMENT TO 705 00:30:59,000 --> 00:31:00,280 OUR OUTER LAYER. 706 00:31:00,280 --> 00:31:05,520 THE OUTER LAYER WAS HYALURONIC 707 00:31:05,520 --> 00:31:08,560 ACID BUT WE ADDED AN ANTI BODY 708 00:31:08,560 --> 00:31:10,720 WHICH BINDS TO THE CD-20 709 00:31:10,720 --> 00:31:12,480 RECEPTORS AND IN THIS WORK, WE 710 00:31:12,480 --> 00:31:13,920 FOUND THAT WE WERE ABLE TO GET 711 00:31:13,920 --> 00:31:16,480 MORE EFFECTIVE TARGETING AND I 712 00:31:16,480 --> 00:31:17,680 DON'T HAVE TIME TO GO OVER THE 713 00:31:17,680 --> 00:31:19,560 DATA WITH THE COMBINATION SYSTEM 714 00:31:19,560 --> 00:31:23,360 AND WE WERE ABLE TO SEE GREATER 715 00:31:23,360 --> 00:31:25,280 SURVIVALABILITY IN THIS LYMPHOMA 716 00:31:25,280 --> 00:31:27,120 MODEL JUST WITH THE APPLICATION 717 00:31:27,120 --> 00:31:31,040 OF THIS SIBCL2 AND HERE WE CAN 718 00:31:31,040 --> 00:31:34,040 SEE THE COMBINATION GIVES US A 719 00:31:34,040 --> 00:31:36,440 MUCH LOWER AMOUNT OF CANCER 720 00:31:36,440 --> 00:31:40,040 SHOWN AS THIS STRONGLY 721 00:31:40,040 --> 00:31:43,400 LUMINESCENT THAT YOU CAN SEE IN 722 00:31:43,400 --> 00:31:44,120 THE ANIMALS HERE. 723 00:31:44,120 --> 00:31:48,680 WE'VE ALSO LOOKED AT THE IMPACT 724 00:31:48,680 --> 00:31:50,880 OF THE MECHANIC AT PROPERTIES OF 725 00:31:50,880 --> 00:31:53,400 THESE NANO CHEM KELLS INSPIRED 726 00:31:53,400 --> 00:32:02,320 BY WORK AS OTHERS SUCH AS DEBRA 727 00:32:02,320 --> 00:32:03,200 AND ESPECIALLY WORK THERE WAS 728 00:32:03,200 --> 00:32:07,720 FOUND THAT ELASTICITY OF 729 00:32:07,720 --> 00:32:08,320 NANOPARTICLES CAN INFLUENCE 730 00:32:08,320 --> 00:32:11,960 BLOOD CIRCULATION TIME AND HALF 731 00:32:11,960 --> 00:32:16,480 LIFE AND AND HERE WE THOUGHT 732 00:32:16,480 --> 00:32:19,320 BECAUSE OUR NANOPARTICLE IS VERY 733 00:32:19,320 --> 00:32:21,600 FLEXIBLE, WE CAN APPLY IT TO 734 00:32:21,600 --> 00:32:26,120 BOTH SOFT AND RIDGE ENTER 735 00:32:26,120 --> 00:32:28,160 NANOPARTICLES AND USE THAT CORE 736 00:32:28,160 --> 00:32:29,960 TO DETERMINE THE TRAFFICKING AND 737 00:32:29,960 --> 00:32:33,480 NATURE OF TRAFFICKING FOR THE 738 00:32:33,480 --> 00:32:33,880 NANOPARTICLE. 739 00:32:33,880 --> 00:32:42,080 WE USE LYPO SEEM LINE LIPOSOMES AND 740 00:32:42,080 --> 00:32:46,320 BECAUSE WE'RE USING FULLY UNSAT 741 00:32:46,320 --> 00:32:47,440 RAIDED LIPIDS THE CHOLESTEROL TO 742 00:32:47,440 --> 00:32:48,680 BE USED TO ESSENTIALLY TAKE US 743 00:32:48,680 --> 00:32:51,280 FROM A MORE CRYSTALLY KIND OF 744 00:32:51,280 --> 00:32:52,480 NANOPARTICLE WHICH IS RIDGED TO 745 00:32:52,480 --> 00:32:55,280 A SOFTER AND MORE FLUENT-LIKE 746 00:32:55,280 --> 00:32:56,960 LIPID LAYER AND WE CAN LAYER BY 747 00:32:56,960 --> 00:32:58,600 LAYER ON TOP OF BOTH OF THOSE 748 00:32:58,600 --> 00:33:02,040 AND GET NEARLY THE SAME RESULTS, 749 00:33:02,040 --> 00:33:05,440 SHOWN BY THE BLUE AND GREEN BARS 750 00:33:05,440 --> 00:33:06,880 IN TERMS OF THE CHARGE AND THE 751 00:33:06,880 --> 00:33:07,080 SIZE. 752 00:33:07,080 --> 00:33:09,480 THE CRYO EM IMAGES ARE 753 00:33:09,480 --> 00:33:12,200 CONSISTENT WITH THAT AND HERE 754 00:33:12,200 --> 00:33:14,680 WE'RE BASICALLY LOOKING AT 755 00:33:14,680 --> 00:33:16,080 BEFORE AND AFTER WE INTRODUCE 756 00:33:16,080 --> 00:33:19,440 THE LAYERS ON OUR RIDGED AND OUR 757 00:33:19,440 --> 00:33:22,080 SOFT NANOPARTICLES. 758 00:33:22,080 --> 00:33:24,440 WE DO FIND THAT THERE IS AN 759 00:33:24,440 --> 00:33:26,920 ENHANCEMENT IN HALF LIFE IN THIS 760 00:33:26,920 --> 00:33:27,280 SYSTEM. 761 00:33:27,280 --> 00:33:29,160 WHEN WE LOOK AT THE SOFTER 762 00:33:29,160 --> 00:33:30,400 NANOPARTICLES WITH THE SAME 763 00:33:30,400 --> 00:33:32,240 OUTER LAYER. 764 00:33:32,240 --> 00:33:34,640 AND VERY BRIEFLY, WE FOUND THAT 765 00:33:34,640 --> 00:33:39,320 THE SOFTER LBO NANOPARTICLES 766 00:33:39,320 --> 00:33:40,320 HAVE HIGHER TUMOR ACCUMULATION 767 00:33:40,320 --> 00:33:42,040 AS SHOWN HERE ON THE RIGHT AS 768 00:33:42,040 --> 00:33:43,800 WELL AS FROM THE IMAGES HERE 769 00:33:43,800 --> 00:33:45,120 WHERE THE TOP ARE THE RIDGED AND 770 00:33:45,120 --> 00:33:46,880 THE BOTTOM ARE THE SOFT AND 771 00:33:46,880 --> 00:33:51,560 WE'RE LOOKING FOR THE SIGNAL OF 772 00:33:51,560 --> 00:33:55,840 THE TUMOR. 773 00:33:55,840 --> 00:33:56,080 CY7. 774 00:33:56,080 --> 00:33:59,080 WHEN WE LOOK CROSS SECTIONS, OF 775 00:33:59,080 --> 00:34:01,120 THE TUMORS, IN THESE CASES AND 776 00:34:01,120 --> 00:34:03,680 LOOKED AT THE PENETRATION AND 777 00:34:03,680 --> 00:34:06,680 HERE WE'RE LOOKING AT OVARIAN 778 00:34:06,680 --> 00:34:08,520 TUMORS, WE SEE THAT THERE'S A 779 00:34:08,520 --> 00:34:10,880 SIGNIFICANT ENHANCEMENT OF 780 00:34:10,880 --> 00:34:13,640 PRESENCE OF THE NANO PART CAL 781 00:34:13,640 --> 00:34:17,080 WHEN WE HAVE THE SOFT LBL 782 00:34:17,080 --> 00:34:18,960 COMPARED TO THE RIDGED 783 00:34:18,960 --> 00:34:20,480 NANOPARTICLE AND WE'VE SEEN THE 784 00:34:20,480 --> 00:34:23,480 RIDGED ONES THAT WE HAVE SURFACE 785 00:34:23,480 --> 00:34:26,640 ACCUMULATION BUT NOT DEEP 786 00:34:26,640 --> 00:34:27,040 PENETRATION. 787 00:34:27,040 --> 00:34:29,520 SO, IN SUMMARY, WE HAVE FOUND 788 00:34:29,520 --> 00:34:31,720 THAT WE CAN USE THIS OUTER LAYER 789 00:34:31,720 --> 00:34:34,600 CHEMISTRY AS A WAY TO TARGET OUR 790 00:34:34,600 --> 00:34:35,680 NANOPARTICLES TO TUMORS. 791 00:34:35,680 --> 00:34:37,600 WE CAN ACTUALLY USE THE NATURE 792 00:34:37,600 --> 00:34:41,560 OF THAT OUTER LAYER AS A WAY TO 793 00:34:41,560 --> 00:34:45,680 ESSENTIALLY ADAPT HOW THE NANO 794 00:34:45,680 --> 00:34:49,480 PART CAL TRAFFICKING IN CELLS 795 00:34:49,480 --> 00:34:55,160 AND IT CAN IMPACT THE HALF LIFE 796 00:34:55,160 --> 00:34:59,400 TO THE DEGREE OF TUMOR AND SO WE 797 00:34:59,400 --> 00:35:01,280 HAVE WE ARE LEARNING HOW TO USE 798 00:35:01,280 --> 00:35:04,040 TO ESSENTIALLY ENHANCE THE 799 00:35:04,040 --> 00:35:05,480 PRESENCE OF THESE NANOPARTICLES 800 00:35:05,480 --> 00:35:08,360 AND THE NATURE OF THEIR RELEASE 801 00:35:08,360 --> 00:35:12,800 AND USE THEM AS A WAY TO TARGET 802 00:35:12,800 --> 00:35:14,480 THE DELIVERY OF PROTEINS AS WELL 803 00:35:14,480 --> 00:35:20,080 AS SIRNA AND CHEMOTHERAPY DRUGS. 804 00:35:20,080 --> 00:35:22,080 WITH THAT, I'LL TRANSITION AND 805 00:35:22,080 --> 00:35:26,320 TRY TO BE BRIEFER WITH OUR TOPIC 806 00:35:26,320 --> 00:35:27,080 ON OSTEO ARTHRITIS. 807 00:35:27,080 --> 00:35:31,240 IN THIS CASE, WE'RE ABLE TO 808 00:35:31,240 --> 00:35:33,920 TREAT TRAUMA INDUCED AS TEE OWE 809 00:35:33,920 --> 00:35:34,920 ARTHRITIS SO THIS IS OFTEN 810 00:35:34,920 --> 00:35:39,160 CALLED POST TRAUMATIC OSTEO 811 00:35:39,160 --> 00:35:41,760 ARTHRITIS OR PTOA AND IT HAPPENS 812 00:35:41,760 --> 00:35:47,000 WHEN THERE'S A BIT OF DAMAGE TO 813 00:35:47,000 --> 00:35:48,400 THE CARTILAGE PERHAPS DUE TO A 814 00:35:48,400 --> 00:35:50,520 WORK INCIDENT AND SOME SORT OF 815 00:35:50,520 --> 00:35:53,480 DAMAGE OR TRAUMA A THIS IS 816 00:35:53,480 --> 00:35:54,640 SOMETHING THAT IS OF GREAT 817 00:35:54,640 --> 00:35:57,880 INTEREST TO THE DOD FOR EXAMPLE, 818 00:35:57,880 --> 00:35:59,840 AND FOR SOLDIERS AND MILITARY 819 00:35:59,840 --> 00:36:01,360 PERSONNEL BUT IS OF INTEREST OF 820 00:36:01,360 --> 00:36:03,720 ALSO TO ATHLETES AND TO ANYONE 821 00:36:03,720 --> 00:36:05,320 WHO HAS SIGNIFICANT PHYSICAL 822 00:36:05,320 --> 00:36:09,080 ELEMENTS TO THEIR WORK. 823 00:36:09,080 --> 00:36:10,840 WHEN THIS TEAR OR DAMAGE 824 00:36:10,840 --> 00:36:13,440 HAPPENS, OVER TIME, THERE'S 825 00:36:13,440 --> 00:36:15,320 INFLAMMATION WHICH LEADS TO PAIN 826 00:36:15,320 --> 00:36:19,240 AND WE'VE LEARNED HOW TO HANDLE 827 00:36:19,240 --> 00:36:20,080 THE INPRACTICE MISSION WITH 828 00:36:20,080 --> 00:36:24,280 STEROIDS AND DO A GOODS JOB OR 829 00:36:24,280 --> 00:36:25,840 ORAL NON STEROID ANTI 830 00:36:25,840 --> 00:36:27,120 INFLAMMATORY DRUGS BUT IT'S NOT 831 00:36:27,120 --> 00:36:28,520 REALLY ELIMINATING OR TREATING 832 00:36:28,520 --> 00:36:30,680 THE PROBLEM, IT'S TREATING THE 833 00:36:30,680 --> 00:36:33,920 PAIN AND THE INFLAMMATION. 834 00:36:33,920 --> 00:36:34,720 TYPICALLY WHAT HAPPENS IS THAT 835 00:36:34,720 --> 00:36:38,680 OVER TIME, THIS INFLAMMATION 836 00:36:38,680 --> 00:36:39,880 OCCURS AND THERE'S ENOUGH DAMAGE 837 00:36:39,880 --> 00:36:45,280 THERE'S A NEED FOR A FULL JOINT 838 00:36:45,280 --> 00:36:45,720 REPLACEMENT. 839 00:36:45,720 --> 00:36:48,400 THERE'S NOT A DISEASE MODIFYING 840 00:36:48,400 --> 00:36:51,680 DRUGS WHICH ESSENTIALLY REVERSES 841 00:36:51,680 --> 00:36:54,400 SOME OF THESE PATHWAYS TOWARDS 842 00:36:54,400 --> 00:36:57,760 ESSENTIALLY PROGRESSIVE 843 00:36:57,760 --> 00:36:59,160 INFLAMMATION AND THE REASON FOR 844 00:36:59,160 --> 00:37:02,080 THIS IS NOT BECAUSE WE DON'T 845 00:37:02,080 --> 00:37:03,440 UNDERSTAND THE KINDS OF 846 00:37:03,440 --> 00:37:07,280 THERAPIES THAT MIGHT WORK, THERE 847 00:37:07,280 --> 00:37:09,560 ARE PROTECTORS AND STIMULATE THE 848 00:37:09,560 --> 00:37:12,920 CARTILAGE SITES THAT RECITE 849 00:37:12,920 --> 00:37:14,480 WITHIN CARTILAGE TO PRODUCE MORE 850 00:37:14,480 --> 00:37:16,920 CARTILAGE AND THERE ARE DRUGS 851 00:37:16,920 --> 00:37:19,520 WHICH CAN REUSE THE TENDENCY 852 00:37:19,520 --> 00:37:30,600 TOWARDS INFLAMMATION HOWEVER, TO 853 00:37:30,600 --> 00:37:32,360 MANAGE THE DELIVERY OF PRETEENS 854 00:37:32,360 --> 00:37:33,520 IN THE JOINT AND ONE OF THE 855 00:37:33,520 --> 00:37:34,520 PRIMARY ONES IS THAT THERE'S A 856 00:37:34,520 --> 00:37:36,480 LOT OF RAPID CLEARANCE THAT 857 00:37:36,480 --> 00:37:37,880 TAKES PLACE WITHIN THE JOINT AND 858 00:37:37,880 --> 00:37:41,880 SO IF YOU INTRODUCE A FREE 859 00:37:41,880 --> 00:37:43,080 PROTEIN, INTO THE JOINT, EVEN IF 860 00:37:43,080 --> 00:37:44,840 IT HAS ANNA TRACTION TO THE 861 00:37:44,840 --> 00:37:46,080 CARTILAGE, IT WILL RESIDE THERE 862 00:37:46,080 --> 00:37:48,000 FOR A SHORT TIME PERIOD BECAUSE 863 00:37:48,000 --> 00:37:50,960 THERE'S A TENDENCY FOR THERE TO 864 00:37:50,960 --> 00:37:54,480 BE A CLEARENS THROUGH THE VESSEL 865 00:37:54,480 --> 00:37:58,280 AND THE VENUALS. 866 00:37:58,280 --> 00:37:59,640 THE OTHER ISSUE IS CARTILAGE 867 00:37:59,640 --> 00:38:04,240 ITSELF IS A VERY SENSE 868 00:38:04,240 --> 00:38:07,600 NEGATIVELY CHARGED POLYMER AND 869 00:38:07,600 --> 00:38:12,280 HERE WE SHOW THE PRO KROLL 870 00:38:12,280 --> 00:38:13,280 GLYCANS PRESENT WHICH HAVE 871 00:38:13,280 --> 00:38:17,200 HEAVILY BRANCHED AND CHARGED 872 00:38:17,200 --> 00:38:19,720 THESE ARE ESSENTIALLY NEGATIVE 873 00:38:19,720 --> 00:38:25,080 LOW CHARGED POLY SACKRIDES AND 874 00:38:25,080 --> 00:38:26,920 WE HAVE A PROBLEM THAT ANYTHING 875 00:38:26,920 --> 00:38:31,320 THAT IS LARGER IS GOING TO 876 00:38:31,320 --> 00:38:34,520 ESSENTIALLY BIND TO THE TOP AND 877 00:38:34,520 --> 00:38:35,640 WON'T PENETRATE, EVEN IF IT'S 878 00:38:35,640 --> 00:38:36,480 POSITIVELY CHARGED. 879 00:38:36,480 --> 00:38:39,760 IF IT'S SMALLER, A SMALL 880 00:38:39,760 --> 00:38:41,200 MOLECULE HAS A CHANCE OF GETTING 881 00:38:41,200 --> 00:38:43,120 IN AND SPENDING TIME WITHIN THIS 882 00:38:43,120 --> 00:38:45,880 MATRIX AND REACHING THE SITES 883 00:38:45,880 --> 00:38:47,200 THAT RECITE IN THEM BUT THERE 884 00:38:47,200 --> 00:38:49,320 ARE NO BLOOD VESSELS TO HELP US, 885 00:38:49,320 --> 00:38:50,880 THEY'RE A VASCULAR TISSUES SO 886 00:38:50,880 --> 00:38:53,640 WE'VE BEEN INTERESTING IN 887 00:38:53,640 --> 00:38:56,280 DESIGNING NANO SYSTEMS THAT CAN 888 00:38:56,280 --> 00:38:59,200 HELP DELIVER PROTEIN DRUGS AND 889 00:38:59,200 --> 00:39:02,480 OTHER KINDS OF DRUGS DIRECTLY TO 890 00:39:02,480 --> 00:39:04,280 AND IT'S RELEVANT WHEN WE HAVE A 891 00:39:04,280 --> 00:39:08,760 DRUG THAT NEEDS TO INTERACT 892 00:39:08,760 --> 00:39:10,320 DIRECTLY ON THE CELLS INCLUDING 893 00:39:10,320 --> 00:39:14,880 GROW FACTORS THAT CAN STIMULATE 894 00:39:14,880 --> 00:39:17,360 THE GENERATION CARTILAGE. 895 00:39:17,360 --> 00:39:20,720 WE NEED SMALL ENOUGH TO DEAL 896 00:39:20,720 --> 00:39:22,880 WITH 15 NANO METER OR SMALLER 897 00:39:22,880 --> 00:39:26,080 MESH SIZE THIS MATRIX PRESENTS. 898 00:39:26,080 --> 00:39:28,160 IT NEEDS TO HAVE STRONG POSITIVE 899 00:39:28,160 --> 00:39:30,440 CHARGE IT CAN COMBINE SO IT 900 00:39:30,440 --> 00:39:34,200 CAN'T BE POSITIVE LOW CHARGED, 901 00:39:34,200 --> 00:39:35,120 IT ONLY BINDS TO THE SURFACE BUT 902 00:39:35,120 --> 00:39:36,560 DOESN'T MAKE ITS WAY OVER TIME 903 00:39:36,560 --> 00:39:40,240 PERIODS THAT ARE REASONABLE INTO 904 00:39:40,240 --> 00:39:40,840 THE CARTILAGE. 905 00:39:40,840 --> 00:39:47,480 SO WE DECIDED TO WORK WITH 906 00:39:47,480 --> 00:39:49,080 DENDROMERS BECAUSE THEY'RE VERY 907 00:39:49,080 --> 00:39:52,560 NICE, BEAUTIFULLY BRANCHED 908 00:39:52,560 --> 00:39:56,720 POLYMERIC ARCHITECTURES THAT ARE 909 00:39:56,720 --> 00:39:57,760 HEAVILY CONTROLLED. 910 00:39:57,760 --> 00:39:59,800 THEIR SIZE, DEPENDING ON THE 911 00:39:59,800 --> 00:40:01,680 GENERATION, FOR EACH BRANCHING 912 00:40:01,680 --> 00:40:05,400 EVENT, REPRESENTS A GENERATION, 913 00:40:05,400 --> 00:40:06,720 DETERMINES THE SIZE, GIVES US A 914 00:40:06,720 --> 00:40:09,920 NICE RANGE AND WE CAN PURCHASE 915 00:40:09,920 --> 00:40:10,800 DENDRIMERS IN THE SIZE RANGE OF 916 00:40:10,800 --> 00:40:12,680 FOUR TO SEVEN NANO MEETERS AND 917 00:40:12,680 --> 00:40:16,920 THEY CAN PRESENT ANYWHERE FROM 918 00:40:16,920 --> 00:40:18,240 64 TO 256 THREE GROUPS AND ALL 919 00:40:18,240 --> 00:40:21,400 OF THESE GROUPS PROVIDE AN 920 00:40:21,400 --> 00:40:22,600 OPPORTUNITY FOR POSITIVE CHARGE 921 00:40:22,600 --> 00:40:23,640 SO THAT'S ONE OF THE REASONS 922 00:40:23,640 --> 00:40:27,440 WE'RE INTERESTED IN THIS MOT 923 00:40:27,440 --> 00:40:27,680 MOLECULE. 924 00:40:27,680 --> 00:40:29,080 SIZE AND CHARGE ARE WHERE WE 925 00:40:29,080 --> 00:40:29,680 WANT TO BE. 926 00:40:29,680 --> 00:40:34,280 ON TOP OF THAT, THEY PROVIDE PRE 927 00:40:34,280 --> 00:40:37,080 CHEMICAL HANDALS THAT ALLOW US 928 00:40:37,080 --> 00:40:38,800 TO ATTACH OUR CARGO PROTEIN TO 929 00:40:38,800 --> 00:40:41,720 THE SURFACE THE DENDRIMER. 930 00:40:41,720 --> 00:40:43,080 WITH THAT SAID, ALL OF THIS 931 00:40:43,080 --> 00:40:46,960 CHARGE CAN BE PROBLEMATIC. 932 00:40:46,960 --> 00:40:49,240 BY ITSELF IT'S TOXIC TO CELLS 933 00:40:49,240 --> 00:40:50,400 BECAUSE IT CAN ACTUALLY BREAK 934 00:40:50,400 --> 00:40:52,600 THROUGH A NUMBER OF CELL 935 00:40:52,600 --> 00:40:54,680 MEMBRANES AND IT CAN INTRODUCE 936 00:40:54,680 --> 00:40:55,840 TOXICITY SO WE WANT TO CONTROL 937 00:40:55,840 --> 00:40:57,080 THE CHARGE. 938 00:40:57,080 --> 00:40:59,600 WE WANT TO TITRATE IT. 939 00:40:59,600 --> 00:41:02,040 IF IT'S TOO STICKY, IT WILL GET 940 00:41:02,040 --> 00:41:03,440 STUCK AT THE CARTILAGE SURFACE 941 00:41:03,440 --> 00:41:05,520 SO WE WANT TO MANAGE THAT 942 00:41:05,520 --> 00:41:07,360 STICKINESS ISSUE AS WELL. 943 00:41:07,360 --> 00:41:11,000 AND ALLOW THIS NANOPARTICLE TO 944 00:41:11,000 --> 00:41:12,960 INTERACT WITH THE MATRIX THAT 945 00:41:12,960 --> 00:41:17,520 HAVE AN INTERACTION THAT ALLOWS 946 00:41:17,520 --> 00:41:19,200 BINDING AND DEBINDING SO THAT IT 947 00:41:19,200 --> 00:41:23,440 CAN MAKE ITS WAY INTO THE 948 00:41:23,440 --> 00:41:23,680 CARTILAGE. 949 00:41:23,680 --> 00:41:25,520 ONE WAY OF DOING THIS IS 950 00:41:25,520 --> 00:41:28,480 INTRODUCING POLY ETHYLENE GLY 951 00:41:28,480 --> 00:41:31,920 CON, A HYDRATED SHARP POLYMER 952 00:41:31,920 --> 00:41:33,600 CHAIN WE CAN ADD BECAUSE IT'S 953 00:41:33,600 --> 00:41:35,200 NEUTRAL AND IT HAS A LARGE 954 00:41:35,200 --> 00:41:38,800 AMOUNT OF WATER ASSOCIATION AND 955 00:41:38,800 --> 00:41:43,880 IT'S A VERY FLEXIBLE MOLECULE. 956 00:41:43,880 --> 00:41:47,560 IT'S BEEN KNOWN TO SHIEL KNOWN TO SHIELD A 957 00:41:47,560 --> 00:41:47,800 CHARGE. 958 00:41:47,800 --> 00:41:49,000 IT SHIELDS SOME OF THE CHARGE 959 00:41:49,000 --> 00:41:53,600 THAT IS PRESENT ON THESE 960 00:41:53,600 --> 00:41:55,280 DENDRIMER MOLECULES AND OF 961 00:41:55,280 --> 00:41:59,320 COURSE, EACH REACTION WE HAVE 962 00:41:59,320 --> 00:42:02,760 DOES ELIMINATE ONE OF THE 963 00:42:02,760 --> 00:42:06,360 PRIMARY AMINES AND WE ARE A 964 00:42:06,360 --> 00:42:10,520 LOWER BASIS TEE OF THE AMEEN. 965 00:42:10,520 --> 00:42:12,480 LET'S LOOK AT THE BIG PICTURE. 966 00:42:12,480 --> 00:42:14,600 WE HAVE SOME DESIGN PARAMETER 967 00:42:14,600 --> 00:42:14,880 SPACE. 968 00:42:14,880 --> 00:42:18,040 FOR THE PANAM DENDRIMER, WE 969 00:42:18,040 --> 00:42:19,560 LOOKED AT TWO DIFFERENT 970 00:42:19,560 --> 00:42:19,880 GENERATIONS. 971 00:42:19,880 --> 00:42:22,960 ONE SMALLER AND ONE LARGER. 972 00:42:22,960 --> 00:42:24,920 AND WE ALWAYS ATTACHED IGF, 973 00:42:24,920 --> 00:42:26,640 WHICH IS THE PROTEIN DRUG OF 974 00:42:26,640 --> 00:42:29,280 CHOICE FOR OUR STUDY AND CAN 975 00:42:29,280 --> 00:42:32,920 STIMULATE THE GENERATION OF 976 00:42:32,920 --> 00:42:36,400 MATRIX MOLECULES BY THE CON 977 00:42:36,400 --> 00:42:40,400 DEGREE SITES SO WE ATTACHED THAT 978 00:42:40,400 --> 00:42:47,360 USING A COMMON CON -- WE USE THE 979 00:42:47,360 --> 00:42:49,200 DYE TO TRACK WHAT IS GOING ON. 980 00:42:49,200 --> 00:42:50,560 THE PEG CHAIN BECAME ONE OF OUR 981 00:42:50,560 --> 00:42:53,600 BIGGEST MODIFICATIONS AND WE 982 00:42:53,600 --> 00:42:55,720 LOOKED AT DIFFERENT LENGTHS AS 983 00:42:55,720 --> 00:42:56,920 WELL AS DIFFERENT DENSITIES OF 984 00:42:56,920 --> 00:42:57,720 THE PEG ITSELF. 985 00:42:57,720 --> 00:43:00,440 SO YOU CAN IMAGINE VISUALLY A 986 00:43:00,440 --> 00:43:02,880 LIBRARY IN WHICH WE ARE 987 00:43:02,880 --> 00:43:05,480 INCREASING THE SIZE OF THE 988 00:43:05,480 --> 00:43:06,960 POLYMER CHAINS THAT WE ATTACH AS 989 00:43:06,960 --> 00:43:08,800 WELL AS THE DENSITY OF THE 990 00:43:08,800 --> 00:43:12,480 CHAINS THAT WE PUT DOWN AND OF 991 00:43:12,480 --> 00:43:14,600 COURSE, THE LESS THAT WE HAVE 992 00:43:14,600 --> 00:43:15,760 PRESENT, THE HIGHER THE NET 993 00:43:15,760 --> 00:43:18,840 CHARGE OF THE MOLECULE. 994 00:43:18,840 --> 00:43:26,000 WE THEN LOOK AT HOW DEEPLY THE 995 00:43:26,000 --> 00:43:27,640 NANOMATERIALS PENETRATE INTO 996 00:43:27,640 --> 00:43:28,720 CARTILAGE AS WELL AS THE NET 997 00:43:28,720 --> 00:43:31,480 AMOUNT THAT IS TAKEN UP OR THE 998 00:43:31,480 --> 00:43:35,200 UPTAKE BY USING BOTH CARTILAGE 999 00:43:35,200 --> 00:43:40,880 DISKS TO ESSENTIALLY LOOK AT 1000 00:43:40,880 --> 00:43:43,880 THESE LABELED NANOMATERIALS. 1001 00:43:43,880 --> 00:43:46,520 IN DOING THIS WORK, WE MEASURED 1002 00:43:46,520 --> 00:43:48,880 NOT ONLY THAT PERCENT UPTAKE OR 1003 00:43:48,880 --> 00:43:51,440 NET UPTAKE INTO THE CARTILAGE, 1004 00:43:51,440 --> 00:43:55,640 WE ALSO LOOKED AT CELL 1005 00:43:55,640 --> 00:43:56,920 VIABILITY. 1006 00:43:56,920 --> 00:43:58,360 ESSENTIALLY, WE'RE INTERESTED IN 1007 00:43:58,360 --> 00:44:00,480 SYSTEMS WHICH GAVE US A VERY 1008 00:44:00,480 --> 00:44:05,040 HIGH PERCENT VIABILITY OF CELLS 1009 00:44:05,040 --> 00:44:10,560 CLOSE TO 100% IN DOING SO, WE 1010 00:44:10,560 --> 00:44:12,280 COULD SEE A TREND WHICH 1011 00:44:12,280 --> 00:44:14,880 INCREASING PEG A LAYING OF OUR 1012 00:44:14,880 --> 00:44:17,800 DEN DEMER LED TO ESSENTIALLY 1013 00:44:17,800 --> 00:44:19,520 HIGH UPTAKE UP TO A CERTAIN 1014 00:44:19,520 --> 00:44:21,480 POINT AND THEN WE REACHED A 1015 00:44:21,480 --> 00:44:25,120 POINT OF PEG WHICH THE UPTAKE 1016 00:44:25,120 --> 00:44:27,640 DROPS SIGNIFICANTLY THE INVERSE 1017 00:44:27,640 --> 00:44:28,920 BEHAVIOR FOR VIABILITY IN WHICH 1018 00:44:28,920 --> 00:44:31,960 WE SEE THAT VIABILITY IS VERY 1019 00:44:31,960 --> 00:44:33,640 LOW UP TO A CERTAIN POINT AND WE 1020 00:44:33,640 --> 00:44:35,760 SEE VIABILITY IS PRESERVED AND 1021 00:44:35,760 --> 00:44:39,920 SO, WE'RE LOOKING FOR A SWEET 1022 00:44:39,920 --> 00:44:42,320 SPOT WHERE WE MAINTAIN VIABILITY 1023 00:44:42,320 --> 00:44:43,960 WHILE HAVING HIGH UPTAKE. 1024 00:44:43,960 --> 00:44:46,200 AND WE FOUND THAT THAT SWEET 1025 00:44:46,200 --> 00:44:48,640 SPOT INTENDED TO EXIST SOMEWHERE 1026 00:44:48,640 --> 00:44:51,320 BETWEEN THE POINT WHERE WE HAVE 1027 00:44:51,320 --> 00:44:52,480 THESE PEG CHAINS PACKING RIGHT 1028 00:44:52,480 --> 00:44:53,920 NEXT TO EACH OTHER IF WE CAN 1029 00:44:53,920 --> 00:44:55,720 IMAGINE THAT THEY'RE FLEXIBLE 1030 00:44:55,720 --> 00:44:57,480 AND THEY'RE SWITCHING AROUND AND 1031 00:44:57,480 --> 00:45:01,040 THEY'RE RANDOM WALK ON THE DEN 1032 00:45:01,040 --> 00:45:03,880 DRUM SURFACE THEY'RE BEGINNING 1033 00:45:03,880 --> 00:45:10,160 TO TOUCH THAT WE SEE THAT WE ARE 1034 00:45:10,160 --> 00:45:11,480 ENTERING A WINDOW OF GOOD 1035 00:45:11,480 --> 00:45:12,880 VIABILITY AND WE CONTINUE IN 1036 00:45:12,880 --> 00:45:14,120 THAT WINDOW OF GOOD VIABILITY 1037 00:45:14,120 --> 00:45:16,200 AND DROP IN UPTAKE WHEN WE GET 1038 00:45:16,200 --> 00:45:20,680 BEYOND ABOUT TWO TIMES THAT 1039 00:45:20,680 --> 00:45:21,320 DENSITY. 1040 00:45:21,320 --> 00:45:22,560 NOW, THAT PREVIOUS WORK WAS DONE 1041 00:45:22,560 --> 00:45:27,360 BY MY FORMER GRADUATE STUDENT 1042 00:45:27,360 --> 00:45:29,880 BRETT, GUYGER AND NOW BRANDON 1043 00:45:29,880 --> 00:45:31,440 JOHNSTON IN OUR LAB IS LOOKING 1044 00:45:31,440 --> 00:45:33,720 AT THE SPECIFIC INTERACTIONS 1045 00:45:33,720 --> 00:45:35,280 THESE PEG CHAINS HAVE WHEN THEY 1046 00:45:35,280 --> 00:45:37,480 ARE ON THIS ATTACHED SURFACE AND 1047 00:45:37,480 --> 00:45:40,200 THIS INCLUDES HYDROGEN PONDING 1048 00:45:40,200 --> 00:45:42,440 WHICH CONTRIBUTES TO THE 1049 00:45:42,440 --> 00:45:45,560 SHIELDER, OF THE PEG CHAIN AND 1050 00:45:45,560 --> 00:45:47,640 AS WELL AS THE UMBRELLA EFFECT 1051 00:45:47,640 --> 00:45:50,320 OF ESSENTIALLY THIS PEG CHAIN 1052 00:45:50,320 --> 00:45:51,680 SURROUNDING THE CHARGE. 1053 00:45:51,680 --> 00:45:55,720 AND HE WAS ABLE TO DERIVE A WAY 1054 00:45:55,720 --> 00:45:58,280 OF CORRELATING THE AMOUNT OF 1055 00:45:58,280 --> 00:46:01,440 SORT OF FREELY AVAILABLE OR 1056 00:46:01,440 --> 00:46:02,960 ACCESSIBLE PRIMARY MEANS THAT 1057 00:46:02,960 --> 00:46:04,600 WILL CONTRIBUTE TO THE CHARGE 1058 00:46:04,600 --> 00:46:05,840 BEHAVIOR OF THE SYSTEM AS 1059 00:46:05,840 --> 00:46:07,480 OPPOSED TO THE ONES THAT ARE 1060 00:46:07,480 --> 00:46:09,640 ESSENTIALLY HIDDEN BY PEG AND HE 1061 00:46:09,640 --> 00:46:13,760 DID THIS BY USING A COMPETITIVE 1062 00:46:13,760 --> 00:46:16,080 SCREENING ASSAY IN WHICH YOU 1063 00:46:16,080 --> 00:46:17,880 LOOK AT HOW MUCH SALT IS 1064 00:46:17,880 --> 00:46:20,920 REQUIRED BEFORE YOU GET COMPLETE 1065 00:46:20,920 --> 00:46:24,120 DISRUPTION OF THE DENDRIMER FROM 1066 00:46:24,120 --> 00:46:25,080 THE CARTILAGE. 1067 00:46:25,080 --> 00:46:25,280 MATRIX. 1068 00:46:25,280 --> 00:46:26,720 I DON'T HAVE TIME TO GO INTO THE 1069 00:46:26,720 --> 00:46:28,480 DETAILS OF THIS APPROACH. 1070 00:46:28,480 --> 00:46:29,040 IT'S A BEAUTIFUL APPROACH. 1071 00:46:29,040 --> 00:46:32,480 THAT ALLOWED US TO CORRELATE THE 1072 00:46:32,480 --> 00:46:34,760 NUMBER OF FREE AMINES THAT PRO 1073 00:46:34,760 --> 00:46:37,040 CHARGE VERSUS THOSE THAT ARE 1074 00:46:37,040 --> 00:46:37,440 OFFERED UP BY PEG. 1075 00:46:37,440 --> 00:46:39,040 THAT ALLOWED US TO MAKE MORE 1076 00:46:39,040 --> 00:46:40,880 DIRECT COMPARISONS BETWEEN OUR 1077 00:46:40,880 --> 00:46:44,120 DIFFERENT FORMULATIONS AND LOOK 1078 00:46:44,120 --> 00:46:44,960 FOR TRENDS. 1079 00:46:44,960 --> 00:46:46,120 SO, THIS IS A LITTLE BIT MORE 1080 00:46:46,120 --> 00:46:48,400 ABOUT HOW THIS WORK WAS DONE AND 1081 00:46:48,400 --> 00:46:52,280 I'LL SKIP AHEAD A LITTLE BIT 1082 00:46:52,280 --> 00:46:54,480 JUST TO EXPLAIN THAT IN BEING 1083 00:46:54,480 --> 00:46:57,560 ABLE TO MAKE THESE CORRELATIONS, 1084 00:46:57,560 --> 00:46:58,280 WE CAN PLOT SOMETHING LIKE THE 1085 00:46:58,280 --> 00:47:01,680 NUMBER OF ACCESSIBLE CHARGED 1086 00:47:01,680 --> 00:47:04,680 AMINES ON ONE POINT, ON ONE AXIS 1087 00:47:04,680 --> 00:47:07,240 AGAINST THE TOTAL NUMBER OF 1088 00:47:07,240 --> 00:47:09,200 GROUPS THAT WERE MODIFIED AND WE 1089 00:47:09,200 --> 00:47:11,480 CAN SEE THAT AS WE INCREASE THE 1090 00:47:11,480 --> 00:47:15,240 PEG CHAIN LENGTH, WE CAN SEE A 1091 00:47:15,240 --> 00:47:16,800 TREND IN WHICH WE'RE GETTING 1092 00:47:16,800 --> 00:47:21,840 LESS AND LESS ACCESSIBLE CHARGE 1093 00:47:21,840 --> 00:47:23,880 ON THESE MOLECULES SO WE CAN 1094 00:47:23,880 --> 00:47:26,360 ACTUALLY TUNE THAT WITH A GREAT 1095 00:47:26,360 --> 00:47:32,280 DEAL OF ACCURACY. 1096 00:47:32,280 --> 00:47:33,560 WE'VE DONE THIS FOR TWO 1097 00:47:33,560 --> 00:47:35,400 DIFFERENT GENERATIONS, 1098 00:47:35,400 --> 00:47:36,680 GENERATION 4 AND 6 AND WE CAN 1099 00:47:36,680 --> 00:47:39,160 MAKE CORRELATIONS WITH RESPECT 1100 00:47:39,160 --> 00:47:41,000 TO THE LENGTH OF THE PEG CHAIN 1101 00:47:41,000 --> 00:47:46,960 AND THE AMOUNT OF SCREENING WE 1102 00:47:46,960 --> 00:47:47,120 GET. 1103 00:47:47,120 --> 00:47:48,640 THIS ALLOWS US TO LOOK AT THE 1104 00:47:48,640 --> 00:47:53,160 BALANCE OF UPTAKE AND HOW LONG 1105 00:47:53,160 --> 00:47:57,680 THAT DENDRIMER RESIDES IN THE 1106 00:47:57,680 --> 00:48:05,200 MATRIX AS WELL AS THE AB OPTION 1107 00:48:05,200 --> 00:48:07,920 ABSORPTION KEN ET TICKS AND WE 1108 00:48:07,920 --> 00:48:09,320 HAVE DOPE PENETRATION AND THE 1109 00:48:09,320 --> 00:48:10,560 TIME IN THE CARTILAGE. 1110 00:48:10,560 --> 00:48:12,760 WE LOOK AT HOW WE MEASURE UPTAKE 1111 00:48:12,760 --> 00:48:15,720 OVER 24 HOURS SO NOW WE'RE 1112 00:48:15,720 --> 00:48:19,160 LOOKING AT A TIMED UPTAKE AND WE 1113 00:48:19,160 --> 00:48:21,040 CAN SEE THERE ARE SYSTEMS WHICH 1114 00:48:21,040 --> 00:48:22,680 GIVE US SIGNIFICANTLY MORE 1115 00:48:22,680 --> 00:48:24,640 UPTAKE AND THIS IS THE PEG 4 1116 00:48:24,640 --> 00:48:27,480 SYSTEM AND EVEN THOUGH WE HAVE 1117 00:48:27,480 --> 00:48:30,280 THE SAME NUMBER OF ACCESSIBLE 1118 00:48:30,280 --> 00:48:33,880 CHARGED AMINES IN THIS 1119 00:48:33,880 --> 00:48:34,760 COMPARISON. 1120 00:48:34,760 --> 00:48:37,480 THIS IS BECAUSE FASTER UPTAKE 1121 00:48:37,480 --> 00:48:39,240 HAPPENS WITH THE SHORTER PEG 1122 00:48:39,240 --> 00:48:39,480 CHAINS. 1123 00:48:39,480 --> 00:48:40,440 THAT'S PART OF THE STORY. 1124 00:48:40,440 --> 00:48:42,000 WE CAN GET VERY RAPID UPTAKE 1125 00:48:42,000 --> 00:48:43,600 WITH THE SHORTER PEG CHAINS 1126 00:48:43,600 --> 00:48:45,920 GIVING THE SAME AMOUNT OF 1127 00:48:45,920 --> 00:48:46,800 SHIELDING. 1128 00:48:46,800 --> 00:48:50,040 WHEN THE PEG CHAIN LENGTH GETS 1129 00:48:50,040 --> 00:48:56,800 LONGER, THEY CONTRIBUTE TO THE 1130 00:48:56,800 --> 00:49:01,440 NATURE OF THE CONJIGATE AND IF 1131 00:49:01,440 --> 00:49:03,400 WE WAIT LONGER TIME PERIODS, 1132 00:49:03,400 --> 00:49:05,440 EVEN THOUGH IT'S FASTER FOR THE 1133 00:49:05,440 --> 00:49:07,080 SHORTER CHAINS, OVER LONGER TIME 1134 00:49:07,080 --> 00:49:14,080 PERIODS THE UPTAKE IS GREATER 1135 00:49:14,080 --> 00:49:15,080 WHEN WE HAVE LONGER CHAINS. 1136 00:49:15,080 --> 00:49:17,600 IF WE LOOK AT LONG TIME PERIODS, 1137 00:49:17,600 --> 00:49:18,880 THE LONGER CHAINS, ALTHOUGH THEY 1138 00:49:18,880 --> 00:49:20,800 TAKE LONGER TO GET IN, MORE OF 1139 00:49:20,800 --> 00:49:24,000 THEM GET INTO THE MIDDLE 1140 00:49:24,000 --> 00:49:25,280 THICKNESS OF THE CARTILAGE OVER 1141 00:49:25,280 --> 00:49:26,480 A PERIOD OF SEVERAL DAYS. 1142 00:49:26,480 --> 00:49:28,520 AND WE THINK ABOUT THESE 1143 00:49:28,520 --> 00:49:31,520 INJECTIONS, WE'RE ABLE TO THEN 1144 00:49:31,520 --> 00:49:33,400 MONITOR HOW LONG WE HAVE TO GET 1145 00:49:33,400 --> 00:49:34,800 INTO THE CARTILAGE, THAT TERMS 1146 00:49:34,800 --> 00:49:37,080 WHICH ONE OF THESE FORMULATIONS 1147 00:49:37,080 --> 00:49:38,240 WE GO WITH. 1148 00:49:38,240 --> 00:49:41,240 NOW WE TOOK ONE OF OUR OPTIMIZED 1149 00:49:41,240 --> 00:49:47,120 SYSTEMS AND LOOKED AT 1150 00:49:47,120 --> 00:49:50,120 ESSENTIALLY THE DEN DEGREE MER 1151 00:49:50,120 --> 00:50:00,480 IGF-1 AND WE'RE LOOKING AT 45% 1152 00:50:00,480 --> 00:50:03,320 PEG 1153 00:50:03,320 --> 00:50:04,520 WE'RE LOOKING AT THE JOINT OF 1154 00:50:04,520 --> 00:50:07,320 THE ANIMAL, FOR IGF ALONE WHICH 1155 00:50:07,320 --> 00:50:10,600 IS LABELS, WE CAN SEE A 1156 00:50:10,600 --> 00:50:11,480 SIGNIFICANT ENHANCEMENT IN THE 1157 00:50:11,480 --> 00:50:13,360 TIME IN THE CARTILAGE. 1158 00:50:13,360 --> 00:50:15,880 WE SEE VERY RAPID CLEARANCE FOR 1159 00:50:15,880 --> 00:50:17,680 THE IGF ONE ALONE. 1160 00:50:17,680 --> 00:50:19,600 IF WE MEASURE IT, THE CLEARANCE 1161 00:50:19,600 --> 00:50:21,320 IS IN LESS THAN A DAY WE'VE LOST 1162 00:50:21,320 --> 00:50:22,640 ALMOST ALL OF IT. 1163 00:50:22,640 --> 00:50:26,440 WHEREAS THE HALF LIFE FOR OUR 1164 00:50:26,440 --> 00:50:30,480 IGF IS 4.2 DAYS. 1165 00:50:30,480 --> 00:50:35,720 WHEN WE LOOK AT THE TIME AT 1166 00:50:35,720 --> 00:50:37,200 THERAPEUTIC EFFICACY, PRE IGF 1167 00:50:37,200 --> 00:50:40,400 GIVES US A FEW DAVIS EFFICACY IN 1168 00:50:40,400 --> 00:50:42,520 TERMS OF THERAPEUTIC PRESENCE AS 1169 00:50:42,520 --> 00:50:45,640 OPPOSED TO 30 DAYS THAT WE CAN 1170 00:50:45,640 --> 00:50:50,400 SEE IN THE PANAM AND FINALLY, 1171 00:50:50,400 --> 00:50:52,840 HERE WE CAN SEE FROM BLUE 1172 00:50:52,840 --> 00:50:55,240 STAINING, HERE THAT WE HAVE 1173 00:50:55,240 --> 00:50:56,440 INJURY MODEL. 1174 00:50:56,440 --> 00:50:58,440 HERE WE'VE REMOVED OUR CAUSED 1175 00:50:58,440 --> 00:51:00,440 DAMAGE TO PART OF THE CARTILAGE, 1176 00:51:00,440 --> 00:51:03,360 AND WE LOOK AT THE RECOVERY OF 1177 00:51:03,360 --> 00:51:05,280 THIS DARK BLUE STAIN OVER TIME 1178 00:51:05,280 --> 00:51:08,160 WHEN WE INJECT WITH IGF-1 ALONE 1179 00:51:08,160 --> 00:51:09,840 WE CAN SEE THAT WE'RE NOT 1180 00:51:09,840 --> 00:51:17,360 GETTING AS MUCH REGENERATION 1181 00:51:17,360 --> 00:51:19,080 HOWEVER, WE CAN SEE SIGNIFICANT 1182 00:51:19,080 --> 00:51:19,960 REGENERATION OF THE CARTILAGE 1183 00:51:19,960 --> 00:51:25,120 AND IT LOOKS ALMOST LIKE THE 1184 00:51:25,120 --> 00:51:25,360 CONTROL. 1185 00:51:25,360 --> 00:51:26,880 NOW WE'RE LOOKING AT WAYS WHERE 1186 00:51:26,880 --> 00:51:29,920 WE CAN MAKE THESE SYSTEMS MORE 1187 00:51:29,920 --> 00:51:33,400 RESPONSIVE, BY HAVING THEM 1188 00:51:33,400 --> 00:51:35,640 RESPOND TO A VERY INFLAMMATORY 1189 00:51:35,640 --> 00:51:38,080 ENVIRONMENT USING MMP RESPONSIVE 1190 00:51:38,080 --> 00:51:41,080 SYSTEMS THAT MAKE THE SYSTEM 1191 00:51:41,080 --> 00:51:42,440 MORE CHARGED AND WE HAVE BEGUN 1192 00:51:42,440 --> 00:51:45,880 TO LOOK AT WAYS IN WHICH WE CAN 1193 00:51:45,880 --> 00:51:47,960 GENERATE THESEN TIME SENSITIVE 1194 00:51:47,960 --> 00:51:48,920 FORM LEASE WITH THE SAME LEVEL 1195 00:51:48,920 --> 00:51:51,400 OF CONTROL THAT WE WERE ABLE TO 1196 00:51:51,400 --> 00:51:53,520 GENERATE THE CHARGE PEG SYSTEMS. 1197 00:51:53,520 --> 00:51:56,680 SO I'LL STOP HERE AND I TALKED 1198 00:51:56,680 --> 00:51:58,360 ABOUT ELECTROSTATIC ASSEMBLY AND 1199 00:51:58,360 --> 00:52:02,520 HOW WE APPLY IT TO NANOMATERIALS 1200 00:52:02,520 --> 00:52:05,240 AND USE IT TO GET MULTI-DRUG 1201 00:52:05,240 --> 00:52:15,080 RELEASE TARGETED TISSUE 1202 00:52:15,080 --> 00:52:16,480 CAPABILITIES AND WE HAVE 1203 00:52:16,480 --> 00:52:18,360 TARGETING ELEMENTS TO OUR SYSTEM 1204 00:52:18,360 --> 00:52:20,280 HOW WE CAN CONTROL TRAFFICKING, 1205 00:52:20,280 --> 00:52:23,000 BOTH WITH NOT THE TISSUE AND 1206 00:52:23,000 --> 00:52:24,880 WITH THE CELL AND HOW WE CAN 1207 00:52:24,880 --> 00:52:27,680 LEVERAGE THIS TO TARGET 1208 00:52:27,680 --> 00:52:28,880 DIFFERENT CELL TYPES AND ADDRESS 1209 00:52:28,880 --> 00:52:30,520 DISEASE SO I'D LIKE TO 1210 00:52:30,520 --> 00:52:32,200 ACKNOWLEDGE THE STUDENTS AND 1211 00:52:32,200 --> 00:52:34,240 POSTDOCS WHO CONTRIBUTED TO THIS 1212 00:52:34,240 --> 00:52:36,080 WORK WHOSE NAMES ARE HERE BOTH 1213 00:52:36,080 --> 00:52:39,480 ON THE NANOPARTICLE SIDE AND THE 1214 00:52:39,480 --> 00:52:42,320 DENDRIMER SIDE FOR OUR AS TRIO 1215 00:52:42,320 --> 00:52:43,680 ARTHRITIS. 1216 00:52:43,680 --> 00:52:45,520 COLLABORATIONORS, FOR THESE 1217 00:52:45,520 --> 00:52:48,760 PROJECTS, DARYL IRVIN ANDAL 1218 00:52:48,760 --> 00:52:52,480 INAND THE FUNDING WHICH INCLUDES 1219 00:52:52,480 --> 00:52:56,280 NIH, NIBIB AND NIH-NCI WE HAVE 1220 00:52:56,280 --> 00:52:58,080 FUNDING FROM THE DLD AND IN 1221 00:52:58,080 --> 00:53:05,120 PARTICULAR FOR THE A OSTEO 1222 00:53:05,120 --> 00:53:06,560 ARTHRITIS AND WE FOCUS ON 1223 00:53:06,560 --> 00:53:08,080 OVARIAN CANCER AND I'D LIKE TO 1224 00:53:08,080 --> 00:53:09,040 WELCOME ANY QUESTIONS WITH THE 1225 00:53:09,040 --> 00:53:12,480 TIME WE HAVE LEFT. 1226 00:53:12,480 --> 00:53:16,320 THANK YOU. 1227 00:53:16,320 --> 00:53:17,720 >> THANK YOU, THERE ARE MORE 1228 00:53:17,720 --> 00:53:19,120 QUESTIONS COMING IN AND WE'LL 1229 00:53:19,120 --> 00:53:22,840 HAVE TIME TO GET TO WE CAN GIVE 1230 00:53:22,840 --> 00:53:25,680 A FEW. 1231 00:53:25,680 --> 00:53:29,880 SO, FOR THE HA INCORPORATING 1232 00:53:29,880 --> 00:53:32,520 PARTICLES, WHAT MOLECULAR WEIGHT 1233 00:53:32,520 --> 00:53:34,640 HA IS AT? 1234 00:53:34,640 --> 00:53:37,640 BECAUSE, YOU KNOW, DEPENDING ON 1235 00:53:37,640 --> 00:53:41,880 THE MOLECULAR WEIGHT, IT WAS 1236 00:53:41,880 --> 00:53:42,360 FIFTH DESIGN ELEMENT? 1237 00:53:42,360 --> 00:53:43,520 >> VERY GOOD QUESTION. 1238 00:53:43,520 --> 00:53:45,440 WHEN WE FIRST STARTED THIS WORK, 1239 00:53:45,440 --> 00:53:48,640 WE WERE WORKING WITH 1240 00:53:48,640 --> 00:53:50,320 INTERMEDIATE MOLECULAR WEIGHTS, 1241 00:53:50,320 --> 00:53:52,760 20 TO 50,000, THIS RANGE, AND 1242 00:53:52,760 --> 00:53:54,600 MORE RECENTLY, MY STUDENTS HAVE 1243 00:53:54,600 --> 00:53:58,040 BEGUN TO LOOK AT WHETHER WE CAN 1244 00:53:58,040 --> 00:54:00,440 SEE DIFFERENCES WITH MOLECULAR 1245 00:54:00,440 --> 00:54:02,680 WEIGHT WHEN WE ABSORB ON THE 1246 00:54:02,680 --> 00:54:05,800 NANOPARTICLE AND WE KNOW THAT WE 1247 00:54:05,800 --> 00:54:07,720 ARE ESSENTIALLY ENGAGING THE 1248 00:54:07,720 --> 00:54:09,960 CD-44 RECEPTOR AND IT'S NOT 1249 00:54:09,960 --> 00:54:11,840 CLEAR WHETHER THE MOLECULAR 1250 00:54:11,840 --> 00:54:13,400 WEIGHT IS GOING TO MAKE A 1251 00:54:13,400 --> 00:54:17,520 DIFFERENCE IN TERMS OF TLR 1252 00:54:17,520 --> 00:54:18,320 RECEPTORS AND UP WITH OF THE 1253 00:54:18,320 --> 00:54:19,560 THINGS THAT I SHOULD MENTION IS 1254 00:54:19,560 --> 00:54:23,680 THAT WHEN WE ABSORB THESE 1255 00:54:23,680 --> 00:54:27,400 POLYMER CHAINS, THEY'RE 1256 00:54:27,400 --> 00:54:29,320 EXHIBITING TAIL-LIKE BEHAVIOR SO 1257 00:54:29,320 --> 00:54:32,720 IT'S AS IF WE HAVE FRAGMENTS 1258 00:54:32,720 --> 00:54:36,000 WAVING ABOUT AS OPPOSED TO 1259 00:54:36,000 --> 00:54:37,600 HAVING LONG CHAINS THAT ARE 1260 00:54:37,600 --> 00:54:38,200 TETHERED AT ONE END. 1261 00:54:38,200 --> 00:54:43,320 >> IT'S VERY INTERESTING. 1262 00:54:43,320 --> 00:54:45,720 >> THINK OF A INCH WORM ON A 1263 00:54:45,720 --> 00:54:54,560 SURFACE AS OPPOSED TO A SINGLE 1264 00:54:54,560 --> 00:54:54,800 TEETHER. 1265 00:54:54,800 --> 00:54:59,880 >> WAS THERE INTERNALIZED BY A 1266 00:54:59,880 --> 00:55:01,720 CELL WHAT HAPPENS TO THEM NEXT. 1267 00:55:01,720 --> 00:55:03,640 HO HOW ARE THEY DEGRADED AND HOW 1268 00:55:03,640 --> 00:55:07,120 DOES THAT FACTOR INTO YOUR 1269 00:55:07,120 --> 00:55:07,360 DESIGN? 1270 00:55:07,360 --> 00:55:08,680 >> GREAT QUESTION. 1271 00:55:08,680 --> 00:55:14,200 WHEN WE WORK WITH HYPO ZOMAL 1272 00:55:14,200 --> 00:55:17,800 CHARACTERS, WE HAVE THE CONTENT 1273 00:55:17,800 --> 00:55:23,000 OF THE CELL THAT UNDERGOES IT'S 1274 00:55:23,000 --> 00:55:25,600 OWN SORT OF TRACKING AND WE HAVE 1275 00:55:25,600 --> 00:55:28,680 THESE POLYMERS WHICH TEND TO BE 1276 00:55:28,680 --> 00:55:32,280 POLY STEP SIDES SO WE THINK THEY 1277 00:55:32,280 --> 00:55:34,200 UNDERGO A MORE TYPICAL CLEAR NOT 1278 00:55:34,200 --> 00:55:38,680 AND EARLY ON, WE DID STUDIES AND 1279 00:55:38,680 --> 00:55:41,320 WE CAN SEE SOME OF THESE 1280 00:55:41,320 --> 00:55:44,240 POLYMERS EXCRETED WITH POLY L 1281 00:55:44,240 --> 00:55:46,440 LICING AND POLY L. 1282 00:55:46,440 --> 00:55:52,440 WITH THE POLY L GLUTAMIC 1283 00:55:52,440 --> 00:55:54,200 STUDIES, WE EXPECT SIMILAR 1284 00:55:54,200 --> 00:55:57,200 RESULTS AND THE LGA DOES 1285 00:55:57,200 --> 00:56:02,160 BREAKDOWN SO WHEN WE USE THE 1286 00:56:02,160 --> 00:56:06,320 PLGA CORE, WE KNOW THAT ALSO 1287 00:56:06,320 --> 00:56:09,480 BREAKS DOWN AND OWN FAIRLY 1288 00:56:09,480 --> 00:56:10,120 REASONABLE BLEE SHORT TIMEFRAMES 1289 00:56:10,120 --> 00:56:11,600 BECAUSE IN NANOPARTICLE FORM, 1290 00:56:11,600 --> 00:56:13,400 THEY BREAKDOWN MUCH MORE RAPIDLY 1291 00:56:13,400 --> 00:56:14,840 THAN THEY WOULD IF THEY WERE IN 1292 00:56:14,840 --> 00:56:19,760 A MACRO SCOPIC FORM. 1293 00:56:19,760 --> 00:56:21,120 >> GREAT. 1294 00:56:21,120 --> 00:56:25,560 >> AND SO, ARE YOU FAMILIAR WITH 1295 00:56:25,560 --> 00:56:27,720 A PAPER THAT CAME OUT ONE OR TWO 1296 00:56:27,720 --> 00:56:29,360 YEARS GO ABOUT A DORE THRESHOLD 1297 00:56:29,360 --> 00:56:39,080 OF NANOPARTICLE DELIVERY AND 1298 00:56:39,080 --> 00:56:42,240 IT'S OVER DELIVER IS THE DOSE OF 1299 00:56:42,240 --> 00:56:42,880 NANOPARTICLES SOMETHING THAT YOU 1300 00:56:42,880 --> 00:56:46,040 CONSIDER YOUR SYSTEMIC DELIVERY 1301 00:56:46,040 --> 00:56:47,080 AND DO YOU OBSERVE THAT 1302 00:56:47,080 --> 00:56:48,040 PHENOMENON? 1303 00:56:48,040 --> 00:56:51,120 >> I REMEMBER HEARING ABOUT THAT 1304 00:56:51,120 --> 00:56:52,920 WORK AND I INTEND TO TAKE A 1305 00:56:52,920 --> 00:56:54,440 DEEPER DIVE INTO IT. 1306 00:56:54,440 --> 00:56:59,080 WE HAVE NOT THOUGHT ABOUT 1307 00:56:59,080 --> 00:56:59,320 FLOODING. 1308 00:56:59,320 --> 00:57:02,000 YOU CAN FLOOD THE SYSTEM WITH 1309 00:57:02,000 --> 00:57:09,080 NANOPARTICLES AND INTRODUCE THE 1310 00:57:09,080 --> 00:57:10,840 TRULY THEY ARE. 1311 00:57:10,840 --> 00:57:13,000 WHEN WE WORK WITH THE MODELS WE 1312 00:57:13,000 --> 00:57:15,480 WORK WITH, WE'RE REALLY WORKING 1313 00:57:15,480 --> 00:57:18,440 TO GET HIGH DOSE OF OUR 1314 00:57:18,440 --> 00:57:19,760 NANOPARTICLE IN AND SOMETIMES 1315 00:57:19,760 --> 00:57:24,640 EVEN THE NUMBER OF INJECTIONS 1316 00:57:24,640 --> 00:57:26,480 CAN CONSTRAIN HOW WE SET UP OUR 1317 00:57:26,480 --> 00:57:27,080 EXPERIMENT. 1318 00:57:27,080 --> 00:57:30,200 SO, WE HAVEN'T TRIED THAT AND IT 1319 00:57:30,200 --> 00:57:34,040 WOULD PROBABLY REQUIRED SOME 1320 00:57:34,040 --> 00:57:41,160 WORK WITH OUR CURRENT ANIMAL 1321 00:57:41,160 --> 00:57:54,840 INFORMED IT WOULD BE I. I'M MUCH 1322 00:57:54,840 --> 00:57:59,240 IS THEY STICK TO THE TUMOR THEN 1323 00:57:59,240 --> 00:58:00,440 LET'S SAY TRYING TO TRICK 1324 00:58:00,440 --> 00:58:02,080 SYSTEMIC DELIVERY INTO HELPING 1325 00:58:02,080 --> 00:58:08,040 US ALTHOUGH, I'M DEFINITELY 1326 00:58:08,040 --> 00:58:08,640 READY TO TRY TRICKS THAT WORK. 1327 00:58:08,640 --> 00:58:10,680 >> IT'S TO GET THEM TO 1328 00:58:10,680 --> 00:58:11,160 ACCUMULATE, RIGHT? 1329 00:58:11,160 --> 00:58:12,440 >> ABSOLUTELY. 1330 00:58:12,440 --> 00:58:12,720 ABSOLUTELY. 1331 00:58:12,720 --> 00:58:15,960 AND I THINK IF YOU ARE ARE 1332 00:58:15,960 --> 00:58:17,440 WORKING WITH SYSTEMS THAT ARE 1333 00:58:17,440 --> 00:58:20,680 POTENT ENOUGH AND SYSTEMIC 1334 00:58:20,680 --> 00:58:21,960 INJECTIONS 8% INJECTED DOSE IS 1335 00:58:21,960 --> 00:58:23,680 GOING TO GET YOU THERE AND YOU 1336 00:58:23,680 --> 00:58:25,640 DON'T HAVE ANY SIDE EFFECTS 1337 00:58:25,640 --> 00:58:27,720 THEN, YOU ARE ALREADY IN A SWEET 1338 00:58:27,720 --> 00:58:29,280 SPOT COMPARED TO PRE DRUG. 1339 00:58:29,280 --> 00:58:30,960 >> GREAT. 1340 00:58:30,960 --> 00:58:32,760 WELL, THAT IS ABOUT TIME. 1341 00:58:32,760 --> 00:58:35,880 THANK YOU AGAIN FOR YOUR TALK. 1342 00:58:35,880 --> 00:58:38,280 I REALLY ENJOYED IT AND I KNOW A 1343 00:58:38,280 --> 00:58:42,400 LOT OF FOLKS HERE ENJOYED IT AS 1344 00:58:42,400 --> 00:58:45,840 WELL AND THANK YOU AGAIN AND IT 1345 00:58:45,840 --> 00:58:48,440 WAS GREAT HAVING YOU TODAY. 1346 00:58:48,440 --> 00:58:50,880 IT WAS GREAT TO HAVE A CHANCE TO 1347 00:58:50,880 --> 00:58:51,080 PRESENT. 1348 00:58:51,080 --> 00:58:52,680 THANK YOU, EVERYONE, VERY MUCH 1349 00:58:52,680 --> 00:58:55,560 AND I HOPE TO MEET YOU IN THE 1350 00:58:55,560 --> 00:58:55,800 FUTURE. 1351 00:58:55,800 --> 00:58:57,200 >> OF COURSE. 1352 00:58:57,200 --> 00:58:58,880 >> AND EVERYONE ELSE IN THE 1353 00:58:58,880 --> 00:59:00,640 BIOMEDICAL ENGINEERING SIG, 1354 00:59:00,640 --> 00:59:01,800 WE MEET AGAIN NEXT MONTH AND 1355 00:59:01,800 --> 00:59:03,840 WE'LL SEE YOU ALL THEN. 1356 00:59:03,840 --> 00:59:04,440 THANK YOU. 1357 00:59:04,440 --> 01:01:07,200 >> BYE-BYE.