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[ C  .C,$@# 02 \  Z d @ S" `?< !2 ]  3 r vd @?8 <P " `2 ^   f vd @?8 <P " `Dm2 _   f vd @?8 <P " `D9 ` s DA Cytochrome-C"`Ux,$@$ 0 a s DA Cytochrome-C"`[~,$@% 0 b s DA Cytochrome-C"`,$@& 0$2 c s Rv @?"6@ `NNN?Nq,$@' 0 d s DA Cytochrome-C"`[<~,$@( 0 e s DA Cytochrome-C"`6,$@) 0 f s DA Cytochrome-C"`,$@* 0$2 g s Rv @?"6@ `NNN?NS{,$@+ 0$2 h s Rv @?"6@ `NNN?N,$@, 0B i Z`f(D?"0@NNN?N;,$@- 0B j Z`f(D?"0@NNN?N,$@. 0B k Z`f(D?"0@NNN?N$(=,$@/ 0B l Z`f(D?"0@NNN?N,$@0 02 m # lvd @?"6@ `NNN?N,$@1 02 n # lvd @?"6@ `NNN?N &=#,$@2 02 o # lvd @?"6@ `NNN?N,$@3 02 p # lvd @?"6@ `NNN?N"9,$D4 08 P|  P|  r  TA ?"6@ NNN?N l@ @Mammalian cell s  s 0e0e    BCvDE4F A@  A5% 8c8c     ?1 d0u0@Ty2 NP'p<'pA)BCD|E|| en[7\R|c\v @    s " 0e@  `     @ABC DEEFGHIJK5%LMNOPQRSTUWYZ[ \]^_ `abN E5%  N E5%  N F   5%    !"?N@ABC DEFFGHIJK5%LMNOPQRSTUWYZ[ \]^_ `ab %  t  TA ?"6@ NNN?NPPp V$Mesoporous Silica Nanoparticle (MSN)%% u B  0e0e    BCvDE4F @  5% 8c8c     ?1 d0u0@Ty2 NP'p<'pA)BCD|E|| en[7\R|c\v @    s " 0e@  `     @ABC DEFGHIJK5%LMNOPQRSTUWYZ[ \]^_ `abN 5%  N 5%  N    5%    !"?N@ABC DEFGHIJK5%LMNOPQRSTUWYZ[ \]^_ `ab @  |   |@ D ,  D ,H v  TA ?"6@ NNN?N ,  ~NSurface functional group for recognition or control of cellular uptake of MSN.OO? w  T A ?"6@ NNN?N  uERemovable cap to enable control over the release of loaded molecules.FFK x  TxA ?"6@ NNN?N` dG  /Drug or biomolecule to be delivered by the MSN.00 @ D@   ~ D@  B y  ZDo?"0@NNN?ND 4 2 z  S ~+)i\d @?"6@ NNN?N%@  2 |  c Rv @?"6@ `NNN?N| }  c >A Cytochrome-C"` G t   TA ?"6@ NNN?N0| XClick the slide to observe an animation describing the drug/biomolecule delivery by MSN.YY<  l f   f ,$@ 0   TA ?"6@ NNN?Nf    During the formation of the endosome (vesicle containing the up taken MSN) a layer of protein (clathrin) forms around it. Click to continue.,<&   Tl"A ?"6@ NNN?N4  REndosome     c j0e0e    BCPDE(F A@  A5% 8c8c     ?1 d0u0@Ty2 NP'p<'pA)BCD|E|| h44hP0P @   s " 0e@  `     @ABC DEEFGHIJK5%LMNOPQRSTUWYZ[ \]^_ `abN E5%  N E5%  N F   5%    !"?N@ABC DEFFGHIJK5%LMNOPQRSTUWYZ[ \]^_ `ab  T0&A ?"6@ NNN?N ,$ 0 The MSN is endocytosed by the cell with an efficiency that is dependent on the surface charge and the nature of the functional groups in their surface. Click to continue.   T*A ?"6@ NNN?N (,$ 0 Later on, probably because of the buffering capacity of its silanol groups, the MSN is able to escape from the endosome. Click to continue.o  T2A ?"6@ NNN?NW  ,$6 0 Finally, a specific stimulus, which depends on the chemistry employed in the design of the composite, triggers the removal of the caps and the pre-loaded drugs or biomolecules are able to diffuse into the cytoplasm.H  0޽h ? 33___PPT10f.Pг+qD"' = @B D' = @BA?%,( < +O%,( < +DX' =%(D' =%(D' =4@BBBB%(D' =1:Bhidden*o3>+B#style.visibility<* %(D' =%(D8' =A@BB BB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =-g6B fade*<3<* D' =4@BBBB%()?)?D' =.7 BBBBBM 1.66667E-6 -1.85185E-6 C 0.0033 0.01296 0.00382 0.00949 0.01562 0.01111 C 0.02812 0.01019 0.03628 0.0088 0.04792 0.00695 C 0.05399 0.00417 0.05955 0.00671 0.06458 0.01111 C 0.06927 0.03009 0.06042 0.03033 0.05 0.03195 C 0.04219 0.03542 0.05191 0.03079 0.04375 0.03611 C 0.03993 0.03866 0.03524 0.03889 0.03125 0.04028 C 0.02917 0.04213 0.02708 0.04398 0.025 0.04584 C 0.02361 0.04722 0.02535 0.05046 0.02604 0.05278 C 0.02795 0.05949 0.03403 0.05972 0.03854 0.06111 C 0.04861 0.06991 0.03854 0.05949 0.04271 0.09445 C 0.04305 0.09722 0.0493 0.10394 0.05104 0.10556 C 0.05364 0.11088 0.05816 0.11204 0.06111 0.11597 *3>*B ppt_xB ppt_y=V0BBfffffffffffffpBB؂ =B{ m=<*D' =4@BBBB%()?)?D' =.7 BBBBBM 3.33333E-6 1.11111E-6 C 0.02205 -0.00741 0.04531 -0.00139 0.06771 1.11111E-6 C 0.06892 0.00463 0.07066 0.00787 0.07187 0.0125 C 0.07222 0.0162 0.0717 0.02014 0.07291 0.02361 C 0.07343 0.025 0.075 0.0243 0.07604 0.025 C 0.08021 0.02778 0.08402 0.03125 0.08854 0.03333 C 0.09392 0.04398 0.0842 0.05949 0.09375 0.06805 C 0.09652 0.07917 0.10642 0.08333 0.11666 0.08333 *3>*B ppt_xB ppt_y=L0BBffffffffpBBn=B =<*D2' =%(D$%' =%(D6' =A@BB BB0B%(D' =-g6B fade*<3<* D' =1:Bhidden*o3>+B#style.visibility<* %(D+' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =-g6B fade*<3<* D+' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<*'%(D' =-g6B fade*<3<*'D+' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<*(%(D' =-g6B fade*<3<*(D+' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<*,%(D' =-g6B fade*<3<*,D+' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<*0%(D' =-g6B fade*<3<*0D+' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<*8%(D' =-g6B fade*<3<*8D$' =4@BBBB%()?)?Dx' =.@7 BBBBBuM -2.22222E-6 0.0 C -0.00156 -0.00602 -0.00399 -0.01065 -0.00556 -0.01667 C -0.00451 -0.02315 -0.00434 -0.03426 -2.22222E-6 -0.03889 C 0.0026 -0.04167 0.00972 -0.03912 0.00972 -0.04444 *3>*B ppt_xB ppt_y=0BB fffA<*'DL' =4@BBBB%()?)?D' =.h7 BBBBBM 3.33333E-6 -1.85185E-6 C -0.00539 -0.02176 -0.01598 -0.00648 -0.025 -0.01852 *3>*B ppt_xB ppt_y=0BBfA<*0D' =4@BBBB%()?)?Db' =.*7 BBBBBQM 1.11111E-6 3.7037E-6 C 0.00191 -0.00996 0.00278 -0.01204 0.00972 -0.01667 C 0.01337 -0.02408 0.0158 -0.02385 0.02222 -0.02593 C 0.02274 -0.02778 0.02361 -0.02963 0.02361 -0.03148 C 0.02361 -0.03542 0.02153 -0.04051 0.02083 -0.04445 C 0.02014 -0.04815 0.02066 -0.05209 0.01944 -0.05556 C 0.01875 -0.05764 0.01667 -0.0581 0.01528 -0.05926 C 0.01441 -0.06111 0.01319 -0.06273 0.0125 -0.06482 C 0.0118 -0.06667 0.01215 -0.06898 0.01111 -0.07037 C 0.00868 -0.07361 0.00555 -0.07523 0.00278 -0.07778 C 0.00156 -0.07894 -0.00139 -0.07963 -0.00139 -0.07963 *3>*B ppt_xB ppt_y=+0BBffffffffffA<*,D' =4@BBBB%()?)?D' =.7 BBBBBM 3.33333E-6 -2.22222E-6 C -0.00087 -0.00416 -0.00504 -0.01551 -0.00695 -0.01759 C -0.00903 -0.01991 -0.01198 -0.01944 -0.01389 -0.02153 C -0.01511 -0.02291 -0.01632 -0.0243 -0.01736 -0.02546 C -0.01823 -0.0294 -0.0191 -0.03333 -0.01979 -0.03727 C -0.02014 -0.03912 -0.02084 -0.04305 -0.02084 -0.04282 C -0.01997 -0.05347 -0.0191 -0.06273 -0.01632 -0.07222 *3>*B ppt_xB ppt_y=J0BBffffffApBB*B?<*8D' =4@BBBB%()?)?Di' =.17 BBBBB7M -2.22222E-6 -2.22222E-6 C -0.00521 -0.01157 -0.01354 -0.01088 -0.02222 -0.01227 C -0.02708 -0.01713 -0.03368 -0.02662 -0.03611 -0.03472 C -0.03732 -0.03842 -0.03889 -0.04676 -0.03889 -0.04653 C -0.03837 -0.05162 -0.03889 -0.05671 -0.0375 -0.06111 C -0.0368 -0.06319 -0.03455 -0.0618 -0.03333 -0.06319 C -0.03333 -0.06296 -0.02569 -0.07268 -0.025 -0.07338 C -0.02344 -0.08241 -0.025 -0.0794 -0.02222 -0.08333 *3>*B ppt_xB ppt_y=L0BBfffffffApBBIB*<*(Dx ' =%(D)' =4@BB BB%(D' =-g6B fade*<3<*'D' =1:Bhidden*o3>+B#style.visibility<*'%(D)' =4@BB BB%(D' =-g6B fade*<3<*(D' =1:Bhidden*o3>+B#style.visibility<*(%(D)' =4@BB BB%(D' =-g6B fade*<3<*,D' =1:Bhidden*o3>+B#style.visibility<*,%(D)' =4@BB BB%(D' =-g6B fade*<3<*0D' =1:Bhidden*o3>+B#style.visibility<*0%(D)' =4@BB BB%(D' =-g6B fade*<3<*8D' =1:Bhidden*o3>+B#style.visibility<*8%(D+' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =-g6B fade*<3<*DN' =%(D' =%(D)' =4@BB BB%(D' =-g6B fade*<3<* D' =1:Bhidden*o3>+B#style.visibility<* %(D' =%(D8' =A@BB BB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =-g6B fade*<3<* D' =%(D ' =4@BBBB%()?)?D^' =.&7 BBBBBGM 7.77778E-6 -1.85185E-6 C 0.00122 0.00232 0.00209 0.00324 0.00417 0.00417 C 0.00365 0.01181 0.00487 0.01273 0.00053 0.01459 C -0.00086 0.01736 -0.00312 0.01968 -0.0052 0.02153 C -0.00607 0.025 -0.00833 0.02523 -0.01041 0.02709 C -0.0111 0.02847 -0.01249 0.02894 -0.01301 0.03056 C -0.01371 0.03264 -0.01406 0.0375 -0.01406 0.0375 C -0.01336 0.04584 -0.01406 0.04213 -0.01249 0.04861 C -0.01215 0.05 -0.00208 0.05209 -0.00156 0.05209 C 0.00035 0.05371 0.00018 0.05533 0.00209 0.05695 C 0.00365 0.06297 0.00087 0.0544 0.00886 0.05972 C 0.0099 0.06042 0.0099 0.06389 0.0099 0.06389 C 0.0106 0.07408 0.0106 0.07384 0.01772 0.075 C 0.01997 0.07593 0.01876 0.0757 0.02136 0.0757 *3>*B ppt_xB ppt_y=10BBfffffffffffffA<*DC' =4@BBBB%()?)?D' =._7 BBBBB]M 0.06094 0.11482 C 0.06163 0.11482 0.06198 0.12199 0.0625 0.12246 C 0.06319 0.12338 0.05607 0.12847 0.05607 0.12871 C 0.05503 0.13634 0.0526 0.1382 0.04635 0.13982 C 0.04462 0.14121 0.04566 0.14861 0.04375 0.14931 C 0.04253 0.1507 0.04462 0.15486 0.04462 0.15509 C 0.04774 0.16134 0.04045 0.15996 0.04687 0.16111 C 0.04982 0.16366 0.05295 0.16296 0.05625 0.16412 C 0.0625 0.17014 0.05399 0.16968 0.0625 0.17037 C 0.06667 0.175 0.06562 0.16713 0.06823 0.18079 C 0.0684 0.18148 0.0691 0.18658 0.07135 0.18681 C 0.07257 0.18704 0.07864 0.1875 0.07864 0.18773 *3>*B ppt_xB ppt_y=T0BBffffffffffffpBBa B=<*D' =4@BBBB%()?)?DE' =. 7 BBBBB M 0.11649 0.08449 C 0.12187 0.08565 0.12118 0.08912 0.11753 0.09491 C 0.11371 0.10116 0.10729 0.10532 0.10243 0.10949 C 0.10208 0.11389 0.10225 0.11505 0.10052 0.11852 C 0.10069 0.12199 0.10243 0.12708 0.10295 0.13055 C 0.10312 0.13148 0.11215 0.13241 0.11406 0.13333 C 0.11475 0.13611 0.11614 0.13634 0.11718 0.13889 C 0.11736 0.13958 0.12014 0.13981 0.12066 0.14005 C 0.12291 0.14097 0.12222 0.14143 0.12448 0.14167 C 0.12673 0.14606 0.12378 0.15486 0.12951 0.15532 C 0.13177 0.15555 0.1342 0.15764 0.13646 0.15764 *3>*B ppt_xB ppt_y=R0BBfffffffffffpBBO:B=<*D' =%(pD)' =4@BB BB%(D' =-g6B fade*<3<*D' =1:Bhidden*o3>+B#style.visibility<*%(D)' =4@BB BB%(D' =-g6B fade*<3<*D' =1:Bhidden*o3>+B#style.visibility<*%(D0' =%(@D)' =4@BB BB%(D' =-g6B fade*<3<*D' =1:Bhidden*o3>+B#style.visibility<*%(D+' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<*X %(D' =-g6B fade*<3<*X D+' =4@BB BB%(D' 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=1:Bvisible*o3>+B#style.visibility<*j %(D' =-g6B fade*<3<*j D+' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<*k %(D' =-g6B fade*<3<*k D+' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<*l %(D' =-g6B fade*<3<*l D+' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<*m %(D' =-g6B fade*<3<*m D+' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<*n %(D' =-g6B fade*<3<*n D+' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<*o %(D' =-g6B fade*<3<*o D+' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<*p %(D' =-g6B fade*<3<*p DR' =%(D' =%(D6' =A@BB BB0B%(D' =-g6B fade*<3<* D' =1:Bhidden*o3>+B#style.visibility<* %(D8' =A@BB BB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =-g6B fade*<3<* D' =%(D' =4@BBBB%()?)?D7' =.7 BBBBBM -0.00035 -0.00116 C -0.00348 -0.00047 -0.00695 2.59259E-6 -0.00973 -0.00255 C -0.01146 -0.00949 -0.01615 -0.01551 -0.02188 -0.01551 *3>*B ppt_xB ppt_y=B0BB ffApBB[0Bjۻ<*g D' =4@BBBB%()?)?D' =.7 BBBBBM 3.88889E-6 4.44444E-6 C 0.00521 -0.00047 0.00521 -0.00023 0.00903 -0.00278 C 0.01059 -0.00255 0.01215 -0.00278 0.01354 -0.00232 C 0.01597 -0.00139 0.01372 0.00416 0.01424 0.0074 C 0.01441 0.00833 0.01684 0.00879 0.01701 0.00879 C 0.01927 0.01342 0.01615 0.00671 0.01806 0.0199 C 0.0184 0.02291 0.02014 0.02291 0.02014 0.02639 C 0.02031 0.03032 0.02014 0.03403 0.02014 0.03796 *3>*B ppt_xB ppt_y=%0BBfffffffA<*X D ' =%(D' =4@BBBB%()?)?D' =.7 BBBBBM 1.66667E-6 6.66667E-6 C -0.00121 -0.00046 -0.00225 -0.00092 -0.00347 -0.00138 C -0.01215 -0.00069 -0.01128 0.00047 -0.01771 0.00602 C -0.01944 0.0095 -0.02066 0.01366 -0.02291 0.01667 C -0.02361 0.01968 -0.02534 0.02176 -0.02777 0.02176 *3>*B ppt_xB ppt_y=0BB ffffA<*c D' =4@BBBB%()?)?Db' =.*7 BBBBBUM 1.11111E-6 -3.33333E-6 C 0.0026 0.00024 0.00451 0.00116 0.00694 0.00186 C 0.0066 0.00811 0.00642 0.01181 0.00313 0.01621 C 0.00156 0.01829 0.00243 0.01713 0.00069 0.02037 C 0.00035 0.0213 1.11111E-6 0.02315 1.11111E-6 0.02315 C 0.00087 0.03125 0.00122 0.0301 0.00556 0.0338 C 0.00677 0.03866 0.00486 0.04306 0.00417 0.04769 C 0.00451 0.05278 0.00469 0.05579 0.00868 0.05695 C 0.00955 0.0588 0.00938 0.05787 0.00938 0.05973 *3>*B ppt_xB ppt_y='0BBffffffffA<*Y D^ ' =%(pD' =4@BBBB%()?)?DJ' =.7 BBBBBCM 1.66667E-6 -5.18519E-6 C -0.00226 0.00092 -0.00451 0.00185 -0.00694 0.00231 C -0.01076 0.00972 -0.00642 0.00023 -0.00868 0.00833 C -0.0092 0.01041 -0.01059 0.0118 -0.01111 0.01388 C -0.01128 0.02152 -0.01146 0.02939 -0.01181 0.03703 C -0.01181 0.03865 -0.01528 0.04212 -0.01667 0.04212 *3>*B ppt_xB ppt_y=!0BBfffffA<*h D' =4@BBBB%()?)?D\' =.$7 BBBBBKM 6.66667E-6 -4.44444E-6 C 0.00261 -0.00162 0.00521 -0.00347 0.00799 -0.00462 C 0.00851 -0.00879 0.00851 -0.00833 0.01146 -0.00972 C 0.01251 -0.01018 0.01459 -0.01111 0.01459 -0.01111 C 0.01528 -0.01388 0.01546 -0.01643 0.01633 -0.01898 C 0.01667 -0.0199 0.01702 -0.02175 0.01702 -0.02175 C 0.01685 -0.02337 0.01719 -0.025 0.01667 -0.02638 C 0.01633 -0.02754 0.01459 -0.02916 0.01459 -0.02916 C 0.01407 -0.03148 0.01303 -0.03217 0.01251 -0.03472 C 0.01268 -0.0368 0.01251 -0.03912 0.01285 -0.0412 C 0.01442 -0.0493 0.01424 -0.04143 0.01424 -0.0449 *3>*B ppt_xB ppt_y=+0BBffffffffffA<*Z D2' =%(@Dh' =4@BBBB%()?)?D' =.7 BBBBBM 5.E-6 -5.92593E-6 C -0.00035 -0.0014 -0.00052 -0.00255 -0.00157 -0.0014 C -0.00209 -0.00024 -0.00226 0.00069 -0.00313 0.00138 C -0.004 0.00092 -0.00556 -0.0007 -0.00556 -0.0007 C -0.00643 -0.00279 -0.00799 -0.00024 -0.0092 0.00069 C -0.01094 0.00022 -0.01077 -0.00024 -0.01198 -0.0014 C -0.01389 -0.00117 -0.01476 -0.00092 -0.0165 -0.00047 C -0.01719 -5.92593E-6 -0.01806 0.00022 -0.01875 0.00069 C -0.02084 -5.92593E-6 -0.02101 -0.00117 -0.02223 -0.00348 C -0.02257 -0.00603 -0.02379 -0.0051 -0.02535 -0.00464 C -0.02639 -0.00394 -0.02743 -0.00348 -0.02848 -0.00325 C -0.02865 -0.00302 -0.029 -0.00255 -0.02917 -0.00279 C -0.02969 -0.00302 -0.02969 -0.00441 -0.03021 -0.00487 C -0.03091 -0.00556 -0.03195 -0.00626 -0.03264 -0.00695 C -0.03351 -0.00834 -0.03455 -0.00996 -0.03577 -0.01089 C -0.03594 -0.01112 -0.03629 -0.01181 -0.03629 -0.01181 *3>*B ppt_xB ppt_y=50BB#fffffffffffffffA<*` Dj ' =4@BBBB%()?)?D' =.7 BBBBBM -3.33333E-6 2.96296E-6 C 0.00139 -0.00023 0.00139 -0.0007 0.00191 -0.00232 C 0.0033 -0.00208 0.00382 -0.00232 0.00451 -0.0007 C 0.00486 0.00162 0.00625 0.00023 0.00764 -0.00023 C 0.00868 -0.00116 0.00955 -0.00139 0.01076 -0.00162 C 0.0125 -0.00162 0.01424 -0.00185 0.01597 -0.00139 C 0.01788 -0.00093 0.01337 0.00833 0.01927 0.00903 C 0.02101 0.00995 0.02274 0.00949 0.02448 0.01018 C 0.02535 0.01088 0.02691 0.0125 0.02691 0.0125 C 0.02743 0.01389 0.02813 0.01505 0.02847 0.01643 C 0.02882 0.01898 0.0283 0.0213 0.02761 0.02361 C 0.02726 0.02592 0.02622 0.02824 0.02535 0.03032 C 0.025 0.03148 0.02448 0.0338 0.02448 0.0338 C 0.02431 0.0368 0.02292 0.03912 0.02188 0.04167 C 0.02136 0.04491 0.02083 0.04745 0.02326 0.0493 C 0.025 0.05255 0.02691 0.05463 0.02917 0.05694 C 0.02986 0.0588 0.03177 0.06227 0.03177 0.06227 C 0.03247 0.06597 0.03264 0.07083 0.03004 0.07338 C 0.02969 0.07523 0.02969 0.07592 0.02865 0.07755 C 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