1、Delivery of nanomedicines to extracellular and intracellular compartments of a solid tumor,胥洪鵑 2011-7-11,Key words,drug delivery interstitial transport intracellular trafficking endosomal escape endocytosis nanoparticles （NP),Introduction,1.NP offer a suitable means for deliverying diagnostic,imagin

2、g or therapeutic agents. 2.The utility of NP depends on their ability to reach their sites of action 3.The potential target sites include tumor vasculature, tuomr interstitium, cell membrane,and intracellular compartments. 4.Delivery of NP from the injection site to various target sites within a sol

3、id tumor involves multiple kinetic steps.,Delivery of nanoparticles to organ level,Barries to gene transfer,2 Delivery of NP to a solid tumors,NP are distributed to different organs/elimination/removed by the cells The delivery of NP to a solid tumor is determined by physiological factors and the ph

4、ysico-chemical properties of NP,2.1 Distribution and retention of NP in tumors after systemic delivery,In a solid tumor, NP leave the intravascular space within a vessel to enter the interstitium. Diffusion is driven by concentration gradients Transvascular fluid transport is driven by pressure grad

5、ients,2.1.1 Tumor blood flow and blood vasculature,Blood flow within a tissue is determined by the arteriole-venule (A-V) pressure difference and flow resistance. Blood vessel distribution within a tumor depends on the tumor size and the locations within a tumor. Tumor blood vessels are generally le

6、aky due to discontinuity of the endothelium.,A solid tumor comprises three regions: a: avascular-necrotic region with no vasculature b:semi-necrotic region containing capillares c:stably perfused region containg many venous vessels and few arterolar vessels These intratumoral vasculature heterogenei

7、ties contribute to uneven drug distribution,Tumor vs normal tissues,1.tumor blood vessels are generally more heterogeneous in distribution, density, length and diameter, and are larger in size and more permeable. 2.the average blood flow in tumors is lower than in normal tissues 3.tumor vessels are

8、more leaky with pore sizes exceeding 100 nm 4.lack of functional lymphatic drainage in tumors,2.3 Experimental approaches and NP formulation designs,1.Passive targeting via EPR effect:effect of particle size EPR is predominant for compands with molecular weights larger than 40 KD EPR is affected by

9、the tumor size with a greater EPR in smaller tumors The vessel pore size in a majority of experimental tumors ranges grom 380 nm to 780 nm,2.3.2 Surface modification of NP to confer stealth property,Surface modification has been used to minimize RES entrapment and to increase the blood circulation t

10、ime The degree of pegylation affects the stealth properties of NP. Pegylation decreases the transport of NP in tumor interstitium and decrease the cellular internalization,2.3.3 Targeting the acidic microenvionment in tumor matrix,Solid tumors, in part, due to the high glycolysis, usually shows acid

11、ic pH pH gradient affects the ionization and intratumoral distribution and cellular uptake of ionizable drugs in a tumor. NP comprising pH-sensitive polymers are target the tumor extracellular matrix or to promote the release of their contents,2.3.4 Targeting tumor vasculature by electrostatic inter

12、action,The luminal endothelial membrane in vessel is negatively charged and therefore can be targed by cationic NP through electrostatic interactions. However, because the negative charge on luminal endothelial membrane is also found in normal tissues, this made of targeting is quantiative rather th

13、an qualitative Greater tumor selectivity is achieved by conjugating NP with tumor endothelium specific ligands.,3.Interstitial transport(sub-organ level),After entering a tumor via blood circulation, a molecule is transported across the interstitial space to reach individual tumor cells The transpor

14、t processes for small molecules released from NP is by difussion and convection, and NP relies more on convection. Barriers to NP transport in tumor interstitium, and the experimental approaches to overcome such baarriers are as follows,3.1 barriers to convective transvascular and interstitial tranp

15、ort,The high IFP and the lack of a functional lymphatic system reduces the fluid flow and convection transport. Agents are used to lower tumor IFP Reduce the density of tumor cell IFP: interstitial fluid pressure,3.2 Extracellular matrix(ECM),The fibrous proteins and polysaccharides are the barriers

16、 to transport. Enzymes that degrade tumor ECM materials promote intra-tumoral dispersion of NP. Binding barrier,4.NP cellular and subcellular compartments targeting,Trantport of NP in a cell involves several processes: (1) attachment of NP to cell membrane through binding to non-specific or non spec

17、ific binding sites (2) internalization of NP through endocytosis (3) entrapment of NP in endosomes,caveosomes or macropinosomes (4)release of NP from these structures (5)NP transport in cytosol and uptake by other intracellular cytoplasmic organelles (6)transport of NP into the nucleus,4.1 targeting

18、 the cell membrane,non-specific binding Positive surface charge Pegylation, in part by desreasing the positive charge, inhibits NP binding to cell surface.,Specific targeting ligands are internalizaed by the clathrin-mediated endocytosis the density of ligands on partical surface, cell selectivity ,

19、stability,and bypass MDR,4.2 Internalization/endocytosis,4.3 Escape from endosomes to cytosol,agents uesd to promote NP escape/release from endosomes pH sensitive peptides pH buffering polymers fusogenic lipids,4.4 Delivery to nucleus,Passive cytosol- necleus transport uses the aqueous channel of NP

20、C. Active energy-dependent nuclear transport requires the presence of specific targeting sequence(NLS)this process appears to be enhanced by pegylation. endosomes trafficking in cells,Conlusions,With respect to NP properties, some are benificial for one transport process but detrimental to others. b

21、alance pegylation,References,1 ANDREW F. A, KAM W L. Emerging links between surface nanotechnology and endocytosis: impact on nonviral gene deliveryJ. Nano Toady, 2010, 5: 553-560. 2 LI YH, W J. Delivery of nanomedicines to extracellular and intracellular compartments of a solid tumorJ. Advanced Dru

22、g Delivery Reviews, 2011,doi: 0.1016/j.addr.2011.0406. 3 J.L.S.Au, S.H.Jang, M.G.Wientjes. clinical aspects of drug delivery to tumors.J. Journal of Cntrolled Release, 2002, 78:81-95. 4 S.H. Jang, M.C.Wientjes, D.Lu, J.L.S. Au. Drug delivery and transport to solid tumosJ. Pharmaceutical Research, 20

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