Targeted Drug delivery

Question 1

Drug carrier roles:

Answer 1

protect body and drug en route, reduce dose/side effects, prolong effects and alleviate compliance issues

Question 2

Drug targeting roles:

Answer 2

enhances specificity, optimizes sub cellular addressing

Question 3

Enhanced permeability-retention EPR

Answer 3

passive vascular delivery to solid tumors: vascular leakyness and poor lymphatic drainage–>uptake and retention of drugs in solid tumors (20-100 nm)

Question 4

limitations of EPR

Answer 4

low % of dose delivered, slow/poor diffusion in tumors, no control of intracellular delivery, not all tumors applicable, not specific (inflammation/ischemia); works in mice/unproven in humans; drugs must circulate for hours/days

Question 5

What immune mechanisms eliminate carriers?

Answer 5

opsonization by Igs and complement medicated phagocytosis

Question 6

What is stealth technology

Answer 6

PEG coupling to liposomes, its effectiveness depends on PEG surface density and length (limited by lipid bilayer destabilization and effect on biological activity); high mobility and water content of PEG chains resists protein interactions

Question 7

Liposomes vs nanoparticles vs polymersomes

Answer 7

Liposomes facilitate intracellular delivery but have limited PEG grafting and stability issues; nanoparticles have high PEG surface but low loading; polymersomes require processing conditions that reduce biological activity

Question 8

What is good example of liposomal drug formulations:

Answer 8

doxorubicin liposomal systems limit cardiotoxicity but can cause dermal toxicity (EPR like effect); a nonPEGylated version is made that limits dermal toxicity

Question 9

Tumor targeting limitations:

Answer 9

lack of truly specific tumor cell target; even targeted drugs cannot reach all tumor cells (higher affinity–>poorer diffusion through tumor);

Question 10

targeting endothelium in tumors

Answer 10

tTF-antibody specific for VCAM–adhered TF then stimulates coagulation cascade to clot and starve tumor

Question 11

how can you overcome p-glycoprotein MDR?

Answer 11

target drug to internalizable epitopes

Question 12

transendothelial cell drug delivery pathways:

Answer 12

endothelial calveoli; receptor mediated transcytosis, fluid phase transcytosis are part of transcellular pathways; paracellular pathways via transjunctional transport