Biodegradable polymersomes loaded with both paclitaxel and doxorubicin permeate and shrink tumors, inducing apoptosis in proportion to accumulated drug.
Cytotoxicity can in principle be maximized if drugs with different activities can be delivered simultaneously to the same cell. However, combination therapy with drugs having distinct properties such as solubility generally requires use of multiple carriers or solvents, limiting the likelihood of simultaneous delivery. In this brief report, we describe the in vivo use of biodegradable polymersomes for systemic delivery of an anticancer cocktail. These polymer-based shells exploit a thick hydrophobic membrane and an aqueous lumen to efficiently carry both hydrophobic and hydrophilic drugs, respectively paclitaxel and doxorubicin. Polymersomes are long-circulating in vivo but also degrade and release their drugs on a time scale of about 1 day, by which time the tumors treated here will otherwise have almost doubled in volume. A single systemic injection of the dual drug combination shows a higher maximum tolerated dose than the free drug cocktail and shrinks tumors more effectively and more sustainably than free drug: 50% smaller tumors are seen at 5 days with polymersomes. The polymersomes cause two-fold higher cell death in tumors than free drug and show quantitatively similar increases in maximum tolerated dose and drug accumulation within the tumors-suggesting promise for multi-drug delivery.
Ahmed
Fariyal
F
Departments of Chemical-Biomolecular Engineering and Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
Pakunlu
Refika I
RI
Brannan
Aaron
A
Bates
Frank
F
Minko
Tamara
T
Discher
Dennis E
DE
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001711:Biotransformation; D002070:Butadienes / Q000737:chemistry; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004337:Drug Carriers; D004338:Drug Combinations; D020724:Elastomers / Q000737:chemistry; D005260:Female; D006801:Humans; D007700:Kinetics; D007773:Lactates / Q000737:chemistry; D016014:Linear Models; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D036103:Nanotechnology; D017239:Paclitaxel / Q000378:metabolism / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D012995:Solubility; D013997:Time Factors
D000970:Antineoplastic Agents; D002070:Butadienes; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004338:Drug Combinations; D020724:Elastomers; D007773:Lactates; D011108:Polymers; C088513:poly(lactic acid-ethylene glycol); D011092:Polyethylene Glycols; D004317:Doxorubicin; C028834:polybutadiene; D017239:Paclitaxel