Tumor-targeted hyaluronan nanoliposomes increase the antitumor activity of liposomal Doxorubicin in syngeneic and human xenograft mouse tumor models.
Naturally occurring high-Mr hyaluronan, bound to the surface of nanoliposomes (denoted targeted hyaluronan liposomes, or tHA-LIP), is a candidate for active targeting to tumors, many of which overexpress the hyaluronan receptors CD44 and RHAMM. The surface-bound hyaluronan also provides a hydrophilic coat that, similar to polyethylene glycol, may promote long-term circulation. We recently reported the successful targeting of mitomycin C, mediated by tHA-LIP, in tumor-bearing syngeneic mice. Hypothesizing that this targeting is carrier-specific, rather than drug-specific, we report here studies with doxorubicin (DXR)-loaded tHA-LIP, in syngeneic and human xenograft models. Saline, free DXR, DXR-loaded nontargeted liposomes (nt-LIP), and Doxil served as controls. The tHA-LIP were long-circulating, more than all controls, in healthy and tumor-bearing (C57BL/6/B16F10.9; BALB/c/C-26) mice. Mediated by tHA-LIP, DXR accumulation in tumor-bearing lungs was 30-, 6.7-, and 3.5-fold higher than free DXR, nt-LIP, and Doxil, respectively. Key indicators of therapeutic responses--tumor progression, metastatic burden, and survival--were superior (P < .001) in animals receiving DXR-loaded tHA-LIP compared with controls, in tumor-bearing syngeneic mice (BDF1/P388/ADR ascites, C57BL/6/B16F10.9 lung metastasis, and BALB/c/C-26 solid tumors), and in nude mice bearing PANC-1 solid tumors. In conclusion, tHA-LIP, performing as tumor-targeted carriers, have the potential to join the arsenal of carrier-formulated anticancer drugs.
Peer
Dan
D
Department of Biochemistry, The George S. Wise, Life Science Faculty, Tel-Aviv University, Tel Aviv, Israel.
Margalit
Rimona
R
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000627:therapeutic use; D004317:Doxorubicin / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004337:Drug Carriers; D006801:Humans; D006820:Hyaluronic Acid / Q000493:pharmacokinetics; D008081:Liposomes; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D014183:Transplantation, Heterologous
D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D008081:Liposomes; D004317:Doxorubicin; D006820:Hyaluronic Acid