Biodegradable, cationic methacrylamide-based polymers for gene delivery to ovarian cancer cells in mice.
A series of cationic, methacrylamide polymers was tested for use as a biodegradable gene carrier in ovarian cancer. Tumor transfection activity of polyplexes consisting of a reporter gene and different methacrylamide polymers was assessed, after intraperitoneal injection in mice bearing an ovarian cancer xenograft. In this model, polyplexes based on poly(HPMA-DMAE) showed transfection activity similar to polyplexes based on the nondegradable and rather toxic polyethylenimine (PEI22). The tumor transfection activity of the pHPMA-DMAE polyplexes was remarkable considering their poor transfection activity in in vitro assays. Polyplexes based on pHPMA-DMAE were devoid of any cytotoxicity and mediated highest transfection activity at the highest N/P ratio investigated. Tumor cell gene expression after a single administration of these polyplexes rapidly declined within time, at a similar rate to that observed after injection with polyplexes based on PEI22. Incubation of the polyplexes with hyaluronic acid (HA), a polyanion accumulating in the ascitic fluid of ovarian cancer bearing mice, changed the physical characteristics of the pHPMA-DMAE and PEI22 polyplexes. The transfection activity of PEI22-based polyplexes, but not that of pHPMA-DMAE based polyplexes, was strongly impaired by HA. Differences in HA sensitivity might have contributed to the in vivo gene expression activities of pHPMA-DMAE- and PEI22-based polyplexes. pHPMA-DMAE-based polyplexes have potential for use in ovarian cancer therapy due to their considerable transfection activity, their low cytotoxicity, and their HA resistance.
de Wolf
Holger K
HK
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences , Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands.
Luten
Jordy
J
Snel
Cor J
CJ
Storm
Gert
G
Hennink
Wim E
WE
D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism; D008689:Methacrylates / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D010051:Ovarian Neoplasms / Q000628:therapy*; D011094:Polyethyleneimine / Q000008:administration & dosage; D011108:Polymers / Q000008:administration & dosage*; D014162:Transfection
D008689:Methacrylates; D011108:Polymers; D011094:Polyethyleneimine; D006820:Hyaluronic Acid; C049840:2-(dimethylamino)ethyl methacrylate; C032802:hydroxypropyl methacrylate