Folate-mediated intracellular drug delivery increases the anticancer efficacy of nanoparticulate formulation of arsenic trioxide.
Arsenic trioxide (As(2)O(3)) is a frontline drug for treatment of acute promyelocytic leukemia and is in clinical trials for treatment of other malignancies, including multiple myeloma; however, efforts to expand clinical utility to solid tumors have been limited by toxicity. Nanoparticulate forms of As(2)O(3) encapsulated in 100-nm-scale, folate-targeted liposomes have been developed to lower systematic toxicity and provide a platform for targeting this agent. The resultant arsenic "nanobins" are stable under physiologic conditions but undergo triggered drug release when the pH is lowered to endosomal/lysosomal levels. Cellular uptake and antitumor efficacy of these arsenic liposomes have been evaluated in folate receptor (FR)-positive human nasopharyngeal (KB) and cervix (HeLa) cells, as well as FR-negative human breast (MCF-7) tumor cells through confocal microscopy, inductively coupled plasma mass spectroscopy, and cytotoxicity studies. Uptake of folate-targeted liposomal arsenic by KB cells was three to six times higher than that of free As(2)O(3) or nontargeted liposomal arsenic; the enhanced uptake occurs through folate-mediated endocytosis, leading to a 28-fold increase in cytotoxicity. In contrast, tumor cells with lower FR density on the surface (HeLa and MCF-7) showed much less uptake of the folate-targeted drug and lower efficacy. In cocultures of KB and MCF-7 cells, the folate-targeted arsenic liposomes were exclusively internalized by KB cells, showing high targeting specificity. Our studies further indicate that folate-targeted delivery of As(2)O(3) with coencapsulated nickel(II) ions (as a nontoxic adjuvant) potentiates the As(2)O(3) efficacy in relatively insensitive solid tumor-derived cells and holds the promise of improving drug therapeutic index.
Chen
Haimei
H
Department of Chemistry, Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA.
Ahn
Richard
R
Van den Bossche
Jeroen
J
Thompson
David H
DH
O'Halloran
Thomas V
TV
D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage*; D001943:Breast Neoplasms; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D005260:Female; D005434:Flow Cytometry; D005492:Folic Acid / Q000737:chemistry*; D006801:Humans; D008081:Liposomes; D053758:Nanoparticles; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000473:pathology; D010087:Oxides / Q000008:administration & dosage*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001152:Arsenicals; D004337:Drug Carriers; D008081:Liposomes; D010087:Oxides; D005492:Folic Acid; D000077237:Arsenic Trioxide