Polymeric micelles for GSH-triggered delivery of arsenic species to cancer cells.
Arsenic trioxide (ATO), dissolved in water as arsenous acid or inorganic arsenite (As(III)), is an effective chemotherapeutic agent against acute promyelocytic leukemia (APL). It has been under investigation as a potential treatment for a variety of solid tumors although with much poorer efficacy than for APL. The toxicity of As(III) and its derivatives is a common concern that has limited its use. The objective of the current study was to develop a polymeric micelle drug delivery system for efficient and controlled delivery of trivalent arsenicals to solid tumor cells. A polymeric micelle-based drug delivery system can potentially extend the duration of drug circulation in blood, restrict access of encapsulated drug to normal tissues, achieve tumor targeted drug delivery, enhance drug accumulation in the tumor area, and trigger drug release at tumor sites if designed properly. These, in turn, can lead to an improved therapeutic index for the polymeric micellar formulation of arsenic species compared to their free form. Towards this goal, a biodegradable block copolymer with pendent thiol groups on the hydrophobic block, i.e., methoxy poly(ethylene oxide)-block-poly[α-(6-mecaptohexyl amino)carboxylate-ε-caprolactone] [PEO-b-P(CCLC6-SH)], was synthesized and used for conjugation of a trivalent arsenical, phenylarsine oxide (PAO), to free thiol groups on the polymer backbone. PAO-loaded micelles had refined size distribution with an average diameter of 150 nm as evidenced by dynamic light scattering (DLS) in water. Prepared polymeric micelles were characterized for the level of PAO conjugation using inductively coupled plasma mass spectrometry (ICP-MS). The results showed 65% of total free thiols were conjugated to PAO providing an arsenic/polymer loading content of ~2.5 wt%. In vitro release study suggests prolonged release of PAO from its polymeric micellar carrier, which was accelerated in the presence of glutathione (GSH). Cytotoxicity studies against MDA-MB-435 cells show that the IC50 of PEO-b-P(CCLC6-S-PAO) is not significantly different from that of free PAO. The results indicate that PEO-b-P(CCLC6-SH) is a promising carrier for successful arsenic delivery for cancer therapy.
Division of Analytical and Environmental Toxicology, Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2G3, Canada.
Qi
Q
Zhang
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada.
Mohammad Reza
MR
Vakili
Division of Analytical and Environmental Toxicology, Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2G3, Canada.
Xing-Fang
XF
Li
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada. Electronic address: afsaneh@ualberta.ca.
Afsaneh
A
Lavasanifar
Division of Analytical and Environmental Toxicology, Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2G3, Canada. Electronic address: xc.le@ualberta.ca.
X Chris
XC
Le
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000737:chemistry / Q000494:pharmacology*; D002209:Caprolactam / Q000031:analogs & derivatives / Q000138:chemical synthesis; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D005978:Glutathione / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D008823:Micelles; D010087:Oxides / Q000737:chemistry / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000138:chemical synthesis; D011108:Polymers / Q000737:chemistry*
D000970:Antineoplastic Agents; D001152:Arsenicals; D008823:Micelles; D010087:Oxides; D011108:Polymers; C000595097:methoxy poly(ethylene oxide)-block-poly(alpha-(6-mecaptohexyl amino)carboxylate-epsilon-caprolactone); D011092:Polyethylene Glycols; D002209:Caprolactam; D005978:Glutathione; D000077237:Arsenic Trioxide
Arsenic; Drug delivery; Poly(ethylene oxide)-b-poly(α-carboxylate-ε-caprolactone); Polymeric micelles