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.