Abstract17-Allylamino-17-demethoxy geldanamycin (17-AAG), an inhibitor of heat shock protein 90 (Hsp90) function, is being developed as antitumor drug in patients with breast cancer. However, water-insolubility and hepatotoxicity limit its use. The purpose of this study was to begin to address these issues by determining whether 17-AAG can be formulated in long-circulating (PEGylated), biocompatible and biodegradable sterically stabilized phospholipid nanomicelles (SSM) to which vasoactive intestinal peptide (VIP) was grafted as an active targeting moiety and, if so, whether these nanomicelles are cytotoxic to MCF-7 human breast cancer cells. We found that particle size of 17-AAG loaded in VIP surface-grafted SSM was 16±1 nm and drug content was 97±2% (300 μg/ml). Cytotoxicity of 17-AAG loaded in VIP surface-grafted SSM to MCF-7 cells was significantly higher than that of 17-AAG loaded in non-targeted SSM (p<0.05) and similar to that of 17-AAG dissolved in dimethylsulfoxide. Collectively, these data demonstrate that 17-AAG is solubilized at therapeutically relevant concentrations in actively targeted VIP surface-grafted SSM. Cytotoxicity of these nanomicelles to MCF-7 cells is retained implying high affinity VIP receptors overexpressed on these cells mediate, in part, their intracellular uptake thereby amplifying drug potency. We propose that 17-AAG loaded in VIP surface-grafted SSM should be further developed as an actively targeted nanomedicine for breast cancer.

Local delivery of cancer chemotherapeutics enables sustained drug levels at the site of action thereby reducing systemic side effects. A novel insertable polymeric drug delivery system for cervical cancer treatment is presented. Cisplatin, the first line of therapy employed for cervical cancers, was incorporated in a poly(ethylene-co-vinyl acetate) (EVAc) device that is similar to those currently used for vaginal contraceptive delivery. Cisplatin crystals were uniformly dispersed in the polymeric system without undergoing significant dissolution in the polymer matrix. Cisplatin dissolution from the devices was biphasic, consistent with a matrix-type controlled-release system with an initial rapid release phase followed by a slower, linear release phase. Depending on the drug loading in the polymeric devices, the near-linear release phase varied in rate according both empirical, linear curvefitting (0.38±0.15 μg/day to 46.9±10.0 μg/day) and diffusion analysis based upon diffusion through a porous structure (D app from 1.3±0.5×10 −9 cm 2 /s to 5.8±0.3×10 −12 cm 2 /s). The devices were tested for in vitro activity and found to be effective against both HPV positive and HPV negative cervical cancer cell lines. Preliminary studies indicate that this delivery system would be a good candidate for investigation as a choice of treatment in cervical cancers.