Nanoparticulate paclitaxel loaded into sterically stabilized mixed phospholipid micelles to improve chemotherapy of breast cancer

Excerpt

Active targeting of water-insoluble chemotherapeutic drugs, such as paclitaxel, to breast cancer is a highly desirable because of its associated increase in anticancer efficacy coupled with reduced systemic drug toxicity. However, rational design of these drug delivery platforms should take into account both pathobiological attributes of breast cancer, such as enhanced permeability and retention phenomenon and overexpression of vasoactive intestinal peptide (VIP) receptors, as well as biophysical properties of its ingredients, including ease of preparation, water insoluble drug loading capacity, steric hindrance, nanosize, and scale-up production and storage. To this end, we developed and tested a novel biocompatible and biodegradable nanoparticulate formulation of VIP-conjugated sterically stabilized phospholipid mixed micelles (SSMM-VIP; size ~ 14 nm) composed of disteraroyl phosphatidylethanolamnine-poly(ethylenglycol-2000) and egg yolk phosphatidylcholine. This construct solubilized 1 mg/ml paclitaxel (P-SSMM-VIP) and retained its biophysical properties upon lyophylization and reconstitution in saline. Moreover, it exhibited a twofold increase in cytotoxicity to MCF-7 breast cancer cells in comparison with P-SSMM and paclitaxel in DMSO (P < 0.05). In addition, the construct targeted VIP receptors overexpressed in methyl nitrosurea (MNU)-induced in situ rat breast cancer tissues. There was a twofold increase in accumulation of intravenously administered P-SSMM-VIP (1 mg/kg) in MNU-induced rat breast cancer, coupled with a significantly greater regression of breast cancer in comparison with P-SSMM and Taxol (P < 0.05). At the same time there was a significant reduction in P-SSMM-VIP accumulation in bone marrow, spleen and other organs in comparison with P-SSMM and Taxol (P < 0.05). There was no significant change in systemic arterial pressure during administration of P-SSMM-VIP. Collectively, these data indicate that actively targeting paclitaxel passively loaded into biocompatible, biodegradable, long-circulating SSMM to breast cancer through VIP receptors improves drug efficacy and reduces its uptake in injury-prone normal tissues. We suggest that P-SSMM-VIP is an efficacious and safe, actively targeted drug delivery platform to treat breast cancer. …