Multifunctional nanoparticles for co-delivery of elacridar and paclitaxel for breast cancer local treatment.

Breast cancer treatment is often limited by toxicity of systemic chemotherapy and by the development of drug resistance, which reduces the effectiveness of anticancer drugs. Delivering therapeutics directly into the mammary ducts has emerged as a promising strategy to increase drug concentrations at the tumor site while limiting unwanted systemic effects. In this study, we assessed two nanoparticle-based systems to locally co-deliver the anticancer drug paclitaxel with elacridar, an inhibitor of drug-efflux transporters that contribute to chemotherapy resistance. One formulation consisted of nanostructured lipid carriers (NLCs), whereas the other was a NLC-polymeric hybrid nanoparticle (H-NP), in which the polymeric poly(N-isopropylacrylamide) shell was functionalized with SILY, a collagen I-binding peptide, to enhance mammary tissue retention. All formulations exhibited diameter below 400  nm, and negative zeta potential (-16.0 to -8.8 mV). Elacridar was incorporated into the lipid matrix of the NLC (>80% encapsulation efficiency) and in the polymeric shell of the H-NPs (∼70%), which justifies its faster release from H-NPs after 120 h (∼92% compared to 75% from NLC). Compared to nanoparticles containing only paclitaxel, co-encapsulation improved cytotoxicity and reduced IC50 (up to 4.2-fold) in monolayers of paclitaxel-resistant MDA-MB-231 breast cancer and Kasumi-1 (characterized by overexpression P-glycoprotein) cells, as well as in MCF-7 3D spheroids. In an in vivo model of breast cancer, intraductal H-NPs reduced tumor incidence and volume compared to a drug solution, and increased the mammary tissue-to-plasma ratio of paclitaxel by 105-fold, supporting an improved tissue retention. These findings support H-NPs as promising platforms for localized breast cancer therapy.