HSA-Binding Prodrugs-Based Nanoparticles Endowed with Chemo and Photo-Toxicity against Breast Cancer

SIMPLE SUMMARY: In this study, we developed novel bioresponsive HSA-binding nanoparticles co-delivering paclitaxel (PTX) prodrugs and the photosensitizer pheophorbide a (Pba) for the combined photo- and chemo-treatment of breast cancer. Extensive structural characterization allowed us to evaluate the size, stability and morphology of nanoparticles, which exhibited sustained and controlled drug release under the distinctive redox conditions of the tumor environment. HSA-binding PTX/Pba nanoparticles showed higher Pba uptake in human breast cancer cells and a synergistic antitumor effect upon light irradiation. Preliminary in vivo experiments using low drug doses showed the potential of our bioresponsive nanoparticles to reduce the primary tumor mass while diminishing the number of lung metastases, thus suggesting the effectiveness of this novel approach. ABSTRACT: Exploiting the tumor environment features (EPR effect, elevated glutathione, reactive oxygen species levels) might allow attaining a selective and responsive carrier capable of improving the therapeutic outcome. To this purpose, the in situ covalent binding of drugs and nanoparticles to circulating human serum albumin (HSA) might represent a pioneering approach to achieve an effective strategy. This study describes the synthesis, in vitro and in vivo evaluation of bioresponsive HSA-binding nanoparticles (MAL-PTX(2)S@Pba), co-delivering two different paclitaxel (PTX) prodrugs and the photosensitizer pheophorbide a (Pba), for the combined photo- and chemo-treatment of breast cancer. Stable and reproducible MAL-PTX(2)S@Pba nanoparticles with an average diameter of 82 nm and a PTX/Pba molar ratio of 2.5 were obtained by nanoprecipitation. The in vitro 2D combination experiments revealed that MAL-PTX(2)S@Pba treatment induces a strong inhibition of cell viability of MDA-MB-231, MCF7 and 4T1 cell lines, whereas 3D experiments displayed different trends: while MAL-PTX(2)S@Pba effectiveness was confirmed against MDA-MB-231 spheroids, the 4T1 model exhibited marked resistance. Lastly, despite using a low PTX-PDT regimen (e.g., 8.16 mg/Kg PTX and 2.34 mg/Kg Pba), our formulation showed to foster primary tumor reduction and curb lung metastases growth in 4T1 tumor-bearing mice, thus setting the basis for further preclinical validations.