Effect of nanomicelle morphology on peptide activity and ROS generation for enhancing chemotherapy efficacy in breast cancer

In cancer research, targeting specific molecular markers that are overexpressed on the tumor cell membrane has opened up opportunities for drug delivery. Yet, current technologies face challenges in achieving effective targeting. To enhance the targeting efficiency of peptides, researchers have explored different parameters, including the size and shape of nanoparticles, as well as the engineering of peptides. This study focuses on exploring the impact of nanoparticle shape on their uptake by cells and the efficiency of peptides in targeting specific receptors. We synthesized rod-shaped polymeric micelles (AuR-PM) using biodegradable copolymers consisting of zwitterionic methacryloyloxyethyl phosphorylcholine and polycaprolactone, enclosing gold nanoparticles (AuNPs) as the core. They were compared with previously synthesized spherical nanoparticles (AuS-PM) regarding cellular uptake under <i>in vitro</i> and <i>in vivo</i> conditions. The synergistic effect of PMs in combination with sonodynamic therapy was analyzed. Our findings clearly show that AuR-PM achieve a 1.495 ± 0.31 fold increase in intracellular accumulation compared to AuS-PM in static cultures. Additionally, targeted AuR-PM experienced a significant 1.625 ± 0.131 fold boost in cellular uptake over their non-targeted equivalents, representing a 1.307 ± 0.057 fold increase relative to the same comparison with AuS-PM. Based on the results obtained from confocal laser scanning microscopy and flow cytometry, the AuR-PM demonstrated approximately 3.25 ± 0.37 fold higher ROS production compared to AuS-PM in the MDA-MB231 cell line. AuR-PM exhibited improved effects <i>in vivo</i>, which can be attributed to their longer circulation time and greater tumor penetration. Histopathological analyses of essential tissues in mice carrying 4T1 tumors revealed minimal tissue damage following administration of DOX-loaded AuR-PM. These results highlight the importance of nanoparticle geometry in modulating cellular interactions and enhancing tumor targeting efficacy.