Self-promoted Albumin-Based Nanoparticles for Combination Therapy against Metastatic Breast Cancer via a Hyperthermia-Induced "Platelet Bridge".

It has been a great challenge to simultaneously inhibit the outgrowth of both the primary tumor and metastasis in metastatic cancer treatment. Substantial studies have evidenced that the interaction of platelets and cancer cells supports tumor metastasis, and platelets are considered to have metastasis-targeting property. Inspired by injury-targeting and metastasis-targeting properties of platelets, we constructed a photothermal therapy strategy with activated platelet-targeting albumin-based nanoparticles, PSN-HSA-PTX-IR780, to amplify drug delivery in the primary tumor at mild temperatures and simultaneously inhibit metastasis via a "platelet bridge". Human serum albumin (HSA) was premodified with a P-selectin-targeting peptide (PSN peptide) or IR780 serving as a photosensitizer. Hybrid albumin nanoparticles were assembled via the disulfide reprogramming method and encapsulated paclitaxel (PTX) to formulate PSN-HSA-PTX-IR780. The PSN-modified albumin nanoparticles could bind with upregulated P-selectin on activated platelets and subsequently target cancer cells by using platelets as a "bridge". In addition, nanoparticle-generated hyperthermia induced tissue injury and increased tumor-infiltrating platelets, thereby recruiting more nanoparticles into the tumor in a self-promoted way. In vivo studies showed that the drug accumulation of PSN-HSA-PTX-IR780 was 2.86-fold higher than that of HSA-PTX-IR780 at the optimal temperature (45 °C), which consequently improved the therapeutic outcome. Moreover, PSN-HSA-PTX-IR780 also effectively targets and inhibits lung metastasis by binding with metastasis-infiltrating platelets. Altogether, the self-promoted nanoplatform provides a unique and promising strategy for metastatic cancer treatment with enhanced drug delivery efficacy.