Synergistic\nChemo-Immunotherapy Using pH-Responsive\nNanoparticles in Breast Cancer Treatment: In Vitro and In Vivo Studies

Recent research underscores the pivotal role of the heterogeneous\nmulticellular interactome within the tumor microenvironment (TME)\nin tumor progression and survival. Tumor-associated macrophages (TAMs),\namong other nonmalignant cells in the TME, promote an immunosuppressive\nenvironment, fostering tumor cell survival, proliferation, and resistance.\nHence, combining chemotherapy with immunomodulatory agents to transition\nTAMs to an immunostimulatory phenotype holds immense therapeutic potential.\nThe present study focuses on developing tumor-responsive nanoparticles\n(NPs) for combined chemo-immunotherapy using resiquimod (RSQ), a TLR\n7/8 agonist as an immunomodulator, and paclitaxel (PTX) as chemotherapeutics.\nA pH-responsive NP known as PHNP, tailored with a star-shaped PLGA\nconjugated with poly histidine, was engineered to selectively deliver\na consistent ratio of PTX and RSQ directly to the tumor site. In vitro\nstudies demonstrate enhanced drug release at pH 6.4, increased penetration\nin tumor spheroids, and increased cytotoxic efficacy against breast\ncancer cells. Furthermore, PHNPs activate macrophages for antitumor\nactivity. In vivo studies demonstrated a notable rise in plasma AUC\nand improved delivery of drugs to the tumor using PHNPs, resulting\nin enhanced effectiveness against tumor growth in a mouse orthotopic\nbreast cancer model. Notably, PHNP treatment elevated intratumoral\nROS and apoptosis levels and inhibited lung metastasis. Overall, this\nstudy underscores the potential of the PTX and RSQ combination as\na prospective combined chemo-immunotherapeutic modality.