Novel microneedle array loaded with anti-PD-1-cisplatin-nanoparticles for synergistic cancer immuno-chemotherapy

Abstract

Cisplatin (CDDP) is the most widely used DNA-modifying chemotherapeutic drug, which induces apoptosis of cancer cells. Immune profiling in the tumour microenvironment plays a critical role in chemotherapy. Clonal expansion of T cells in the tumour microenvironment correlates with better response to chemotherapy. Furthermore, CD8+ T cells can abolish fibroblast-mediated CDDP chemoresistance by producing interferon-y, which reveals the importance of tumour microenvironment in the interplay between chemotherapy and immunotherapy.

lmmunotherapy using immune checkpoint inhibitor anti-PD-l(aPD-l) has revolutionized cancer treatment. The aPD-l can activate immune response by binding to Programmed Cell Death Protein 1 (PD-l) in T cell membrane, resulting in immune attack on cancer cells. The efficacy of aPD-l correlates with pre-existing CD8+ T cells in the tumour microenvironment. Microneedle arrays can pierce immune-cell-rich epidermis, leading to a robust T cell response in the tumour microenvironment. Our prelimina1_'y study has fabricated microneedles loaded with CDDP-nanoparticles to enhance the anticancer effects and reduce the systemic side effects. These findings led us to hypothesize that microneedles loaded with aPD-l-

CDDP-nanoparticles can provoke robust and durable T cell activity, thus enhancing the efficacy of aPD-l and cytotoxicig of CDDP.

To that end, we propose to: 1) develop a novel microneedle loaded with aPD-l-CDDP-nanoparticles, and evaluate its anticancer effects in vitro, 2) investigate the synergistic immuno-chemotherapeutic effects and elucidate the underlying cellular mechanism in vivo. We will design and fabricate microneedles loaded with pH-responsive tumour-targeted lipid-nanoparticles, which allows a precise local delivery of aPD-l and CDDP to cancer tissues.

Synergistic anticancer mechanisms will be activated via robust T cells response induced

by microneedle, blockage of PD-1 in T cells by aPD-l, and direct cytotoxicity of CDDP in tumour cells. The T cell subsets, T cell exhaustion and reinvigoration, and the production of

IFNY and TNFa will be profiled and compared to reveal the cellular mechanisms in vivo.

This translational study proposes a new concept for the direct local co-delivery of immune checkpoint inhibitor and chemotherapeutic agent by microneedles for synergistic immuno-chemotherapy. The results will pave the way for novel treatment strategies to increase the treatment outcomes in life-threatening cancers.