Microneedle-mediated local delivery of nano-encapsulated chemotherapeutic and immunotherapeutic agents for cancer therapy

Abstract

Head and neck squamous cell carcinoma (HNSCC) is one of the most frequently occurring cancers in the worldwide, with 5-year survival rate of only 50%. Currently, the main treatments for HNSCC consist of surgery, chemotherapy, radiotherapy and the emerging immunotherapy. Cisplatin (CDDP) is the first-line chemotherapeutic agent; however, its systemic toxicity and side effects severely limit its clinical use. Notably, the recently developed immune checkpoint inhibitors could considerably enhance antitumor efficacy in clinical practice. Nonetheless, the objective response rates of these inhibitors are approximately 20%-30% for HNSCC. Research gaps remain in developing novel strategies and approaches to improve the antitumor effects and reduce systemic side effects in chemotherapy and immunotherapy.

The current study investigated for the first time the efficiency and safety of a lipid-coated cisplatin nanoparticles (LCC-NPs) incorporated microneedle to enhance transdermal drug delivery for cancer therapy. Cisplatin was encapsulated by tumor-targeting pH-responsive lipid nanoparticles with a high loading rate of 80%, and the encapsulation per se substantially improved the drug solubility and yet increased its antitumor efficiency in vitro. The LCC-NPs were embedded in dissolving microneedles and released from the MNs after insertion into the skin, thereby enabling the nanoparticles to pass the stratum corneum for local delivery safely. The in vivo study with a xenograft tumor animal model demonstrated that microneedle arrays loaded with cisplatin nanoparticles significantly augmented cytotoxicity and apoptosis in cancer cells with an apoptotic index of 58.6%, significantly resulting in reduced volume and weight of tumors. Moreover, serum platinum, pulmonary toxicity, hepatotoxicity, and nephrotoxicity were not detected in vivo, highlighting that this microneedle technique is bio-safe. The novel cisplatin-nanoparticle microneedle system may offer promising opportunities to enhance antitumor effects and reduce systemic toxicity and side effects.

Programmed cell death protein-1 (PD-1) located on T-cells combined with programmed cell death ligand-1 (PD-L1) critically accounts for tumor immune evasion. Anti-PD-1 (aPD-1) blocks the binding and activates T-cells to attack the tumor cells. However, improving the response rate and overcoming drug resistance are the major challenges in cancer immunotherapy. Skin is a highly active immune organ containing a large population of resident antigen-presenting cells. Microneedle arrays can pierce the immune-cell-rich epidermis, leading to a robust T-cell response in the microenvironment of tumor cells. In this study, microneedles were successfully fabricated with loading of pH-responsive tumor-targeted lipid-nanoparticles, allowing a local delivery of aPD-1 and CDDP precisely to cancer tissues. The SCC VII cell line was injected into the right flank of C3H/HeJ mice. Tumor-bearing mice were treated with aPD-1 drugs or NPs either intraperitoneally or through microneedle delivery. aPD-1-CDDP-NPs delivered through microneedles indicated a remarkable tumor regression effect and effectively boosted the immune response. Synergistic anticancer mechanisms were therefore activated through robust microneedle-induced T-cell response, blockage of PD-1 in T-cells by aPD-1, and increasing direct cytotoxicity of CDDP in tumor cells. This exhibited promise in the treatment of immunotherapy-unresponsive cancers.

Taken together, microneedle-mediated local delivery of nano-encapsulated chemotherapeutic and immunotherapeutic agents provides a novel treatment strategy and provides insights into cancer therapy.