Melanoma Peptide MHC Specific TCR Expressing T-Cell Membrane Camouflaged PLGA Nanoparticles for Treatment of Melanoma Skin Cancer

Abstract

Melanoma is one of the most aggressive skin cancers, and the American Cancer Society reports that every hour, one person dies from melanoma. While there are a number of treatments currently available for melanoma (e.g., surgery, chemotherapy, immunotherapy, and radiation therapy), they face several problems including inadequate response rates, high toxicity, severe side effects due to non-specific targeting of anti-cancer drugs, and the development of multidrug resistance during prolonged treatment. To improve chemo-drug therapeutic efficiency and overcome these mentioned limitations, a multifunctional nanoparticle has been developed to effectively target and treat melanoma. Specifically, poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were coated with a cellular membrane derived from the T cell hybridoma, 19LF6 endowed with a melanoma-specific anti-gp100/HLA-A2 T-cell receptor (TCR) and loaded with an FDA-approved melanoma chemotherapeutic drug Trametinib. T-cell membrane camouflaged Trametinib loaded PLGA NPs displayed high stability, hemo- and cyto-compatibility. They also demonstrated membrane coating dependent drug release profiles with the most sustained release from the NPs proportional with the highest amount of membrane used. 19LF6 membrane-coated NPs produced a threefold increase in cellular uptake toward the melanoma cell line in vitro compared to that of the bare nanoparticle. Moreover, the binding kinetics and cellular uptake of these particles were shown to be membrane/TCR concentration-dependent. The in vitro cancer killing efficiencies of these NPs were significantly higher compared to other NP groups and aligned with binding and uptake characteristics. Particles with the higher membrane content (greater anti-gp100 TCR content) were shown to be more effective when compared to the free drug and negative controls. In vivo biodistribution studies displayed the theragnostic capabilities of these NPs with more than a twofold increase in the tumor retention compared to the uncoated and non-specific membrane coated groups. Based on these studies, these T-cell membrane coated NPs emerge as a potential theragnostic carrier for imaging and therapy applications associated with melanoma.

Nanoparticles Coated with Cell Membranes for Biomedical Applications

“…Recently, PLGA-NPs loaded with trametinib and coated with membrane from T cell hybridoma have also been used for the treatment of melanoma [ 63 ]. These NPs were found to be very stable and drug release was dependent on the amount of membrane used due to the presence of a melanoma-specific anti-gp100/HLA-A2 T-cell receptor (TCR) that promotes binding kinetics and cell uptake.…”

“…Furthermore, these NPs were endocytised to a greater extent by tumor cells compared to uncoated NPs, which led to significant tumor killing in vitro. Therefore, these nanoparticles could be used in therapy associated with melanoma [ 63 ].…”

Cell-mediated and cell membrane-coated nanoparticles for drug delivery and cancer therapy

“…The liposome-treated T cells managed a 5.2-fold reduction in tumor volume and gave a survival advantage of over 14 days over the mice treated with just T cells. As an alternative approach to NP hitchhiking via T cell surface or compartment, our group showed that T cell membrane-coated NPs actively target tumor regions via their specific T cell receptors called TCR [ 15 ] . In this study, chemotherapeutic drug Trametinib loaded PLGA NPs were coated with the membranes of melanoma-specific “anti-gp100/HLA-A2” T-cell receptor (TCR) bearing T cells.…”

Biomimetic Nanoparticles Enabled by Cascade Cell Membrane Coating for Direct Cross‐Priming of T Cells

“…Despite the potential of artificial APCs for adaptive cell-based therapy and the advantage of synthetic particles to penetrate lymph nodes after subcutaneous administration, the construction of artificial systems is complex and time consuming [25][26][27] . Furthermore, epitope-embedded MHC multimer complexes can be engineered only individual epitope of interest has been identified beforehand 28 . Additionally, introducing certain membrane proteins of APCs can solely confer with partial function of the interaction with T cells, largely limiting their application 29 .…”