Tumor cell membrane-based peptide delivery system targeting the tumor microenvironment for cancer immunotherapy and diagnosis

Abstract

The development of an effective delivery system for peptides targeting the tumor microenvironment has always been a hot topic of research in the field of cancer diagnosis and therapy. In this study, superparamagnetic iron oxide nanoparticles (SPIO NPs) were encapsulated with H460 lung cancer cell membranes (SPIO NP@M), and two peptides, namely PD-L1 inhibitory peptide (TPP1) and MMP2 substrate peptide (PLGLLG), were conjugated to the H460 membrane (SPIO NP@M-P). Homologous targeting, cytotoxicity, and pharmacokinetics of SPIO NP@M-P were evaluated. The TPP1 peptide was delivered and released to the tumor microenvironment through the homotypic effect of tumor cell membrane and specific digestion by the tumor-specific enzyme MMP2. The newly developed delivery system (SPIO NP@M-P) for the PD-L1 inhibitory peptide could effectively extend the half-life of the peptides (60 times longer than that for peptides alone) and could maintain the ability to reactivate T cells and inhibit the tumor growth both in vitro and in vivo. Furthermore, SPIO NPs in the system could be used as a tumor imaging agent and thus show the effect of peptide treatment. The SPIO NP@M might serve as a promising theranostic platform for therapeutic application of peptides in cancer therapy. STATEMENT OF SIGNIFICANCE: A multifunctional delivery system (SPIO NP@M) was constructed for effectively delivering therapeutic peptides into the tumor microenvironment for cancer diagnosis and therapy. In this paper, the TPP-1 peptide inhibiting the binding of PD-L1 and PD-1 was delivered and released into the tumor microenvironment by the homotypic targeting of H460 cell membrane and specific digestion by the MMP2 enzyme. SPIO NPs in this system were aggregated effectively at the tumor sites and were used for magnetic resonance imaging of tumors. The SPIO NP@M-P delivery system could effectively extend the half-life of the TPP-1 peptide (60 times longer than that of the free peptide) and could maintain the ability to re-activate T cells and inhibit tumor growth in vitro and in vivo. In conclusion, the SPIO NP@M system coated with lung cancer cell membrane and loaded with the PD-L1-blocking TPP-1 peptide could be a promising integrated platform for tumor diagnosis and treatment.

Keywords: Cancer cell membrane; MR imaging; Nanocarriers; PD-L1 inhibitory peptide; SPIO NPs.