Self-Assembled PD-L1 Downregulator to Boost Photodynamic Activated Tumor Immunotherapy Through CDK5 Inhibition.

The immunosuppressive characteristics and acquired immune resistance can restrain the therapy-initiated anti-tumor immunity. In this work, an antibody free programmed death receptor ligand 1 (PD-L1) downregulator (designated as CeSe) is fabricated to boost photodynamic activated immunotherapy through cyclin-dependent kinase 5 (CDK5) inhibition. Among which, FDA approved photosensitizer of chlorin e6 (Ce6) and preclinical available CDK5 inhibitor of seliciclib (Se) are utilized to prepare the nanomedicine of CeSe through self-assembly technique without drug excipient. Nanoscale CeSe exhibits an increased stability and drug delivery efficiency, contributing to intracellular production of reactive oxygen species (ROS) for robust photodynamic therapy (PDT). The PDT of CeSe can not only suppress the primary tumor growth, but also induce the immunogenic cell death (ICD) to release tumor associated antigens. More importantly, the CDK5 inhibition by CeSe can downregulate PD-L1 to re-activate the systemic anti-tumor immunity by decreasing the tumor immune escape and therapy-induced acquired immune resistance. This work provides an antibody free strategy to activate systemic immune response for metastatic tumor treatment, which may accelerate the development of translational nanomedicine with sophisticated mechanism.

Tumor Homing Chimeric Peptide Rhomboids to Improve Photodynamic Performance by Inhibiting Therapy-Upregulated Cyclooxygenase-2.

Negative therapeutic feedback of inflammation would extensively attenuate the antitumor effect of photodynamic therapy (PDT). In this work, tumor homing chimeric peptide rhomboids (designated as NP-Mel) are fabricated to improve photodynamic performance by inhibiting PDT-upregulated cyclooxygenase-2 (COX-2). The hydrophobic photosensitizer of protoporphyrin IX (PpIX) and palmitic acid are conjugated onto the neuropilin receptors (NRPs) targeting peptide motif (CGNKRTR) to obtain tumor homing chimeric peptide (Palmitic-K(PpIX)CGNKRTR), which can encapsulate the COX-2 inhibitor of meloxicam. The well dispersed NP-Mel not only improves the drug stability and reactive oxygen species (ROS) production ability, but also increase the breast cancer targeted drug delivery to intensify the PDT effect. In vitro and in vivo studies verify that NP-Mel will decrease the secretion of prostaglandin E2 (PGE2) after PDT treatment, inducing the downregulation of IL-6 and TNF-α expressions to suppress PDT induced inflammation. Ultimately, an improved PDT performance of NP-Mel is achieved without inducing obvious systemic toxicity, which might inspire the development of sophisticated nanomedicine in consideration of the feedback induced therapeutic resistance.

Chimeric Peptide-Engineered Self-Delivery Nanomedicine for Photodynamic-Triggered Breast Cancer Immunotherapy by Macrophage Polarization.

A systemic treatment strategy is urgently demanded to suppress the rapid growth and easy metastasis characteristics of breast cancer. In this work, a chimeric peptide-engineered self-delivery nanomedicine (designated as ChiP-CeR) for photodynamic-triggered breast cancer immunotherapy by macrophage polarization. Among these, ChiP-CeR is composed of the photosensitizer of chlorine e6 (Ce6) and the TLR7/8 agonist of lmiquimod (R837), which is further modified with tumor matrix targeting peptide (Fmoc-K(Fmoc)-PEG8 -CREKA. ChiP-CeR is preferred to actively accumulate at the tumor site via specific recognition of fibronectin, which can eradicate primary tumor growth through photodynamic therapy (PDT). Meanwhile, the destruction of primary tumors would trigger immunogenic cell death (ICD) effects to release high-mobility group box-1(HMGB1) and expose calreticulin (CRT). Moreover, ChiP-CeR can also polarize M2-type tumor-associated macrophages (TAMs) into M1-type TAMs, which can activate T cell antitumor immunity in combination with ICD. Overall, ChiP-CeR possesses superior antitumor effects against primary and lung metastatic tumors, which provide an applicable nanomedicine and a feasible strategy for the systemic management of metastatic breast cancer.

Chimeric Peptide Engineered Bioregulator for Metastatic Tumor Immunotherapy through Macrophage Polarization and Phagocytosis Restoration.

Tumor-associated macrophages (TAMs) are the most abundant immune cells in solid tumor tissues, which restrict antitumor immunity by releasing tumor-supporting cytokines and attenuating phagocytosis behaviors. In this work, a chimeric peptide engineered bioregulator (ChiP-RS) is constructed for tumor immunotherapy through macrophage polarization and phagocytosis restoration. ChiP-RS is fabricated by utilizing macrophage-targeting chimeric peptide (ChiP) to load Toll-like receptor agonists (R848) and Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP-2) inhibitor (SHP099). Among which, ChiP-RS prefers to be internalized by TAMs, repolarizing M2 macrophages into M1 macrophages to reverse the immunosuppressive microenvironment. In addition, SHP-2 can be downregulated to promote phagocytotic elimination behaviors of M1 macrophages, which will also activate T cell-based antitumor immunity for metastatic tumor therapy. In vitro and in vivo findings demonstrate a superior suppression effect of ChiP-RS against metastatic tumors without systemic side effects. Such a simple but effective nanoplatform provides sophisticated synergism for immunotherapy, which may facilitate the development of translational nanomedicine for metastatic tumor treatment.

Plasma Membrane-Targeted Photooxidant for Chemotherapy-Enhanced Lipid Peroxidation.

Although photodynamic therapy (PDT) is a promising antitumor strategy for tumor treatment, the short half-life and the limited diffusion distance of reactive oxygen species (ROS) greatly hamper its antitumor efficacy. Moreover, tumor cells develop antioxidative microenvironments to weaken the oxidative damage caused by PDT. Herein, a plasma membrane-targeted photooxidant (designated as SCPP) is prepared by the self-assembly of a chimeric peptide (Pal-K(PpIX)-R4) and sorafenib. Plasma membrane-targeted SCPP could enhance lipid peroxidation (LPO) through in situ PDT upon light irradiation. Moreover, sorafenib-mediated chemotherapy could block cystine/glutamate antiporter xCT (SLC7A11) to inhibit the syntheses of intracellular GSH and glutathione peroxidase 4 (GPX4), which would destroy the antioxidant defense system of tumors. As a consequence, SCPP achieves a highly efficient tumor inhibition through enhanced PDT and ferroptosis therapy. This study might provide guidance for multisynergistic tumor therapy with a sophisticated mechanism under unfavorable conditions.