BackgroundImmunotherapy using checkpoint inhibitors, especially PD-1/PD-L1 inhibitors, has now evolved into the most promising therapy for cancer patients. However, most of these inhibitors are monoclonal antibodies, and their large size may limit their tumor penetration, leading to suboptimal efficacy. As a result, there has been a growing interest in developing low-molecular-weight checkpoint inhibitors.MethodsWe developed a novel biopanning strategy to discover small peptide-based anti-PD-L1 inhibitors. The affinity and specificity of the peptides to PD-L1 were examined using various assays. Three-dimensional (3D) spheroid penetration study was performed to determine the tumor penetration capability of the peptides. Anti-tumor activity of the peptides was evaluated in mice bearing CT26 tumor cells.ResultsWe discover several anti-PD-L1 peptide inhibitors to block PD-1/PD-L1 interaction. The peptides exhibit high affinity and specificity to human PD-L1 protein as well as PD-L1-overexpressing human cancer cells MDA-MB-231 and DU-145. Molecular docking studies indicate that the peptide CLP002 specifically binds to PD-L1 at the residues where PD-L1 interacts with PD-1. The peptide also blocks the CD80/PD-L1 interaction, which may further enhance the immune response of tumor-infiltrating T cells. Compared to antibody, the peptide CLP002 exhibits better tumor penetration in a 3D tumor spheroid model. The peptide CLP002 restores proliferation and prevents apoptosis of T cells that are co-cultured with cancer cells. The peptide CLP002 also inhibits tumor growth and increases survival of CT26 tumor-bearing mice.ConclusionsThis study demonstrated the feasibility of using phage display to discover small peptide-based checkpoint inhibitors. Our results also suggested that the anti-PD-L1 peptide represents a promising low-molecular-weight checkpoint inhibitor for cancer immunotherapy.Electronic supplementary materialThe online version of this article (10.1186/s40425-019-0705-y) contains supplementary material, which is available to authorized users.
Insulin-like growth factor 2 receptor (IGF2R) is overexpressed in activated hepatic stellate cells (HSCs) and therefore can be utilized for HSC-specific drug delivery. We recently discovered an IGF2R-specific peptide using a novel biopanning. Here, we adopted biotin-conjugated IGF2R-specific peptide, cholesterol, and vitamin A as the targeting ligands for the neutravidin-based siRNA nanocomplex to deliver PCBP2 siRNA, a potentially antifibrotic agent, to HSCs. Compared to vitamin A and cholesterol, the IGF2R-specific peptide exhibited the highest targeting effect to human LX-2 HSC, rat HSC-T6 cell line, and activated primary rat HSCs. Accordingly, the IGF2R-specific peptide coupled nanocomplex demonstrated higher silencing activity of PCBP2 and better inhibition on the migration of activated HSCs. Compared to free siRNA and the nanocomplexes coupled with vitamin A and cholesterol, the IGF2R-specific peptide coupled nanocomplex showed the highest uptake in the liver and lowest uptake in the lung and kidney of the rats with CCl-induced liver fibrosis.
Desmoplasia plays a pivotal role in promoting pancreatic cancer progression and is associated with poor clinical outcome. Targeting the desmoplastic tumor microenvironment in combination with chemotherapy is therefore a promising strategy for pancreatic cancer therapy. Here, we report a novel biodegradable copolymer to codeliver LY2109761 (a TGF-β receptor I/II inhibitor) and CPI-613 (a novel chemotherapy agent) to desmoplastic stroma and tumor cells, respectively, in the tumor microenvironment. Hydrophobic CPI-613 is conjugated to the hydrophilic copolymer via a newly designed MMP-2-responsive linker to form a trigger-responsive nanopolyplex. LY2109761 is hydrophobic and encapsulated into the hydrophobic core of the nanopolyplex. The resulting nanopolyplex is modified with a plectin-1-targeting peptide to enhance the accumulation of the nanopolyplex in pancreatic tumors. The nanopolyplex aims to normalize the stroma by blocking the interaction between tumor cells and pancreatic stellate cells to inhibit the activation of pancreatic stellate cells and subsequently reduce the dense extracellular matrix. Normalized stroma increases the penetration of the nanopolyplex into the tumor. The nanopolyplex shows enhanced accumulation in xenograft pancreatic tumors in a biodistribution study. Moreover, the targeted nanopolyplex markedly inhibits tumor growth in an orthotopic pancreatic cancer mouse model by dual-targeting tumor cells and stroma. Overall, the multifunctional nanopolyplex is a promising platform for pancreatic cancer therapy.
To improve the nuclear-targeted delivery of non-viral vectors, extensive effort has been carried out on the development of smart vectors which could overcome multiple barriers. The nuclear envelope presents a major barrier to transgene delivery. Viruses are capable of crossing the nuclear envelope to efficiently deliver their genome into the nucleus through the specialized protein components. However, non-viral vectors are preferred over viral ones because of the safety concerns associated with the latter. Non-viral delivery systems have been designed to include various types of components to enable nuclear translocation at the periphery of the nucleus. This review summarizes the progress of research regarding nuclear transport mechanisms. “Smart” non-viral vectors that have been modified by peptides and other small molecules are able to facilitate the nuclear translocation and enhance the efficacy of gene expression. The resulting technology may also enhance delivery of other macromolecules to the nucleus.
Triple negative breast cancer (TNBC) is the most difficult breast cancer subtype to treat. TNBC patients have significantly higher expression of vascular endothelial growth factor (VEGF) in tumors compared to non-TNBC patients. VEGF not only exerts its pro-angiogenic effects on endothelial cells but also acts as a survival and autocrine growth factor for VEGF receptor (VEGFR) expressing cancer cells. Silencing the expression of VEGF is therefore a potential therapy for TNBC. Methods : A novel biocompatible linear copolymer poly[ bis (ε-Lys-PEI)Glut-PEG] (PLEGP) was developed to deliver VEGF siRNA for TNBC therapy. The copolymer is composed of lysine and glutaric acid, a natural metabolite of amino acids in the body. Low-molecular weight polyethyleneimine (PEI) was grafted to the copolymer to efficiently condense siRNA into nanocomplex without inducing cytotoxicity. Various in vitro studies were performed to evaluate the stability, cellular uptake, tumor penetration, and biological activities of the VEGF siRNA nanocomplex. The anti-tumor activities of the nanocomplex was also evaluated in an orthotopic TNBC mouse model. Results : PEIs with different molecular weights were evaluated, and the copolymer PLEGP 1800 was able to easily form a stable nanocomplex with siRNAs and protect them from serum degradation. The siRNA/PLEGP 1800 nanocomplex exhibited negligible cytotoxicity but showed high cellular uptake, high transfection efficiency, and high tumor penetration. In vitro activity studies showed that the siRNA nanocomplex significantly inhibited migration and invasion of TNBC cells. Moreover, the VEGF siRNA nanocomplex efficiently inhibited tumor growth in an orthotopic TNBC mouse model and down-regulated VEGF expression in the tumor. Conclusion : PLEGP 1800 is a safe and efficient copolymer to deliver siRNAs for TNBC therapy. It could potentially be applied to other cancers by changing the cargo and incorporating tumor-specific ligands.
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