Dataset Information

Cell Penetrating Peptide-Based Self-Assembly for PD-L1 Targeted Tumor Regression.

ABSTRACT: Cell penetrating peptides (CPPs) are peptides that can directly adapt to cell membranes and then permeate into cells. CPPs are usually covalently linked to the surface of nanocarriers to endow their permeability to the whole system. However, hybrids with lipids or polymers make the metabolism much more sophisticated and even more difficult to determine. In this study, we present a continuous sequence of 18 amino acids (FFAARTMIWY(d-P)GAWYKRI). It forms nanospheres around 170 nm, which increase slightly after loading with siRNA and DOX. Notably, it can be internalized by cancer cells mainly through electronic interactions and PD-L1-mediated endocytosis. Compared with poly-l-lysine and polyethyleneimine, it has a much higher efficiency (about four times) of gene transduction while lowering toxicity. In the treatment of cancer, it causes apoptosis (21%) and inhibits the expression of SURVIVIN protein in vitro. In vivo, it shows good biocompatibility as there are no changes in mice's body weight. When administering peptide-siRNA-DOX, tumor growth is inhibited the most (about three times). These results above prove the sequence to be a good candidate for gene therapy and drug delivery.

SUBMITTER: Guo F

PROVIDER: S-EPMC8703959 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Cell Penetrating Peptide-Based Self-Assembly for PD-L1 Targeted Tumor Regression.

Guo Feng F Ke Junfeng J Fu Zhengdong Z Han Wenzhao W Wang Liping L

International journal of molecular sciences 20211210 24

Cell penetrating peptides (CPPs) are peptides that can directly adapt to cell membranes and then permeate into cells. CPPs are usually covalently linked to the surface of nanocarriers to endow their permeability to the whole system. However, hybrids with lipids or polymers make the metabolism much more sophisticated and even more difficult to determine. In this study, we present a continuous sequence of 18 amino acids (FFAARTMIWY(d-P)GAWYKRI). It forms nanospheres around 170 nm, which increase s ...[more]

PMID: 34948105

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Project description:BackgroundPD-1/PD-L1 immune checkpoint inhibitors are currently the most commonly utilized agents in clinical practice, which elicit an immunostimulatory response to combat malignancies. However, all these inhibitors are currently administered via injection using antibody-based therapies, while there is a growing need for oral alternatives.MethodsThis study has developed and synthesized exosome-wrapped gold-peptide nanocomplexes with low immunogenicity, which can target PD-L1 and activate antitumor immunity in vivo through oral absorption. The SuperPDL1exo was characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS), Fourier transform infrared (FTIR), X-ray photoelectron spectroscopy (XPS), and gel silver staining. The transmembrane ability of SuperPDL1exo was evaluated by flow cytometry and immunofluorescence. Cell viability was determined using the Cell Counting Kit-8 (CCK-8) assay. ELISA experiments were conducted to detect serum and tissue inflammatory factors, as well as serum biochemical indicators. Tissue sections were stained with H&E for the evaluation of the safety of SuperPDL1exo. An MC38 colon cancer model was established in immunocompetent C56BL/6 mice to evaluate the effects of SuperPDL1exo on tumor growth in vivo. Immunohistochemistry (IHC) staining was performed to detect cytotoxicity factors such as perforin and granzymes.ResultsFirst, SuperPDL1 was successfully synthesized, and milk exosome membranes were encapsulated through ultrasound, repeated freeze-thaw cycles, and extrusion, resulting in the synthesis of SuperPDL1exo. Multiple characterization results confirmed the successful synthesis of SuperPDL1exo nanoparticles. Furthermore, our data demonstrated that SuperPDL1exo exhibited excellent colloidal stability and superior cell transmembrane ability. In vitro and in vivo experiments revealed that SuperPDL1exo did not cause damage to multiple systemic organs, demonstrating its good biocompatibility. Finally, in the MC38 colon cancer mouse model, it was discovered that SuperPDL1exo could inhibit the progression of colon cancer, and this tumor-suppressive effect was mediated through the activation of tumor-specific cytotoxic T lymphocyte (CTL)-related immune responses.ConclusionThis study has successfully designed and synthesized an oral nanotherapeutic, SuperPDL1exo, which demonstrates small particle size, excellent colloidal stability, transmembrane ability in tumor cells, and biocompatibility. In vivo experiments have shown that it effectively activates T-cell immunity and exerts antitumor effects.

Dataset Information

Cell Penetrating Peptide-Based Self-Assembly for PD-L1 Targeted Tumor Regression.

Publications

Cell Penetrating Peptide-Based Self-Assembly for PD-L1 Targeted Tumor Regression.

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