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Junction opener protein increases nanoparticle accumulation in solid tumors.

ABSTRACT: Carcinomas contain tight junctions that can limit the penetration and therefore therapeutic efficacy of anticancer agents, especially those delivered by nano-carrier systems. The junction opener (JO) protein is a virus-derived protein that can transiently open intercellular junctions in epithelial tumors by cleaving the junction protein desmoglein-2 (DSG2). Co-administration of JO was previously shown to significantly increase the efficacy of various monoclonal antibodies and chemotherapy drugs in murine tumor models by allowing for increased intratumoral penetration of the drugs. To investigate the size-dependent effect of JO on nanocarriers, we used PEGylated gold nanoparticles (AuNPs) of two different sizes as model drugs and investigated their biodistribution following JO protein treatment. By inductively coupled plasma mass spectrometry (ICP-MS), JO was found to significantly increase bulk tumor accumulation of AuNPs of 35nm but not 120nm particles in both medium (200-300mm3) and large (500-600mm3) tumors. Image analysis of tumor sections corroborates this JO-mediated increase in tumor accumulation of AuNPs. Quantitative intratumoral distribution analyses show that most nanoparticles were found within 100?m of the vasculature, and that the penetration profiles of AuNPs are not significantly affected by JO treatment at the 6h timepoint.

SUBMITTER: Wang CE

PROVIDER: S-EPMC5825283 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Junction opener protein increases nanoparticle accumulation in solid tumors.

Wang Christine E CE Yumul Roma C RC Lin Jonathan J Cheng Yilong Y Lieber André A Pun Suzie H SH

Journal of controlled release : official journal of the Controlled Release Society 20180103

Carcinomas contain tight junctions that can limit the penetration and therefore therapeutic efficacy of anticancer agents, especially those delivered by nano-carrier systems. The junction opener (JO) protein is a virus-derived protein that can transiently open intercellular junctions in epithelial tumors by cleaving the junction protein desmoglein-2 (DSG2). Co-administration of JO was previously shown to significantly increase the efficacy of various monoclonal antibodies and chemotherapy drugs ...[more]

PMID: 29305923

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Project description:Cell-based immunotherapy for the treatment of hematologic malignancies, such as leukemia and lymphoma, has seen much success and played an increasingly important role in clinical studies. Nevertheless, the efficacy of immunotherapy in solid tumors still needs improvements due to the immunosuppressive properties of tumor cells and the microenvironment. To overcome these limitations, we prepared a novel tumor-targeting delivery system based on the underlying mechanism of immune-targeted cell death that encapsulated granzyme B protein within a porous polymeric nanocapsule. Methods: A cell-penetrating peptide TAT was attached onto granzyme B (GrB) to enhance its transmembrane transport efficiency and potency to induce cell apoptosis. The endocytosis and internalization pathways of GrB-TAT (GrB-T) were analyzed in comparison with perforin by confocal microscopy and flow cytometry. Furthermore, the positively charged GrB-T was wrapped into nanoparticles by p-2-methacryloyloxy ethyl phosphorylcholine (PMPC)-modified HA (hyaluronic acid). The nanoparticles (called TCiGNPs) were characterized in terms of zeta potential and by transmission electron microscopy (TEM). The in vitro anti-tumor effects of GrB-T were examined by cell apoptosis assay and Western blotting analysis. The in vivo anti-tumor therapeutic efficacy of TCiGNPs was evaluated in a mouse tumor model. Results: The TAT peptide could play a role similar to perforin to mediate direct transmembrane transfer of GrB and improve GrB-induced cell apoptosis. The TCiGNPs were successfully synthesized and accumulated in the solid tumor through enhanced permeability and retention (EPR) effect. In the tumor microenvironment, TCiGNPs could be degraded by hyaluronidase and triggered the release of GrB-T. The TAT peptide enabled the translocation of GrB across the plasma membrane to induce tumor cell apoptosis in vivo. Conclusion: We successfully developed a granzyme B delivery system with a GrB-T core and a PMPC/HA shell that simulated CTL/NK cell-mediated cancer immunotherapy mechanism. The GrB delivery system holds great promise for cancer treatment analogous to the CTL/NK cell-induced immunotherapy.

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Junction opener protein increases nanoparticle accumulation in solid tumors.

Publications

Junction opener protein increases nanoparticle accumulation in solid tumors.

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