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Utilizing Polymer Micelle to Control Dye J-aggregation and Enhance Its Theranostic Capability.

ABSTRACT: We utilize polymer micelle to precisely control indocyanine green (ICG) J-aggregation in a fast and highly efficient way. In addition to simple encapsulation, the polymer micelle plays a role as a host template to drive ICG J-aggregation by the synergy of electrostatic and hydrophobic attractions. We further demonstrate that, due to the robust host-guest interaction, the intact of ICG J-aggregate will be secured by the polymer encapsulation during the intracellular and in vivo incubation. These features make this hierarchical assembly between ICG J-aggregate and the micelle polymer a promising biomedicine for cancer phototheranostics. Therefore the complex micelles are further modified by introduction of doxorubicin for chemotherapy and DNA aptamer for tumor targeting, and the final multi-functional micellar medicine shows high therapeutic efficacy for tumor, i.e., the tumor can be completely eliminated with no local reoccurrence and without long-term toxicity or side effects during a 24-day period after the treatment.

SUBMITTER: Shao C

PROVIDER: S-EPMC6906732 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Utilizing Polymer Micelle to Control Dye J-aggregation and Enhance Its Theranostic Capability.

Shao Chen C Xiao Fan F Guo Heng H Yu Jiantao J Jin Dong D Wu Changfeng C Xi Lei L Tian Leilei L

iScience 20191116

We utilize polymer micelle to precisely control indocyanine green (ICG) J-aggregation in a fast and highly efficient way. In addition to simple encapsulation, the polymer micelle plays a role as a host template to drive ICG J-aggregation by the synergy of electrostatic and hydrophobic attractions. We further demonstrate that, due to the robust host-guest interaction, the intact of ICG J-aggregate will be secured by the polymer encapsulation during the intracellular and in vivo incubation. These ...[more]

PMID: 31786519

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Project description:Synthetic subunit vaccines need to induce CD8(+) cytotoxic T cell (CTL) responses for effective vaccination against intracellular pathogens. Most subunit vaccines primarily generate humoral immune responses, with a weaker than desired CD8(+) cytotoxic T cell response. Here, a neutral, pH-responsive polymer micelle carrier that alters intracellular antigen trafficking was shown to enhance CD8(+) T cell responses with a correlated increase in cytosolic delivery and a decrease in exocytosis. Polymer diblock carriers consisted of a N-(2-hydroxypropyl) methacrylamide corona block with pendent pyridyl disulfide groups for reversible conjugation of thiolated ovalbumin, and a tercopolymer ampholytic core-forming block composed of propylacrylic acid (PAA), dimethylaminoethyl methacrylate (DMAEMA), and butyl methacrylate (BMA). The diblock copolymers self-assembled into 25-30nm diameter micellar nanoparticles. Conjugation of ovalbumin to the micelles significantly enhanced antigen cross-presentation in vitro relative to free ovalbumin, an unconjugated physical mixture of ovalbumin and polymer, and a non-pH-responsive micelle-ovalbumin control. Mechanistic studies in a murine dendritic cell line (DC 2.4) demonstrated micelle-mediated enhancements in intracellular antigen retention and cytosolic antigen accumulation. Approximately 90% of initially internalized ovalbumin-conjugated micelles were retained in cells after 1.5h, compared to only ~40% for controls. Furthermore, cells dosed with conjugates displayed 67-fold higher cytosolic antigen levels relative to soluble ovalbumin 4h post uptake. Subcutaneous immunization of mice with ovalbumin-polymer conjugates significantly enhanced antigen-specific CD8(+) T cell responses (0.4% IFN-?(+) of CD8(+)) compared to immunization with soluble protein, ovalbumin and polymer mixture, and the control micelle without endosome-releasing activity. Additionally, pH-responsive carrier facilitated antigen delivery to antigen presenting cells in the draining lymph nodes. As early as 90min post injection, ova-micelle conjugates were associated with 28% and 55% of dendritic cells and macrophages, respectively. After 24h, conjugates preferentially associated with dendritic cells, affording 30-, 3-, and 3-fold enhancements in uptake relative to free protein, physical mixture, and the non-pH-responsive conjugate controls, respectively. These results demonstrate the potential of pH-responsive polymeric micelles for use in vaccine applications that rely on CD8(+) T cell activation.

Project description:Despite considerable progress with our understanding of glioblastoma multiforme (GBM) and the precise delivery of radiotherapy, the prognosis for GBM patients is still unfavorable with tumor recurrence due to radioresistance being a major concern. We recently developed a cross-linked iron oxide nanoparticle conjugated to azademethylcolchicine (CLIO-ICT) to target and eradicate a subpopulation of quiescent cells, glioblastoma initiating cells (GICs), which could be a reason for radioresistance and tumor relapse. The purpose of our study was to investigate if CLIO-ICT has an additive therapeutic effect to enhance the response of GBMs to ionizing radiation. Methods: NSG™ mice bearing human GBMs and C57BL/6J mice bearing murine GBMs received CLIO-ICT, radiation, or combination treatment. The mice underwent pre- and post-treatment magnetic resonance imaging (MRI) scans, bioluminescence imaging (BLI), and histological analysis. Tumor nanoparticle enhancement, tumor flux, microvessel density, GIC, and apoptosis markers were compared between different groups using a one-way ANOVA and two-tailed Mann-Whitney test. Additional NSG™ mice underwent survival analyses with Kaplan-Meier curves and a log rank (Mantel-Cox) test. Results: At 2 weeks post-treatment, BLI and MRI scans revealed significant reduction in tumor size for CLIO-ICT plus radiation treated tumors compared to monotherapy or vehicle-treated tumors. Combining CLIO-ICT with radiation therapy significantly decreased microvessel density, decreased GICs, increased caspase-3 expression, and prolonged the survival of GBM-bearing mice. CLIO-ICT delivery to GBM could be monitored with MRI. and was not significantly different before and after radiation. There was no significant caspase-3 expression in normal brain at therapeutic doses of CLIO-ICT administered. Conclusion: Our data shows additive anti-tumor effects of CLIO-ICT nanoparticles in combination with radiotherapy. The combination therapy proposed here could potentially be a clinically translatable strategy for treating GBMs.

Dataset Information

Utilizing Polymer Micelle to Control Dye J-aggregation and Enhance Its Theranostic Capability.

Publications

Utilizing Polymer Micelle to Control Dye J-aggregation and Enhance Its Theranostic Capability.

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