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Dandelion-Like Tailorable Nanoparticles for Tumor Microenvironment Modulation.

ABSTRACT: Tumor-associated macrophages (TAMs) constitute over 50% of the number of cells within the tumor, playing a major role in tumor progression and invasion. Remodeling the tumor immune microenvironment by modulating TAM polarization has been emerging as a new and promising therapeutic strategy. However, the high interstitial fluid pressure and dense extracellular matrix lead to insufficient penetration of nanosized therapies. To overcome this dilemma, an acid-triggered size-changeable nanoparticle (aptamer/acid sensitive linker crosslinked DGL/zoledronic acid, i.e., Apt@(DGL-ZA) n NPs) with effective tumor distribution, extravasation, and penetration is designed. Dendrigraft poly-L-lysines (DGLs) which can induce tumor autophagy as mimics of natural abnormal proteins are crosslinked via a mild-acid-responsive linker (1,6-bis(4-formylbenzoyloxy) hexane). Long circulation property and tumor penetration are achieved simultaneously by catching DGLs in neutral pH while releasing them in the tumor's pH, like dandelion seeds in midair. The macrophage conditioning agent zoledronic acid (ZA) is loaded on DGLs by the charge attraction. A Tenascin-C targeting aptamer (GBI-10) is modified onto (DGL-ZA) n NPs for a tumor-homing effect. Apt@(DGL-ZA) n NPs show both enhanced penetration in in vitro 3D triple negative breast cancer spheroids and in vivo tumor tissues. Effective macrophage regulation, enhanced tumor autophagy, and excellent in vivo antitumor efficacy are achieved, suggesting this tactic as a significant antitumor strategy.

SUBMITTER: Guo Q

PROVIDER: S-EPMC6839635 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Dandelion-Like Tailorable Nanoparticles for Tumor Microenvironment Modulation.

Guo Qin Q He Xi X Li Chao C He Yongqing Y Peng Yiying Y Zhang Yu Y Lu Yifei Y Chen Xinli X Zhang Yujie Y Chen Qinjun Q Sun Tao T Jiang Chen C

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20190912 21

Tumor-associated macrophages (TAMs) constitute over 50% of the number of cells within the tumor, playing a major role in tumor progression and invasion. Remodeling the tumor immune microenvironment by modulating TAM polarization has been emerging as a new and promising therapeutic strategy. However, the high interstitial fluid pressure and dense extracellular matrix lead to insufficient penetration of nanosized therapies. To overcome this dilemma, an acid-triggered size-changeable nanoparticle ( ...[more]

PMID: 31728288

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Project description:BackgroundChemoradiotherapy (CRT) remains one of the most common cancer treatment modalities, and recent data suggest that CRT is maximally effective when there is generation of an anti-tumoral immune response. However, CRT has also been shown to promote immunosuppressive mechanisms which must be blocked or reversed to maximize its immune stimulating effects.MethodsTherefore, using a preclinical model of human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC), we developed a clinically relevant therapy combining CRT and two existing immunomodulatory drugs: cyclophosphamide (CTX) and the small molecule inducible nitric oxide synthase (iNOS) inhibitor L-n6-(1-iminoethyl)-lysine (L-NIL). In this model, we treated the syngeneic HPV-HNSCC mEER tumor-bearing mice with fractionated (10 fractions of 3 Gy) tumor-directed radiation and weekly cisplatin administration. We compared the immune responses induced by CRT and those induced by combinatory treatment (CRT + CTX/L-NIL) with flow cytometry, quantitative multiplex immunofluorescence and by profiling immune-related gene expression changes.ResultsWe show that combination treatment favorably remodels the tumor myeloid immune microenvironment including an increase in anti-tumor immune cell types (inflammatory monocytes and M1-like macrophages) and a decrease in immunosuppressive granulocytic myeloid-derived suppressor cells (MDSCs). Intratumoral T cell infiltration and tumor antigen specificity of T cells were also improved, including a 31.8-fold increase in the CD8+ T cell/ regulatory T cell ratio and a significant increase in tumor antigen-specific CD8+ T cells compared to CRT alone. CTX/LNIL immunomodulation was also shown to significantly improve CRT efficacy, leading to rejection of 21% established tumors in a CD8-dependent manner.ConclusionsOverall, these data show that modulation of the tumor immune microenvironment with CTX/L-NIL enhances susceptibility of treatment-refractory tumors to CRT. The combination of tumor immune microenvironment modulation with CRT constitutes a translationally relevant approach to enhance CRT efficacy through enhanced immune activation.

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Dandelion-Like Tailorable Nanoparticles for Tumor Microenvironment Modulation.

Publications

Dandelion-Like Tailorable Nanoparticles for Tumor Microenvironment Modulation.

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