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Cell relay-delivery improves targeting and therapeutic efficacy in tumors.

ABSTRACT: Cell-mediated drug delivery system (CDDS) has shown great potential for cancer therapy. However, a single cell-mediated drug delivery mechanism has not generally been successful, particularly for systemic administration. To augment the antitumor therapy efficacy, herein, we propose a strategy of cell relay-delivery for the use of artificially damaging/aging erythrocytes to hitchhike on circulating monocytes/macrophages for intratumoral accumulation of anticancer drugs. This biomimetic relay-delivery strategy was derived from the manner in which circulating monocytes/macrophages in body specifically engulf damaged/senescent erythrocytes and actively transmigrate into the tumor bulk. The strategy elegantly combines the natural functions of both cells, which therefore provides a new perspective to challenge current obstacles in drug delivery. According to the strategy, we developed biotinylated erythrocyte-poly (lactic-co-glycolic acid) (PLGA) nanoparticle hybrid DDSs (bE-NPs) using avidin-biotin coupling. In such a system, biotinylated erythrocytes can mimic the natural property of damaged/senescent erythrocytes, while PLGA NPs are capable of encapsulating anticancer drugs and promoting sustained drug release. Anticancer drugs can effectively target tumor sites by two steps. First, by using biotinylated erythrocytes as the carrier, the drug-loaded PLGA NPs could be specifically phagocytized by monocytes/macrophages. Second, by taking advantage of the tumor-tropic property of monocytes/macrophages, the drug-loaded PLGA NPs could be efficiently transported into the tumor bulk. After encapsulating vincristine (VIN) as the model drug, bE-NPs exhibited the most favorable antitumor effects in vitro and in vivo by the cell relay-delivery effect. These results demonstrate that the cell relay-delivery provides a potential method for improving tumor treatment efficacy.

SUBMITTER: Feng Y

PROVIDER: S-EPMC7689215 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Cell relay-delivery improves targeting and therapeutic efficacy in tumors.

Feng Ye Y Liu Qianqian Q Li Yi Y Han Yang Y Liang Meng M Wang Hao H Yao Qing Q Wang Yuli Y Yang Meiyan M Li Zhiping Z Gong Wei W Yang Yang Y Gao Chunsheng C

Bioactive materials 20201119 6

Cell-mediated drug delivery system (CDDS) has shown great potential for cancer therapy. However, a single cell-mediated drug delivery mechanism has not generally been successful, particularly for systemic administration. To augment the antitumor therapy efficacy, herein, we propose a strategy of cell relay-delivery for the use of artificially damaging/aging erythrocytes to hitchhike on circulating monocytes/macrophages for intratumoral accumulation of anticancer drugs. This biomimetic relay-deli ...[more]

PMID: 33294731

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Project description:BackgroundBoth ganglioside GD2-targeted immunotherapy and antibody-drug conjugates (ADCs) have demonstrated clinical success as solid tumor therapies in recent years, yet no research has been carried out to develop anti-GD2 ADCs against solid tumors. This is the first study to analyze cytotoxic activity of clinically relevant anti-GD2 ADCs in a wide panel of cell lines with varying GD2 expression and their effects in mouse models of GD2-positive solid cancer.MethodsAnti-GD2 ADCs were generated based on the GD2-specific antibody ch14.18 approved for the treatment of neuroblastoma and commonly used drugs monomethyl auristatin E (MMAE) or F (MMAF), conjugated via a cleavable linker by thiol-maleimide chemistry. The antibody was produced in a mammalian expression system, and its specific binding to GD2 was analyzed. Antigen-binding properties and biodistribution of the ADCs in mice were studied in comparison with the parent antibody. Cytotoxic effects of the ADCs were evaluated in a wide panel of GD2-positive and GD2-negative tumor cell lines of neuroblastoma, glioma, sarcoma, melanoma, and breast cancer. Their antitumor effects were studied in the B78-D14 melanoma and EL-4 lymphoma syngeneic mouse models.ResultsThe ch14.18-MMAE and ch14.18-MMAF ADCs retained antigen-binding properties of the parent antibody. Direct dependence of the cytotoxic effect on the level of GD2 expression was observed in cell lines of different origin for both ADCs, with IC50 below 1 nM for the cells with high GD2 expression and no cytotoxic effect for GD2-negative cells. Within the analyzed cell lines, ch14.18-MMAF was more effective in the cells overexpressing GD2, while ch14.18-MMAE had more prominent activity in the cells expressing low GD2 levels. The ADCs had a similar biodistribution profile in the B78-D14 melanoma model compared with the parent antibody, reaching 7.7% ID/g in the tumor at 48 hours postinjection. The average tumor size in groups treated with ch14.18-MMAE or ch14.18-MMAF was 2.6 times and 3.8 times smaller, respectively, compared with the control group. Antitumor effects of the anti-GD2 ADCs were also confirmed in the EL-4 lymphoma model.ConclusionThese findings validate the potential of ADCs targeting ganglioside GD2 in treating multiple GD2-expressing solid tumors.

Project description:BackgroundThe antiphagocytic molecule CD47 is overexpressed in a wide variety of cancer cells, and antibodies targeting CD47 for cancer therapies are currently under intensive investigation. However, owing to the ubiquitous expression of CD47 on healthy cells, anti-CD47 therapies often achieve only weak therapeutic benefits and can induce severe side effects. Here, we report the generation of a pH-dependent anti-CD47 antibody (BC31M4) which selectively binds to tumors under the acidic solid tumor microenvironment.MethodsBC31M4 was generated using antibody phage display and a pH-dependent selection strategy. The pH-dependent binding and blocking activities of BC31M4 were verified using in vitro assays, and the structural basis of the pH-dependent binding property was characterized. BC31M4's antitumor effect was confirmed by both phagocytosis assays and studies in xenograft models. The tumor selectivity, mechanism of action, PK properties, side effects, and therapeutic efficacy were further evaluated in humanized (hCD47 and its receptor hSIRPα) immunocompetent syngeneic mouse models.ResultsThe crystal structure reveals that two histidines locate within the CDRs of the light chain directly contribute to the pH-dependent binding of BC31M4. BC31M4 promotes macrophage phagocytosis of tumor cells more potently at acidic-pH than at physiological-pH. Our hCD47/hSIRPα humanized syngeneic mouse model results demonstrated that BC31M4 selectively accumulates in tumors but not in normal tissues. BC31M4 causes minimal side effects and exhibits superior PK properties as compared to the other examined anti-CD47 antibodies. When combined with adoptive T cell transfer, BC31M4 efficiently promotes adaptive immune responses against tumors and also induces immune memory. Moreover, we show that BC31M4's antitumor effects rely on an Fc that mediates strong effector functions.ConclusionsOur study illustrates that the development of a tumor-selective, pH-dependent anti-CD47 antibody safely confers strong therapeutic effects against solid tumors, thus providing a promising therapeutic strategy to overcome the challenges of anti-CD47 therapy.

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Cell relay-delivery improves targeting and therapeutic efficacy in tumors.

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Cell relay-delivery improves targeting and therapeutic efficacy in tumors.

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