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- W4245444313 abstract "Passive diffusion of drugs and reagents across the cell's plasma membrane barrier is an inefficient and poorly controlled process, despite its fundamental importance to biotechnology, cell biology, and pharmaceutics. In particular, the fundamental requirement for membrane permeability frequently limits the accumulation of drugs in the cytoplasm, undermining drug efficacy and over-constraining drug design. In contrast, gap junctions, transmembrane protein channels that physically connect the cytoplasm of adjacent cells, bypass the plasma membrane, permitting a diverse range of molecules to move rapidly from the cytoplasm of one cell to the next, from ions and metabolites to siRNA and chemotherapeutics. Our work aims to address the challenge of crossing the plasma membrane barrier by using the cellular gap junction network to deliver drugs directly to the cytoplasm of tumor cells. Specifically, we have developed Connectosomes, cell-derived lipid vesicle materials that contain functional gap junction channels and can form gap junction interfaces with cells. We formed Connectosomes by harvesting plasma membrane vesicles from donor cells that were engineered to overexpress gap junction channels. These novel materials transferred small molecules, including fluorescent dyes and chemotherapeutics, directly to the cellular cytoplasm. Remarkably, using Connectosomes to deliver the chemotherapeutic doxorubicin reduced the therapeutically effective dose of the drug by more than 10 fold in comparison to the free drug and 100 fold in comparison to conventional liposomal doxorubicin. These results demonstrate the ability of Connectosomes to substantially increase the efficiency of molecular transport into the cytoplasm. This increase in efficiency has the potential to boost the effectiveness of existing drugs, such as chemotherapeutics, helping to address long-standing problems such as dose-limiting toxicity and multidrug resistance. Further, in bypassing the plasma membrane barrier, Connectosomes remove a key constraint on therapeutic design, enabling the development and delivery of membrane-impermeable drugs and reagents." @default.
- W4245444313 created "2022-05-12" @default.
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- W4245444313 date "2017-02-01" @default.
- W4245444313 modified "2023-09-26" @default.
- W4245444313 title "Connectosomes for Direct Molecular Delivery to the Cellular Cytoplasm" @default.
- W4245444313 doi "https://doi.org/10.1016/j.bpj.2016.11.1661" @default.
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