4.7 Article

Intracellular Delivery of Charge-Converted Monoclonal Antibodies by Combinatorial Design of Block/Homo Polyion Complex Micelles

期刊

BIOMACROMOLECULES
卷 17, 期 2, 页码 446-453

出版社

AMER CHEMICAL SOC
DOI: 10.1021/acs.biomac.5b01335

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资金

  1. Practical Research for Innovative Cancer Control from Japan Agency for Medical Research and Development (AMED)
  2. Center of Innovation Program (COI) from Japan Science and Technology Agency (JST)
  3. Initiative for Accelerating Regulatory Science in Innovative Drug, Medical Device, and Regenerative Medicine
  4. Challenging Exploratory Research [24659584]
  5. [24689051]
  6. [25750172]
  7. Grants-in-Aid for Scientific Research [24689051, 24659584, 15K12534, 15H04635] Funding Source: KAKEN

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Direct intracellular delivery of antibodies has gained much attention, although only a few agents have been developed, and none of them has reached clinical stages. The main obstacles here are the insufficient characteristics of delivery systems including stability and appropriate ability for intracellular antibody release. We tailored the structure of polyion complex (PIC) micelles by loading transiently charge converted antibody derivatives for achieving enhanced stability, delivery to cytosol, and precise antigen recognition inside cells. Citraconic anhydride was used for the charge conversion of the antibody; the optimized degree of modification was identified to balance the stability of PIC micelles in the extracellular compartment and prompt pH-triggered disintegration after their translocation into the acidic endosomal compartment of target cells. The use of a mixture of homo- and block-catiomers in an appropriate ratio to construct PIC micelles substantially enhanced the endosomal escaping efficacy of the loaded antibody, leading to improved recognition of intracellular antigens.

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