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Research Article

Hyaluronic acid nanoparticle-encapsulated microRNA-125b repolarizes tumor-associated macrophages in pancreatic cancer

    Neha N Parayath

    Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA 02115, USA

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    ,
    Brian V Hong

    Department of Nutrition, University of California at Davis, Davis, CA 95616, USA

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    ,
    Gerardo G Mackenzie

    Department of Nutrition, University of California at Davis, Davis, CA 95616, USA

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    &
    Mansoor M Amiji

    *Author for correspondence: Tel: +1 617 373 3137;

    E-mail Address: m.amiji@northeastern.edu

    Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA 02115, USA

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    Published Online:28 Sep 2021https://doi.org/10.2217/nnm-2021-0080

    Abstract

    Aim: To investigate a novel strategy to target tumor-associated macrophages and reprogram them to an antitumor phenotype in pancreatic adenocarcinoma (PDAC). Methods: M2 peptides were conjugated to HA-PEG/HA-PEI polymer to form self-assembled nanoparticles with miR-125b. The efficacy of HA-PEI/PEG-M2peptide nanoparticles in pancreatic tumors from LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx1-Cre genetically engineered mice was evaluated. Results:In vitro M2 macrophage-specific delivery of targeted nanoformulations was demonstrated. Intraperitoneal administration of M2-targeted nanoparticles showed preferential accumulation in the pancreas of KPC-PDAC mice and an above fourfold increase in the M1-to-M2 macrophage ratio compared with transfection with scrambled miR. Conclusion: M2-targeted HA-PEI/PEG nanoparticles with miR-125b can transfect tumor-associated macrophages in pancreatic tissues and may have implications for PDAC immunotherapy.

    Lay abstract

    In pancreatic ductal adenocarcinoma (PDAC) tumor-associated macrophages (TAM) play a major role in tumor progression. Reprogramming of TAMs from a predominant protumoral phenotype to antitumoral phenotype is a promising strategy for PDAC. CD44 targeting hyaluronic acid-poly(ethylenimine) (HA-PEI/PEG)-based nanoparticles encapsulating miR-125b and macrophage-specific delivery and accumulation in the tumor tissue of LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx1-Cre (KPC) genetically engineered mice were found. The pancreatic tumors show a switch of macrophage phenotype from protumoral to antitumoral.

    Graphical abstract

    Papers of special note have been highlighted as: •• of considerable interest

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