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Reverting chemoresistance of targeted agents by a ultrasoluble dendritic nanocapsule

Qida Hu1, Wangteng Wu2, Meng Wang1

  • 1Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.

Journal of Controlled Release : Official Journal of the Controlled Release Society
|November 23, 2019
PubMed

Insights

Nanoparticle drug delivery overcomes chemoresistance in insoluble targeted agents. This novel nanocapsulation strategy enhances drug exposure and efficacy, particularly for pancreatic cancer treatment.

Area of Science:

  • Oncology
  • Nanomedicine
  • Drug Delivery

Background:

  • Insoluble targeted cancer agents exhibit low dose exposure, leading to poor therapeutic responses and rapid drug resistance.
  • Nanoparticle drug formulations can potentially overcome chemoresistance by increasing drug exposure and modulating resistance pathways.

Purpose of the Study:

  • To develop a self-assembled nanocapsulation strategy using a multiarm polymer and novel dendrimer series (MAP-mG3) for encapsulating insoluble targeted agents.
  • To evaluate the efficacy of MAP-mG3 encapsulating the mammalian target of rapamycin (mTOR) inhibitor OSI-027 (MAP-mG3/OSI-027) in overcoming chemoresistance in pancreatic cancer.

Main Methods:

  • Construction of a nanocomplex (MAP-mG3/OSI-027) via self-assembled nanocapsulation using a nucleotide lock mechanism.
  • Assessment of loading capacity, solubility, release kinetics, and intracellular accumulation of MAP-mG3/OSI-027.
  • Evaluation of the in vitro efficacy of MAP-mG3/OSI-027 in inhibiting pancreatic cancer cell growth and attenuating mTOR phosphorylation.
  • Investigation of the ability of MAP-mG3/OSI-027 to revert chemoresistance by analyzing intracellular dose exposure, ABCB1 expression, and compensatory pathways.

Main Results:

  • MAP-mG3/OSI-027 demonstrated superior loading capacity, enhanced solubility, controlled release, and increased intracellular tumor accumulation compared to free OSI-027.
  • MAP-mG3/OSI-027 significantly inhibited pancreatic cancer cell growth and attenuated mTOR phosphorylation more effectively than free OSI-027.
  • The nanocapsulation strategy successfully reverted chemoresistance to OSI-027 in resistant pancreatic cancer cells by increasing intracellular drug exposure and modulating ABCB1 expression and related pathways.

Conclusions:

  • The developed MAP-mG3 nanocapsulation strategy provides an effective platform for engineering and reactivating insoluble targeted agents.
  • This approach holds significant promise for overcoming drug resistance in challenging malignancies like pancreatic cancer.
  • Optimized nanodesign is crucial for enhancing the therapeutic potential of targeted therapies against chemoresistant cancers.
Keywords:
ChemoresistanceDendritic nanocapsuleFunctional deliveryTargeted agents

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