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Autophagy responsive intra-intercellular delivery nanoparticles for effective deep solid tumor penetration.

Fengling Wang1, Dandan Xie1, Wenjing Lai1

  • 1Department of Pharmacy, The Second Affiliated Hospital of Army Medical University, No. 183 Xinqiao Road, Chongqing, China.

Journal of Nanobiotechnology
|June 25, 2022
PubMed
Summary

Deep tumor cells are hard to treat due to their location. Autophagy-responsive nanoparticles were designed to target these cells, enhancing drug delivery and improving antitumor efficacy in vivo.

Keywords:
Autophagy responsiveDeep penetrationSolid tumorsTranscellular transport

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Area of Science:

  • Biomedical Engineering
  • Nanotechnology
  • Oncology

Background:

  • Deep tumor cells are resistant to conventional therapies due to their location.
  • These cells contribute to drug tolerance, metastasis, recurrence, and immune suppression.
  • Higher autophagy levels in deep tumor cells present a therapeutic target.

Purpose of the Study:

  • To design and evaluate autophagy-responsive multifunctional nanoparticles (PGN) for enhanced drug accumulation in deep tumor cells.
  • To improve the efficacy of cancer treatment by targeting refractory deep tumor cells.
  • To leverage the characteristic autophagy levels in deep tumor cells for targeted drug delivery.

Main Methods:

  • Developed multifunctional nanoparticles (PGN) by coating poly(lactic-co-glycolic acid) (PLGA) with an autophagy-responsive peptide (GR9) and modified DSPE-PEG.
  • Utilized docetaxel (DTX) and chloroquine (CQ) loaded d-PGN, where CQ inhibits lysosomal fusion to enhance autophagy.
  • Investigated nanoparticle characteristics, including size (122.4 nm) and surface charge (0.21 mV), for optimal blood circulation and tumor penetration.
  • Evaluated the pH-sensitive hydrolysis of DMA for GR9 peptide exposure and the enzyme-cleavable nature of GR9 in deep tumor cells.

Main Results:

  • Nanoparticles exhibited suitable size and charge-neutral surface for prolonged blood circulation.
  • Acidic tumor microenvironment triggered DMA hydrolysis, exposing GR9 for enhanced tumor penetration.
  • Autophagy shear enzymes in deep tumor cells cleaved GR9, leading to nanoparticle retention and degradation.
  • Drug-loaded d-PGN demonstrated significant in vivo antitumor efficacy, achieving an 82.1% inhibition rate.
  • CQ loading enhanced autophagy sensitivity and deep tumor retention of the nanoparticles.

Conclusions:

  • Autophagy-responsive multifunctional nanoparticles offer a promising strategy for targeting deep tumor cells.
  • This approach enhances drug accumulation in refractory tumor regions, improving therapeutic outcomes.
  • The designed nanoparticles effectively overcome drug resistance associated with deep tumor cell location.