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Nanoparticles (NPs)-mediated lncMALAT1 silencing to reverse cisplatin resistance for effective hepatocellular

Ting Wang1,2, Qianyao Li1,2,3, Rui Xu2,3

  • 1The Second Affiliated Hospital, Department of Pharmacy, Hengyang Medical School, University of South China, Hengyang, China.

Frontiers in Pharmacology
|August 14, 2024
PubMed

Insights

This study introduces a novel nanoparticle platform for co-delivering chemotherapy drugs and gene silencing agents to combat drug-resistant liver cancer. The nanoplatform effectively reverses cisplatin resistance by targeting nuclear long non-coding RNAs.

Area of Science:

  • Biomedical Engineering
  • Nanotechnology
  • Oncology

Background:

  • Platinum-based chemotherapy is a cornerstone of cancer treatment but faces significant challenges due to acquired drug resistance.
  • Long non-coding RNAs (lncRNAs) play crucial roles in cancer progression and drug resistance, presenting potential therapeutic targets.
  • Targeting lncRNAs is challenging due to their diverse subcellular localization, including the nucleus, mitochondria, and endoplasmic reticulum.

Purpose of the Study:

  • To develop an endosomal pH-responsive nanoparticle platform for the co-delivery of small interfering RNA (siRNA) and a cisplatin prodrug.
  • To investigate the efficacy of this platform in treating cisplatin-resistant hepatocellular carcinoma (HCC).
  • To explore the potential of targeting nuclear lncRNA metastasis-associated lung adenocarcinoma transcript 1 (lncMALAT1) to overcome chemoresistance.

Main Methods:

  • Fabrication of a nanoparticle platform with a polyethylene glycol (PEG) shell and a poly (2-(diisopropylamino)ethyl methacrylate) (PDPA) core.
  • Encapsulation of a cisplatin prodrug and nucleus-targeting amphiphilic peptide (NTPA)/siRNA complexes within the nanoparticles.
  • Utilizing the 'proton sponge' effect triggered by endosomal pH for enhanced endosomal escape and drug/siRNA release.
  • Specific delivery of siRNA to the nucleus via NTPA for silencing lncMALAT1 expression.

Main Results:

  • The nanoparticle platform demonstrated effective co-delivery of cisplatin prodrug and siRNA to tumor cells.
  • Endosomal pH triggered nanoparticle dissociation and enhanced the release of therapeutic payloads.
  • The NTPA/siRNA complexes successfully delivered siRNA into the nucleus, leading to the silencing of lncMALAT1.
  • The treatment significantly inhibited the growth of cisplatin-resistant HCC tumors, demonstrating reversal of drug resistance.

Conclusions:

  • The developed endosomal pH-responsive nanoparticle platform offers a promising strategy for co-delivering therapeutic agents for cancer treatment.
  • This platform effectively overcomes cisplatin resistance in HCC by targeting nuclear lncMALAT1 via siRNA delivery.
  • The study highlights the potential of nanomedicine in combination with gene silencing for enhancing cancer therapy efficacy.
Keywords:
chemotherapyco-deliverylncRNAnanoplatformresistance

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