Aptamer-targeted delivery of Bcl-xL shRNA using alkyl modified PAMAM dendrimers into lung cancer cells

Sara Ayatollahi1, Zahra Salmasi2, Maryam Hashemi2

  • 1Pharmaceutical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Insights

This study presents a novel targeted delivery system for cancer gene therapy using modified PAMAM nanoparticles and an AS1411 aptamer. The system effectively delivers shRNA to cancer cells, reducing Bcl-xL expression and inducing apoptosis with high selectivity.

Area of Science:

  • Biotechnology
  • Nanomedicine
  • Cancer Therapeutics

Background:

  • RNA interference (RNAi)-based gene therapy offers a promising strategy for cancer treatment.
  • Targeted delivery of therapeutic agents to tumor cells is crucial for enhancing efficacy and minimizing side effects.
  • Aptamers offer high specificity and affinity for targeted delivery applications in cancer therapy.

Purpose of the Study:

  • To develop a novel targeted non-viral delivery system for shRNA-mediated gene silencing in cancer cells.
  • To enhance transfection efficiency and target cancer cells specifically using modified PAMAM nanoparticles and an AS1411 aptamer.
  • To evaluate the efficacy of the targeted system in down-regulating Bcl-xL protein expression and inducing apoptosis in cancer cells.

Main Methods:

  • Development of a targeted delivery platform using modified polyamidoamine (PAMAM) dendrimers with 10-bromodecanoic acid (10C) and 10C-PEG.
  • Conjugation of AS1411 aptamer for targeting nucleolin on cancer cells and incorporation of shRNA plasmid for Bcl-xL knockdown.
  • Evaluation of transfection efficiency in A549 cells and assessment of gene silencing and apoptosis induction via gene silencing and apoptosis assays.

Main Results:

  • The modified vector demonstrated significantly improved transfection efficiency compared to non-targeted vectors in A549 cells.
  • The targeted shRNA delivery system effectively down-regulated Bcl-xL expression by up to 25%.
  • The system induced 14% late apoptosis in target cancer cells, exhibiting strong cell selectivity.

Conclusions:

  • A novel targeted non-viral delivery system for shRNA-mediated gene silencing in cancer cells was successfully developed.
  • The modified PAMAM-based vector with AS1411 aptamer enhances transfection efficiency and provides targeted delivery to cancer cells.
  • This targeted system shows potential for effective and selective cancer gene therapy by down-regulating Bcl-xL and inducing apoptosis.