Biocompatible AIEgen/p-glycoprotein siRNA@reduction-sensitive paclitaxel polymeric prodrug nanoparticles for overcoming chemotherapy resistance in ovarian cancer

Theranostics. 2021 Jan 27;11(8):3710-3724. doi: 10.7150/thno.53828. eCollection 2021.

Abstract

Nanoparticle drug delivery system (NDDS) is quite different from the widely studied traditional chemotherapy which suffers from drug resistance and side effect. NDDS offers the straightforward solution to the chemotherapy problem and provides an opportunity to monitor the drug delivery process in real time. In this vein, we developed one NDDS, namely Py-TPE/siRNA@PMP, to relieve resistance and side effects during chemotherapy against ovarian cancer. The Py-TPE/siRNA@PMP is a multifunctional polymeric nanoparticle contained several parts as follows: (1) a nanoparticle (NP) self-assembled by reduction-sensitive paclitaxel polymeric prodrug (PMP); (2) the glutathione (GSH)-responsive release of paclitaxel (PTX) for the suppression of ovarian cancer cells; (3) the P-glycoprotein (P-gp) siRNA for restoring the sensitivity of chemo-resistant tumor cells to chemotherapy; (4) the positively charged aggregation-induced emission fluorogen (AIEgen) Py-TPE for tumor imaging and promoting encapsulation of siRNA into the nanoparticle. Methods: The Py-TPE/siRNA@PMP nanoparticles were prepared by self-assembly method and characterized by the UV-Vis absorption spectra, zeta potentials, TEM image, stability assay and hydrodynamic size distributions. The combinational therapeutic effects of Py-TPE/siRNA@PMP on overcoming chemotherapy resistance were explored both in vitro and in vivo.Result: The Py-TPE/siRNA@PMP exhibited an average hydrodynamic size with a good stability. Meanwhile they gave rise to the remarkable chemotoxicity performances in vitro and suppressed the tumors growth in both SKOV-3/PTX (PTX resistance) subcutaneous and intraperitoneal metastasis tumor models. The investigations on ovarian cancer patient-derived xenografts (PDX) model revealed that Py-TPE/siRNA@PMP was able to effectively overcome their chemo-resistance with minimal side effects. Conclusion: Our findings demonstrated the Py-TPE/siRNA@PMP as a promising agent for the highly efficient treatment of PTX-resistant cells and overcoming the shortage of chemotherapy in ovarian cancer.

Keywords: aggregation-induced emission; chemotherapy resistance; drug delivery; ovarian cancer; p-glycoprotein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • Animals
  • Antineoplastic Agents, Phytogenic / administration & dosage*
  • Antineoplastic Agents, Phytogenic / pharmacokinetics
  • Biocompatible Materials / administration & dosage
  • Biocompatible Materials / chemical synthesis
  • Cell Line, Tumor
  • Drug Delivery Systems
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Humans
  • Materials Testing
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Multifunctional Nanoparticles / administration & dosage
  • Multifunctional Nanoparticles / chemistry
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / therapy*
  • Paclitaxel / administration & dosage*
  • Paclitaxel / pharmacokinetics
  • Precision Medicine
  • Prodrugs / administration & dosage
  • Prodrugs / pharmacokinetics
  • RNA, Small Interfering / administration & dosage*
  • RNA, Small Interfering / genetics
  • Xenograft Model Antitumor Assays

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents, Phytogenic
  • Biocompatible Materials
  • Prodrugs
  • RNA, Small Interfering
  • Paclitaxel