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Updated: Jun 28, 2025
Anticancer Efficacy of Photodynamic Therapy with Lung Cancer-Targeted Nanoparticles
Published on: December 1, 2016
Codelivery of CPT and siPHB1 with GSH/ROS Dual-Responsive Hybrid Nanoparticles Based on a [12]aneN3-Derived Lipid for
Ya-Xuan Liang1, Xue-Yi Sun1, De-Zhong Xu1
1Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
Abstract:
The combination of small-interfering RNA (siRNA)-mediated gene silencing and chemotherapeutic agents for lung cancer treatment has attracted widespread attention in terms of a greater therapeutic effect, minimization of systemic toxicity, and inhibition of multiple drug resistance (MDR). In this work, three amphiphiles, CBN1-CBN3, were first designed and synthesized as a camptothecin (CPT) conjugate and gene condensation agents by the combination of CPT prodrugs and di(triazole-[12]aneN3) through the ROS-responsive phenylborate ester and different lengths of alkyl chains (with 6, 9, 12 carbon chains for CBN1-CBN3, respectively). CBN1-CBN3 were able to be self-assembled into liposomes with an average diameter in the range of 320-240 nm, showing the ability to effectively condense siRNA. Among them, CBN2, with a nine-carbon alkyl chain, displayed the best anticancer efficiency in A549 cells. In order to give nanomedicines a stealth property and PEGylation/dePEGylation transition, a GSH-responsive PEGylated TPE derivative containing a disulfide linkage (TSP) was further designed and prepared. A combination of CBN2/siRNA complexes and DOPE with TSP resulted in GSH/ROS dual-responsive lipid-polymer hybrid nanoparticles (CBN2-DP/siRNA NPs). In present GSH and H2O2, CBN2-DP/siRNA NPs were decomposed, resulting in the controlled release of CPT drug and siRNA. In vitro, CBN2-DP/siPHB1 NPs showed the best anticancer activity for suppression of about 75% of A549 cell proliferation in a serum medium. The stability of CBN2-DP/siRNA NPs was significantly prolonged in blood circulation, and they showed effective accumulation in the A549 tumor site through an enhanced permeability and retention (EPR) effect. In vivo, CBN2-DP/siPHB1 NPs demonstrated enhanced synergistic cancer therapy efficacy and tumor inhibition as high as 71.2%. This work provided a strategy for preparing lipid-polymer hybrid NPs with GSH/ROS dual-responsive properties and an intriguing method for lung cancer therapy.
Insights
This study developed dual-responsive lipid-polymer hybrid nanoparticles for lung cancer therapy, combining chemotherapy and gene silencing. The nanoparticles demonstrated significant tumor inhibition and improved therapeutic effects in vivo.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Lung cancer treatment faces challenges including systemic toxicity and multidrug resistance (MDR).
- Combining small-interfering RNA (siRNA) for gene silencing with chemotherapy offers a promising strategy to enhance efficacy and reduce side effects.
- Developing targeted and responsive drug delivery systems is crucial for effective cancer therapy.
Purpose of the Study:
- To design and synthesize novel amphiphiles (CBN1-CBN3) for camptothecin (CPT) conjugation and siRNA delivery.
- To create dual-responsive (GSH/ROS) lipid-polymer hybrid nanoparticles (CBN2-DP/siRNA NPs) for controlled drug and siRNA release.
- To evaluate the in vitro and in vivo anticancer efficacy of the developed nanoparticles for lung cancer treatment.
Main Methods:
- Synthesis of CPT-conjugated amphiphiles (CBN1-CBN3) with varying alkyl chain lengths.
- Self-assembly of amphiphiles into liposomes and subsequent complexation with siRNA.
- Preparation of GSH-responsive PEGylated TPE derivative (TSP) for stealth properties and controlled dePEGylation.
- Formation of dual-responsive lipid-polymer hybrid nanoparticles (CBN2-DP/siRNA NPs) via combination of CBN2/siRNA complexes, DOPE, and TSP.
- In vitro evaluation of cytotoxicity and cell proliferation inhibition in A549 lung cancer cells.
- In vivo studies to assess tumor accumulation, stability, and therapeutic efficacy in a tumor-bearing mouse model.
Main Results:
- Amphiphiles CBN1-CBN3 effectively condensed siRNA and self-assembled into liposomes.
- CBN2, with a nine-carbon chain, showed superior in vitro anticancer efficiency in A549 cells.
- CBN2-DP/siRNA NPs exhibited dual responsiveness to GSH and ROS, enabling controlled release of CPT and siRNA.
- In vitro studies showed suppression of ~75% of A549 cell proliferation by CBN2-DP/siPHB1 NPs.
- In vivo studies demonstrated prolonged blood circulation, enhanced tumor accumulation via EPR effect, and significant tumor inhibition (71.2%) by CBN2-DP/siPHB1 NPs.
Conclusions:
- Lipid-polymer hybrid nanoparticles with GSH/ROS dual-responsive properties were successfully prepared.
- The developed nanoparticles offer a synergistic approach for lung cancer therapy by combining chemotherapy and gene silencing.
- This strategy provides an intriguing method for enhancing lung cancer treatment efficacy and reducing systemic toxicity.
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