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pH and ROS sequentially responsive podophyllotoxin prodrug micelles with surface charge-switchable and
Chao Li1, Yifan Wang2, Shuo Zhang1
1Department of Infectious Disease, Wuhu No. 1 People's Hospital, Wuhu, China.
Abstract:
Multidrug resistance (MDR) is one of the main reasons for tumor chemotherapy failure. Podophyllotoxin (PPT) has been reported that can suppress MDR cancer cell growth; however, effective delivery of PPT to MDR cancer cells is challenged by cascaded bio-barriers. To effectively deliver PPT to MDR cancer cells, a PPT polymeric prodrug micelle (PCDMA) with the charge-conversion capability and self-acceleration drug release function are fabricated, which is composed of a pH and reactive oxygen species (ROS) sequentially responsive PPT-polymeric prodrug and an ROS generation agent, cucurbitacin B (CuB). After reach to tumor tissue, the surface charge of PCDMA could rapidly reverse to positive in the tumor extracellular environment to promote cellular uptake. Subsequently, the PCDMA could be degraded to release PPT and CuB in response to an intracellular high ROS condition. The released CuB is competent for generating ROS, which in turn accelerates the release of PPT and CuB. Eventually, the released PPT could kill MDR cancer cells. The in vitro and in vivo studies demonstrated that PCDMA was effectively internalized by cancer cells and produces massive ROS intracellular, rapid release drug, and effectively overcame MDR compared with the control cells, due to the tumor-specific weakly acidic and ROS-rich environment. Our results suggest that the pH/ROS dual-responsive PCDMA micelles with surface charge-reversal and self-amplifying ROS-response drug release provide an excellent platform for potential MDR cancer treatment.
Insights
This study developed a novel micelle system (PCDMA) that effectively delivers podophyllotoxin (PPT) to multidrug-resistant (MDR) cancer cells. The system enhances drug release and overcomes MDR by utilizing tumor-specific environments for targeted treatment.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Multidrug resistance (MDR) significantly limits the efficacy of cancer chemotherapy.
- Podophyllotoxin (PPT) shows potential against MDR cancer cells but faces delivery challenges due to biological barriers.
Purpose of the Study:
- To develop a charge-converting, self-accelerating drug release micelle (PCDMA) for effective PPT delivery to MDR cancer cells.
- To investigate the potential of PCDMA in overcoming MDR through enhanced cellular uptake and drug release.
Main Methods:
- Fabrication of a pH and reactive oxygen species (ROS) sequentially responsive PPT-polymeric prodrug micelle (PCDMA) incorporating cucurbitacin B (CuB) as an ROS generator.
- Evaluation of PCDMA's charge-conversion, ROS-triggered drug release, cellular uptake, and efficacy in overcoming MDR using in vitro and in vivo models.
Main Results:
- PCDMA exhibited rapid surface charge reversal to positive in tumor extracellular environments, enhancing cellular uptake.
- Intracellularly, PCDMA degraded in response to high ROS, releasing PPT and CuB, with CuB amplifying further ROS generation and drug release.
- In vitro and in vivo studies confirmed PCDMA's effective internalization, massive ROS production, rapid drug release, and significant overcoming of MDR.
Conclusions:
- The pH/ROS dual-responsive PCDMA micelles demonstrate a promising platform for MDR cancer treatment.
- The developed system leverages tumor-specific microenvironments for targeted drug delivery, charge reversal, and self-amplifying drug release.
