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GSH/pH dual responsive chitosan nanoparticles for reprogramming M2 macrophages and overcoming cancer chemoresistance
Xinzhi Zhao1, Chunxiong Zheng1,2, Ying Wang1
1State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials of Ministry of Education, College of Chemistry, Nankai University, Tianjin 300071, China. yliu@nankai.edu.cn.
Abstract:
The combination of two or more drugs with different mechanisms of action is a promising strategy for circumventing multidrug resistance (MDR). However, the antitumor effect of nanosystems is usually limited due to the simultaneous release of different payloads at a single location rather than at their respective sites of action. Herein, we report a GSH and pH dual responsive nanoplatform encapsulated with doxorubicin (DOX) and resiquimod (R848) (GPNP) for combinatorial chemotherapy against cancer cells with drug resistance. GPNP possesses a core-shell structure wherein the polymer shell detaches in the acidic and sialic acid (SA)-rich environment. This leads to the release of R848 into the tumor microenvironment (TME), thereby reprogramming M2 macrophages into M1 macrophages and exposing the core CS(DOX)-PBA to kill MCF-7/ADR cells. Additionally, the nitric oxide (NO) generated by M1 macrophages can suppress the P-glycoprotein (P-gp) expression to reduce the efflux of chemotherapy drugs, thus playing a combined role in overcoming MDR. In vitro studies have demonstrated the effectiveness of GPNP in reprogramming M2 macrophages and inducing apoptosis in MCF-7/ADR cells, resulting in enhanced antitumor efficacy. This work proposed an effective combination strategy to combat chemoresistance, providing new insights into the development of innovative combinatorial therapies against MDR tumors.
Insights
This study introduces a dual-responsive nanoplatform (GPNP) combining doxorubicin and resiquimod to overcome multidrug resistance (MDR) in cancer. GPNP effectively reprograms macrophages and induces cancer cell apoptosis, enhancing antitumor efficacy.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Multidrug resistance (MDR) remains a significant challenge in cancer chemotherapy.
- Current nanosystems often release multiple drugs simultaneously, limiting targeted action and efficacy.
- Developing strategies to overcome drug resistance is crucial for improving cancer treatment outcomes.
Purpose of the Study:
- To develop a dual-responsive nanoplatform (GPNP) for combinatorial chemotherapy against drug-resistant cancer cells.
- To investigate the ability of GPNP to overcome multidrug resistance by reprogramming tumor microenvironment.
- To evaluate the synergistic antitumor effect of doxorubicin (DOX) and resiquimod (R848) delivered via GPNP.
Main Methods:
- Fabrication of a core-shell nanoplatform (GPNP) responsive to glutathione (GSH) and pH.
- Encapsulation of doxorubicin (DOX) and resiquimod (R848) within the nanoplatform.
- In vitro evaluation of GPNP's ability to reprogram M2 macrophages to M1, induce apoptosis in MCF-7/ADR cells, and inhibit P-glycoprotein (P-gp) expression.
Main Results:
- GPNP demonstrated successful drug release in response to acidic and sialic acid-rich tumor microenvironments.
- Resiquimod (R848) effectively reprogrammed M2 macrophages to M1, which generated nitric oxide (NO).
- NO suppressed P-glycoprotein (P-gp) expression, reducing drug efflux and enhancing doxorubicin (DOX) efficacy, leading to increased apoptosis in MCF-7/ADR cells.
Conclusions:
- The developed GPNP nanoplatform offers an effective strategy for combinatorial chemotherapy against drug-resistant cancers.
- This approach enhances antitumor efficacy by reprogramming the tumor microenvironment and overcoming multidrug resistance.
- The study provides valuable insights for designing innovative combinatorial therapies for MDR tumors.
