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Reactive Oxygen Species (ROS)-Responsive Polymersomes with Site-Specific Chemotherapeutic Delivery into Tumors via
Eliézer Jäger1, Vladimir Sincari1, Lindomar J C Albuquerque2
1Institute of Macromolecular Chemistry, Heyrovsky Sq. 2, 162 06 Prague, Czech Republic.
Abstract:
The lack of cellular and tissue specificities in conventional chemotherapies along with the generation of a complex tumor microenvironment (TME) limits the dosage of active agents that reaches tumor sites, thereby resulting in ineffective responses and side effects. Therefore, the development of selective TME-responsive nanomedicines is of due relevance toward successful chemotherapies, albeit challenging. In this framework, we have synthesized novel, ready-to-use ROS-responsive amphiphilic block copolymers (BCs) with two different spacer chemistry designs to connect a hydrophobic boronic ester-based ROS sensor to the polymer backbone. Hydrodynamic flow focusing nanoprecipitation microfluidics (MF) was used in the preparation of well-defined ROS-responsive PSs; these were further characterized by a combination of techniques [1H NMR, dynamic light scattering (DLS), static light scattering (SLS), transmission electron microscopy (TEM), and cryogenic TEM (cryo-TEM)]. The reaction with hydrogen peroxide releases an amphiphilic phenol or a hydrophilic carboxylic acid, which affects polymersome (PS) stability and cargo release. Therefore, the importance of the spacer chemistry in BC deprotection and PS stability and cargo release is herein highlighted. We have also evaluated the impact of spacer chemistry on the PS-specific release of the chemotherapeutic drug doxorubicin (DOX) into tumors in vitro and in vivo. We demonstrate that by spacer chemistry design one can enhance the efficacy of DOX treatments (decrease in tumor growth and prolonged animal survival) in mice bearing EL4 T cell lymphoma. Side effects (weight loss and cardiotoxicity) were also reduced compared to free DOX administration, highlighting the potential of the well-defined ROS-responsive PSs as TME-selective nanomedicines. The PSs could also find applications in other environments with high ROS levels, such as chronic inflammations, aging, diabetes, cardiovascular diseases, and obesity.
Insights
Novel nanomedicines using ROS-responsive polymersomes enhance chemotherapy by targeting the tumor microenvironment (TME). Spacer chemistry design improves drug delivery, reduces side effects, and shows potential for treating various ROS-related diseases.
Area of Science:
- Biomaterials Science
- Nanomedicine
- Polymer Chemistry
Background:
- Conventional chemotherapy faces challenges due to lack of specificity and complex tumor microenvironments (TME), limiting drug efficacy and causing side effects.
- Developing selective, TME-responsive nanomedicines is crucial for improving chemotherapy outcomes.
- Reactive oxygen species (ROS) are key indicators of the TME, presenting an opportunity for targeted drug delivery.
Purpose of the Study:
- To synthesize novel ROS-responsive amphiphilic block copolymers (BCs) with varying spacer chemistries for TME-selective nanomedicine development.
- To investigate the impact of spacer chemistry on polymersome (PS) stability, drug release, and therapeutic efficacy.
- To evaluate the potential of these ROS-responsive PSs for targeted delivery of chemotherapeutic agents like doxorubicin (DOX).
Main Methods:
- Synthesis of ROS-responsive amphiphilic block copolymers (BCs) with boronic ester-based ROS sensors.
- Preparation of well-defined polymersomes (PSs) using hydrodynamic flow focusing nanoprecipitation microfluidics (MF).
- Characterization using techniques including 1H NMR, DLS, SLS, TEM, and cryo-TEM.
- In vitro and in vivo evaluation of drug release, anti-tumor efficacy, and side effects using doxorubicin (DOX) in EL4 T cell lymphoma models.
Main Results:
- The synthesized ROS-responsive PSs demonstrated tunable stability and cargo release triggered by hydrogen peroxide (H2O2) via spacer chemistry modulation.
- Spacer chemistry significantly influenced BC deprotection, PS stability, and drug release kinetics.
- In vivo studies showed enhanced DOX efficacy, reduced tumor growth, and prolonged survival in mice with EL4 T cell lymphoma compared to free DOX.
- Reduced side effects, including weight loss and cardiotoxicity, were observed with the developed nanomedicines.
Conclusions:
- Spacer chemistry is a critical design element for developing effective ROS-responsive polymersomes for TME-selective drug delivery.
- These novel nanomedicines offer a promising strategy to improve chemotherapy efficacy and reduce associated toxicities.
- The developed ROS-responsive PSs hold potential for treating cancers and other diseases associated with high ROS levels, such as chronic inflammation and diabetes.
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