Session: 14-04-01: Micro/Nano Devices and Medical Systems

Paper Number: 166655

Biomimetic Nanosystem for Efficient Chemodynamic Cancer Therapy 

Cancer cells adapt to rapid proliferation by altering their metabolism and protein translation, leading to elevated levels of reactive oxygen species (ROS).¹ To survive in this oxidative environment, cancer cells upregulate antioxidant systems to maintain ROS levels below the cytotoxic threshold.² While this elevated basal ROS level is essential for tumor growth, it also renders cancer cells more susceptible to additional oxidative stress compared to normal cells.^{3, 4} Leveraging this vulnerability, therapies such as photodynamic therapy (PDT), sonodynamic therapy (SDT), and chemodynamic therapy (CDT) have been developed to amplify ROS production within tumors. Among these ROS, hydroxyl radicals (•OH) are particularly lethal, generated through Fenton or Fenton-like reactions involving hydrogen peroxide (H₂O₂) and catalytic metals. However, traditional Fe-based Fenton agents, such as Fe₃O₄,^{5, 6} FeS,⁷ FeS₂,^{8, 9} and Fe₂P,¹⁰ require strongly acidic conditions (pH 3-4) to initiate these reactions-conditions that are difficult to achieve in the mildly acidic tumor microenvironment (TME).¹¹ Moreover, the efficacy of CDT is often limited by the slow Fenton reaction cycle, characterized by the rapid precipitation of Fe³⁺ at neutral pH and its sluggish reduction back to Fe²⁺,^{12, 13} coupled with insufficient H₂O₂ levels (50-100 µM) within the TME.

Strategies to supply sufficient H₂O₂ include stimulating in situ generation by disrupting the TME’s redox balance or introducing exogeneous sources of H₂O₂, such as metal peroxides. In situ generation of H₂O₂ can be enhanced by promoting the conversion of superoxide ions within TME into H₂O₂, and reducing its elimination (e.g. inhibition of catalase).¹⁴ However, this approach requires complex nanocatalyst designs and may still result in inadequate H₂O₂ levels. Exogenous sources like CuO₂ and CaO₂ can provide ample H₂O₂, however, these metal peroxides poses safety risks due to potential premature leakage and toxic metal ion release in physiological environments.¹⁴ Therefore, design of novel metal peroxide systems that remain stable in physiological environments while degrade rapidly within the TME is highly desirable for CDT.

To accelerate Fenton reaction cycle, a straightforward approach is to increase the availability of Fe³⁺ by preventing its precipitation. This can be achieved by forming stable Fe³⁺-chelate complexes, particularly with poly-chelates that provide multiple Fe²⁺/Fe³⁺ binding sites. Tannic acid (TA) is a noteworthy molecule capable of serving both as a chelate and a reductive agent. TA can chelate Fe³⁺ ions to boost CDT,^15-17 but it also act as a potent radical scavenger, particularly for H₂O₂ and •OH^{18, 19}, and has even been used as an inhibitor of the Fenton reaction. Acid-terminated poly(lactic-co-glycolic) acid (PLGA) presents a promising alternative due to its multiple carboxylic groups, biocompatibility, and ease of nanoparticle modification.²⁰ PLGA not only enhances Fe³⁺ availability but also provide a protective coating that reduces the premature leakage of metal peroxides. Nonetheless, developing novel reductive molecules that can accelerate the Fenton reaction cycle with minimal interference with •OH remain crucial for effective CDT.

In this context, nitric oxide (NO) emerges as a potential enhancer for CDT. NO has a high affinity for hemoglobin and can preferentially reduce ferric hemoglobin (Fe³⁺) to its ferrous form (Fe²⁺) at low concentrations.²¹ Studies have shown that NO can boost the Fenton reaction by reducing Fe³⁺ into Fe²⁺ in both chemical systems²² and microorganisms (e.g. E.coli).^23-25 Additionally, NO-mediated cytotoxicity in human ovarian cancer cells has been linked to enhanced Fenton reactions through Fe³⁺ reduction or catalase inhibition which stabilizes H₂O₂.²² Despite its potential, the direct role of NO in Fenton chemistry within the TME remains largely unexplored.

To address these challenges, we developed a TME-responsive nanoparticle system using PLGA-encapsulated Ca-Fe peroxide nanoparticles (CaFe NPs) and polyarginine (R). To enhance tumor targeting, cancer cell membrane (CCM) was utilized to camouflage our nanoparticles, exploiting the homotypic targeting ability.  Under physiological conditions, PLGA shell remains stable while within the TME, H₂O₂ degrades PLGA, releasing CaFe NPs and producing Fe²⁺ and H₂O₂. This degradation triggers the Fenton reaction, generating •OH and further degrading PLGA, leading to a self-accelerating reaction cycle. Additionally, the released H₂O₂ reacts with polyarginine to produce NO, enhancing the Fenton reaction cycle and promoting efficient hydroxyl radical generation within the TME. Collectively, this novel TME-initiated, self-accelerating CDT platform offers a promising approach for efficient chemodynamic tumor therapy.

Presenting Author: Shiren Wang Texas A&M University

Presenting Author Biography: Dr. Wang is a professor in the Department of Industrial and Systems Engineering, with joint appointment appointments at the Department of Materials Science and Engineering and the Department of Biomedical Engineering, Texas A&M University. His research is focused on advanced manufacturing and Bio/nano-systems.

Authors:

Jun Ma Texas A&M University
Jenny Qiu Texas A&M University
Shiren Wang Texas A&M University