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Jing Zhang, Speaker at Drug Delivery Conferences
Technical University of Denmark, Denmark
Title : MMPs (Matrix Metalloproteinases) -Responsive ‘smart’ nanomedicine in cancer treatment

Abstract:

The overexpression of specific matrix metalloproteinases (MMPs) is a hallmark of many cancers, making these enzymes ideal targets for the development of stimuli-responsive nanomedicines. In this context, MMP-responsive ‘smart’ nanomedicine has been engineered to deliver cytokines, enhancing therapeutic efficacy while minimizing off-target effects. Briefly, immunoregulatory agents such as cytokines are conjugated onto the surface of polymeric nanoparticle cores. These cytokines are then transformed into prodrugs by coating them with MMP-responsive peptides and polyethylene glycol (PEG), thereby protecting their bioactivity.

Compared to free cytokines, this design has shown an obvious improvement in immune response during in vitro testing. Notably, this approach requires a smaller amount of cytokines to achieve effective immunotherapy compared to encapsulated dosage forms. The straightforward conjugation method also potentially enables personalized treatments, as the type of cytokine can be tailored to match the patient's tumor characteristics and immune profile. The modularity of the design allows it to be adapted for different cytokines and therapeutic strategies, making it highly versatile for various cancer treatments.

Additionally, the design facilitates controlled and timely release of therapeutic agents, triggered by elevated MMP activity within the tumor microenvironment. This mechanism allows for precise spatial and temporal regulation of cytokine release, which is particularly advantageous for modulating immune responses dynamically within the tumor. As a result, the risk of systemic cytokine release syndrome (CRS) is significantly reduced, addressing a key concern associated with immune-modulating therapies. By targeting the activation of cytokines locally within the tumor site, the design minimizes the potential for immune overactivation and associated toxicities.

The PEG coating further enhances the system by stabilizing the conjugated cytokines, which are often vulnerable to rapid degradation during circulation. This protective layer shields the cytokines from proteolytic enzymes and other degrading agents in the bloodstream, ensuring their bioactivity is preserved until they are released in the tumor microenvironment. In addition, the PEG coating improves the stealth properties of the nanoparticles, reducing their detection by the mononuclear phagocyte system (MPS) and prolonging their circulation time. This extended circulation enhances the accumulation of nanoparticles at the tumor site via the enhanced permeability and retention (EPR) effect, which is crucial for achieving effective drug delivery to solid tumors.

Overall, MMP-responsive ‘smart’ nanomedicine, utilizing conjugated cytokines as prodrugs, represents a superior approach by combining immunotherapy with targeted drug delivery. This strategy ensures protection and controlled release of immunoregulatory agents, reducing systemic toxicity, improving tumor-specific activation, and enhancing therapeutic outcomes. Additionally, it offers personalized treatment opportunities, positioning this system as an innovative and multifunctional alternative to other MMP-responsive nanomedicines.

Biography:

Jing Zhang studied pharmaceutical design and engineering at Technical University of Denmark and graduated as MS in 2022. She then is studying as a PhD student in the research group of Prof. Yi Sun at Technical University of Denmark, focusing on design and engineering of nanomedicine for cancer treatment. She has published 2 research articles in the Journal of Colloid and Interface Science, Nano Letters respectively during PhD studies.

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