Mathur, Sanjay | Hallek, Michael - B 05 (TP)

We propose an advanced drug delivery platform utilizing stimuli-responsive antibody@lipid-silica (AB@LS) nanocarriers, precisely engineered for targeted intervention and active remodeling of the tumor microenvironment (TME). This next-generation hybrid nanocarriers outperform pure inorganic (e.g., gold silica) or organic (e.g., liposomes, biopolymers) systems by integrating the structural stability and tunable loading of silica with the biocompatibility and responsive release properties of liposomes, enabling more effective and controlled drug delivery. Notably, the mesoporous silica efficiently encapsulates unstable or hydrophobic  molecules whereas a pH-sensitive, PEGylated lipid shell ensures selective and high-affinity antibody-mediated targeting with tumor-triggered release. The proposed AB@LS nanocarriers are designed to overcome key therapeutic barriers through (i) on-demand payload release in the acidic TME, thereby reducing off-target toxicity (ii) multimodal therapeutic action through combined actions of cytotoxic, redox-active, and immunoregulatory agents and (iii) reprogramming tumor-associated macrophages. The availability of chemically engineered nanocarriers within CMMC would enable precise modulation of drug delivery kinetics, substantially enhance therapeutic efficacy, and offer the capability to reshape the immunological landscape of solid tumors through targeted and controlled interventions. 

Building on our previous research on the TME in chronic lymphocytic leukemia (CLL), we propose to apply this innovative nanocarrier platform for precise and selective drug delivery in this disease context. We will employ FAP@LS, functionalized with antibodies against fibroblast activation protein (FAP) to target fibroblasts within the leukemic microenvironment, where FAP is overexpressed compared to healthy tissue. In parallel, CD206@LS nanocarriers will address tumor-supportive macrophages, leveraging the selective expression of CD206 on these immunosuppressive myeloid cells. Proof-of-concept experiments will be conducted using established in vitro co-culture systems to assess targeting specificity, cellular uptake, and controlled drug release. These nanocarriers will be loaded with Src family kinase inhibitors - including dasatinib, bosutinib, 

and saracatinib - which we have previously identified as potent modulators of the CLL microenvironment via inhibition of LYN and related kinases. We hypothesize that targeted delivery of these inhibitors will disrupt leukemia-supportive stromal interactions while minimizing systemic toxicity and off-target effects. To evaluate therapeutic efficacy and safety, we will combine in vitro functional assays with in vivo testing in murine CLL models. 

Given that both FAP and CD206 are also highly relevant targets in the microenvironment of various solid tumors, this platform holds promise for broader oncological applications. Ultimately, this project aims to develop a novel, dual-function nanotherapeutic that selectively modulates the tumor microenvironment. By combining precise cellular targeting with the localized delivery of kinase inhibitors, we envision a strategy that reprograms the malignant niche while sparing healthy tissues, thus offering a path toward more effective and less toxic cancer therapies.

The tumor microenvironment promotes cancer progression and resistance, thus representing a promising therapeutic target. However, targetability is limited due to systemic toxicity, as microenvironmental cells cannot be easily distinct from physiological cells. Novel, precise TME drug delivery would enhance therapeutic potential with reduced systemic toxicity. AB@LS carriers deliver drugs to tumors with precision, reducing toxicity and improving cancer outcomes. Its design combines targeting, pH response, and overcome limitation of poor drug solubility, rapid clearance, and lack of tumor selectivity -while modulating both cancer cells and the immune landscape. It bridges the existing gap between drug carriers and clinical oncology, facilitating rapid translation from academic innovation to the clinic. Its modularity allows the customization to various tumor types and therapeutic cargos, supporting broad clinical applicability. It provides tools for real-time interrogation of the TME, enhancing understanding of disease mechanisms and treatment response. The nanocarriers would reduce systemic load (and drug waste), contributing to more sustainable cancer therapy development with improved well-being of the patients. Selected target antigens FAP and CD206 are overexpressed by fibroblasts and macrophages, respectively in the microenvironment of CLL and other cancers, representing promising targets for specific intervention.

• Covalent Chemistry for the enginering of antibody-functionalized lipid silica nanocarriers that combine silica stability with lipid biocompatibility for controlled and targted  drug transportation.
• Load kinase inhibitors to antibody-functionalized lipid silica to achieve multimodal action against tumor supportive cells.
• Enable tumor specific targeting through antibody recognition and pH responsive release to improve therapeutic accuracy and reduce off target toxicity.
• Validate targeting specificity, safety, and therapeutic efficacy through integrated in vitro assays and in vivo disease models, supporting future clinical translation.

Targeted drug delivery (TDD) is a fundamental paradigm in drug sciences. Paul Ehrlich postulated already a century ago that targeting of drugs would be a major medical progress. He compared such substances with "Zauberkugeln" (magic bullets). Development of hybrid nanocarriers (Lipid@Silica) such as AB@LS represents a next-generation, high-risk/high-gain technology with strong translational potential, directly addressing unmet clinical needs in oncology by enabling precise, immune-modulating drug delivery to tumors. Given the tumor induced reprogramming of normal cells in the microenvironment into tumor promoting states, precise interventions to prohibit this reprogramming without affecting physiological cells within the rest of the body are promising for advancing translational TME. The establishment of a nanocarrier platform will not only advance the scientific and clinical frontiers of TME-targeted therapy but 4 is also well-aligned to the core values of CMMC to promote innovation, collaboration, and researcher development, making it a good fit. 

By unifying the materials chemistry expertise of “Research Group Mathur” in the rational design and synthesis of AB@LSwith the immunological and tumor microenvironment insights of “Research Group Hallek”, our collaboration enables real-time, iterative optimization from bench to bedside-accelerating the development of precision drug delivery systems, deepening mechanistic understanding of nanocarrier uptake and their role in immune modulation, as well as enhancing clinical translation beyond what either discipline could achieve alone.

For more information, please check Prof. Mathur´s and Prof. Hallek´s site. 

• Center for Molecular Medicine Cologne (CMMC)
• Institute of Inorganic and Materials Chemistry, University of Cologne, Germany