(572f) Transport- and Reaction-Modeling of Nanocarriers for Cancer Therapeutics Via Experimental and in-Silico approaches

Introduction: Solid tumors account for 80-90% of all reported cancer cases. Various therapies leveraging different properties exhibited by tumors have been experimented with over the last few years. At the same time, there have been multiple mathematical models developed to model the response of cancer cells and of tumors to therapies. Yet, we realize that there is a disconnect between the two communities: sophisticated nanoparticles are reported usually without dosimetric analysis, which could in principle enable extrapolation of the reported results to other tumors and/or types of therapeutics. The experimental community has yet to fully embrace the functionality of the modeling, as it is rarely "personalizable" and, thus, difficult to exploit. It is abundantly clear that cross-fertilization between the experimental and the in-silico research approaches to solid tumor drug delivery carrier design should be particularly valuable for fast turnaround results. A user friendly, personalizable tool, UMA (User-friendly Modular Algorithm) of this kind, which could (a) help estimate/evaluate the limitations and abilities of drug delivery carriers currently under development without the need for extensively time-consuming experiments and (b) allow for designs of hypothetical carriers exploring future materials, is a much needed development as such a tool does not currently exist. We are interested in the interplay of different (and novel) carrier design options, different transport and binding steps –many of them pH profile dependent- and different spheroid types (used as in vitro surrogates of the avascular tumor regions).

Materials and Methods: To characterize multicellular spheroids comprising the HER2-positive and triple negative breast cancer cell lines BT-474 and MDA-MB-231, respectively, the interstitial pH_e profiles of different spheroid sizes were evaluated using a membrane impermeant (SNARF-4F) fluorescent pH indicator. Liposomes were used as ideal analog simulators of other drug carriers and were designed to have different behavioral characteristics such as binding specificity, drug release kinetics, cell internalization etc. and were utilized to help validate the in-silico model. Liposomes possessing combinations of these properties were formed using the thin film hydration method. They were further characterized by evaluating the aforementioned properties. Doxorubicin (DXR) and cisplatin (CDDP) were chosen to be evaluated as the delivered therapeutic agents, and the dose responses to these agents were evaluated on the same cell lines. Temporal microdistributions of liposomal carriers and of their therapeutic cargo were also evaluated in spheroids.

Results and Discussion: The efficacy of a drug-carrier system is determined as the combined result of different processes, namely, transport, binding, drug release and drug availability at the active site(s). Experiments were performed to isolate each process - when possible - and to evaluate the necessary and required parameters, characterizing these processes. Parameters obtained by fitting the processes (including but not limited to binding, internalization, trafficking, release, killing etc.) to rate laws were used to experimentally inform the mathematical model. Since the focus of this study is on established tumors which develop acidic interstitial regions, in several of the processes mentioned above, parameters were found to be a function of the local pH which is in turn a function of the location within the spheroid (i.e. the radial distance).

Conclusion: The developed tool is intended to serve as a guide to reduce the number of iterations in designing novel carrier systems and in addressing specific challenges in therapy by taking into account the intratumoral and intertumoral heterogeneities. The developed tool will go beyond simply validation and help multiple labs evaluate multiple carrier systems and make informative and quantitative decisions about their therapeutic potential.