| Description |
The overall objective of this project is to develop methods that can help us to understand the movement of drugs and carriers along their routes inside solid tumors. The origins and current paradigm of targeted drug delivery offer a lot of promising strategies. However, the carriers often struggle with challenges in optimizing their own characteristics against that of the tumor's. Ultimately, they struggle with translation into the clinical setting. It is apparent that solid tumors pose a unique challenge in drug delivery. Many drug carrier characteristics are designed to take advantage of the pathophysiology of the tumor environment. However, this passive delivery and accumulation is constrained to partial distribution within the tumor. Many uncertainties remain regarding how nanoparticles enter and travel through the tumor environment. The barriers to intratumoral distribution are still currently being probed. The research herein identified transport barriers using human fibroid tumors known to have impaired drug transport. After perfusing human uteri containing fibroids with stains, probe distribution was found to correlate with features of the pathophysiology such as blood vessel characteristics, tissue and collagen density, interstitial fluid pressure, and solid stress. Methods, including custom MATLAB code, were developed to analyze the spatiotemporal distribution of two uniquely fluorescent nanoparticle doses in xenograft mice. It shows how three-dimensional distance measurements of nanoparticles from nearest blood vessels are more precise than two-dimensional measurements. Colocalization analysis on the fluorescent signals showed the two different doses (administered hours apart from each other) did not accumulate in the same locations with the tumor. Furthermore, intravital imaging showed that some vessels of the tumor would only provide access to the first dose of nanoparticles. Future work suggests further analysis of multidose interdependence and implementing these methods to screen strategies in the literature of modifying drug carriers and the tumor environment to improve intratumoral distribution of cancer drugs. The more understanding we have of the solid tumor environment and its barriers, the better we can navigate treatments to reach the tumor. |
