Targeted drug delivery to tumor microenvironment

DESCRIPTION provided by applicant The goal of this project is to test the feasibility of targeted delivery of andquot re programmingandquot liposomal drugs to tumor associated macrophages TAMs TAMs are the major component of tumor microenvironment that generally supports tumor growth and interferes with anti tumor therapy These effects are significantly mediated by about of TAMs that are located in tumor perivascular areas and are the major source of pro tumorigenic and pro angiogenic mediators specifically implicated in promotion of tumor angiogenesis and metastatic dissemination There is evidence that various re programming cues can be used to reduce the pro tumorigenic potential of TAMs creating an opportunity for more efficient anti cancer therapy To target perivascular TAMs we selected liposomal formulations of a TLR ligand poly I C that we named Lip PIC The TLR activation stimulates re polarization in TAMs which appears to be relatively safe as it is being developed for various vaccination protocols and at the same time rather efficient in tumor growth inhibition at least in animal tumor models We reasoned that Lip PIC would extravasate through the leaky tumor vasculature to perivascular space the very area of the location of perivascular TAMs To further increase the probability of targeted drug delivery to TAMs we propose to test Lip PIC decorated with annexin V that targets tumor cells undergoing apoptosis Pro tumorigenic TAMs are the known andquot eatersandquot of tumor apoptotic cells presenting an opportunity to use tumor apoptotic cells as andquot Trojan Horseandquot to feed Lip PIC to TAMs Given the complexity of tumor microenvironment that is impossible to reconstruct in tissue culture we reasoned that only in vivo system would be adequate for the proposed proof of principle experiments Therefore we will test our approach in orthotopic T luc mouse breast tumor xenografts in immunocompetent Balb c mice Our Specific Aims are Specific Aim Evaluate the effects of delivery of liposomal poly I C formulation to perivascular TAMs in a breast cancer tumor model Specific Aim Establish if delivery of liposomal poly I C to TAMs could be enhanced by recruitment of apoptotic cells indoxorubicin treated breast cancer model Accomplishing these Specific Aims will provide a proof of principle for using liposomal formulations for delivery of re programming drugs to perivascular TAMs in vivo We envision that the eventual commercial product will be a proprietary optimized liposomal formulation for targeting perivascular TAMs in primary tumor as a part of combination anti cancer therapy PUBLIC HEALTH RELEVANCE The goal of this project is to test the feasibility of targeted delivery of andquot re programmingandquot liposomal drugs to specific cells in tumor microenvironment in order decrease their tumor supporting potential and increase their tumor fighting capabilities Two strategies will be tested one based on delivering liposomal drugs to the same andquot neighborhoodandquot where tumor supporting cells reside and the other based on targeting liposomal drugs to dying tumor cells that are expected to serve as andquot Trojan Horseandquot in feeding pro tumorigenic cells in tumor microenvironment