The goal of this project is to test the feasibility of targeted delivery of "re-programming" 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 50% 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 TLR3 ligand, poly(I:C), that we named Lip(PIC). The TLR3 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 "eaters" of tumor apoptotic cells presenting an opportunity to use tumor apoptotic cells as "Trojan Horse" 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 4T1luc mouse breast tumor xenografts in immunocompetent Balb/c mice. Our Specific Aims are: Specific Aim #1. Evaluate the effects of delivery of liposomal poly(I:C) formulation to perivascular TAMs in a breast cancer tumor model. Specific Aim #2. 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 Statement:
Public Health Relevance: The goal of this project is to test the feasibility of targeted delivery of "re-programming" 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 "neighborhood" where tumor-supporting cells reside, and the other based on targeting liposomal drugs to dying tumor cells that are expected to serve as "Trojan Horse" in feeding pro-tumorigenic cells in tumor microenvironment.
Project Terms:
angiogenesis; Animals; annexin A5; Apoptosis; Apoptotic; Area; base; Breast Cancer Model; Breast Carcinoma; breast lumpectomy; cancer therapy; cancer type; Caring; Cells; Clinic; Cues; design; Development; Doxorubicin; Drug Delivery Systems; Drug Formulations; Equus caballus; Excision; feeding; fighting; Gene Expression Profile; Goals; Immunocompetent; in vivo; Lead; Ligands; Lip structure; Liposomes; Location; macrophage; malignant breast neoplasm; Mammary Neoplasms; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Names; Neighborhoods; Neoadjuvant Therapy; neoplastic cell; novel; novel therapeutics; Operative Surgical Procedures; Patients; Perivascular Neoplasm; Permeability; Pharmaceutical Preparations; Phase; Play; Poly I-C; pre-clinical; Primary Neoplasm; Probability; programs; Protocols documentation; public health relevance; Radical Mastectomy; Regimen; research study; response; Role; Source; success; Supporting Cell; System; targeted delivery; Testing; Therapeutic; Time; tissue culture; TLR3 gene; tumor; Tumor Angiogenesis; tumor growth; Tumor Immunity; tumor microenvironment; tumor xenograft; tumorigenic; Unresectable; Vaccination
