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    Awarded Grants
    A Lymph Node Targeted Anti-Cancer Drug Delivery System for Breast Cancer Metastases Based on Calcium Phosphate Particulates

    Scientific Abstract:
    In our ongoing research of anti-cancer drug delivery systems, we have developed calcium phosphate nanocrystalline/cisplatin (CaP/CDDP) conjugates that inhibit primary mouse mammary tumor growth after local intratumoral injection. In this proposal we will expand our targeted, less toxic chemotherapy drug delivery system to the lymphatic tissues for the treatment and prevention of breast cancer metastases that have a high tendency for lymphatic dissemination. Previous studies have demonstrated that interstitially administered colloidal carrier systems, in the form of particles, emulsions, liposomes, etc. can deliver diagnostic and therapeutic agents into regional lymphatic circulation and lymph nodes. Lymphatic localization of the particles has been shown to depend on particle size and surface characteristics. Our hypothesis is that the CaP particle size and surface characteristics can be optimized to accumulate chemotherapy in the draining lymphatic tissues following peritumoral injection and thereby inhibit metastases. The study design centers on the use of a metastatic murine breast cancer cell line (66cl4) that metastasizes via the lymph system. In Aim 1 we will test various particle sizes of CaP particulates and various suspending agents to optimize CDDP drug accumulation in the draining lymph nodes of tumor free animals. CDDP concentration will be measured from platinum analysis of digested lymph nodes. In Aim 2 we will evaluate the antimetastatic potential of the optimized CaP/CDDP conjugates in the 66c14 mouse model. Primary tumors will be initiated by injection of 66cl4 cells in the mammary fat pad of BALB/c mice. Study groups will consist of: peritumoral CaP/CDDP, intraperitoneal chemotherapy, CaP alone, or no treatment either prior to or after the initiation of metastasis. Draining lymph nodes will be harvested and metastatic tumor cells will be quantitated by a clonogenic assay utilizing the fact that 66cl4 is thioguanine resistant. Serum BUN levels will be measured to assess nephrotoxicity of the CDDP treatments. We envision eventual clinical prevention and treatment of metastases through targeted neoadjuvant or presurgical peritumoral injections of anticancer drug conjugates. This research has great potential to enhance the prospect of longer disease-free survival for breast cancer patients by targeting metastases and to minimize side effects of both current and future chemotherapy drugs.

    Lay Abstract:
    The success or failure of breast cancer treatments is related to whether metastasis can be controlled; therefore, this study is focused on developing a lymph node targeted chemotherapy treatment of breast cancer that has a high tendency to metastasize lymphatically. Previous studies have shown it is possible to image the lymphatic drainage patterns of breast cancer by injecting dye-carrying or radioactive particulate materials at the periphery of the main tumor. We propose to use this same technology to target chemotherapy to the draining lymph nodes. Instead of carrying a dye or radioactivity, our particulates have been chemically modified to deliver an anti-cancer drug and will localize the toxic chemotherapy exactly where it is needed by following the same path as the cancer cell. In our ongoing research of anti-cancer drug delivery systems, we have developed calcium phosphate nanoparticulate/cisplatin (CaP/CDDP) conjugates that inhibit primary mouse mammary tumor growth after local intratumoral injection. We have demonstrated that dose-limiting side effects are greatly reduced by injecting the tumor directly as compared to a systemic injection. Concern regarding breast cancer metastasis to the lymph nodes has led us to propose to optimize our system for the accumulation of anti-cancer drug in the lymph nodes as well as the primary tumor. Our hypothesis is that the CaP particle size and surface characteristics can be optimized to accumulate chemotherapy in the draining lymph nodes following peritumoral injection and thereby inhibit and treat metastases. In Aim 1 we will optimize CDDP drug accumulation in the draining lymph nodes of tumor free animals by modification of the size and surface of the CaP particulates. In Aim 2 we will evaluate the antimetastatic potential of the optimized CaP/CDDP conjugates in the lymph node metastasizing 66c14 mouse model. Study groups will consist of: peritumoral CaP/CDDP, intraperitoneal CDDP, CaP alone, or no treatment either prior to or after the initiation of metastasis. A decrease or absence of lymph node tumor cells and reduced drug side effects in the CaP/CDDP group is the positive outcome we anticipate. We envision clinical prevention and treatment of metastases through presurgical peritumoral injections of anticancer drug conjugates. This research has great potential to enhance the prospect of longer disease-free survival for breast cancer patients and to minimize side effects of both current and future chemotherapy drugs.