Most current chemotherapeutics are untargeted formulations that have little to no selectivity for cancerous tissue. As a result, these drugs often cause damage to healthy tissues which leads to uncomfortable and at times intolerable dose-limiting toxic side effects. The American Cancer Society estimates that over 1.4 million patients will be diagnosed with cancer in 2008 and many of those will be treated with chemotherapeutics. These startling statistics make the improvement of these drugs a necessity for improving the quality of patient's lives and an utmost goal for government, business and medical interests. Doxorubicin, also known as Adriamycin, is an anthracycline antibiotic that is used as a front-line treatment for breast cancer, ovarian cancer, lymphoma, neuroblastoma and Hodgkin's disease among others. However, the use of Doxorubicin has been limited by severe cardiotoxic side effects that limit the total lifetime dose that can be given to a patient. Nanoparticle delivery systems have the ability to localize chemotherapeutics to tumors as evidenced by Doxorubicin nano-delivery systems such as Doxil. However, many nanoparticulates, including Doxil, suffer from complicating factors such as toxicity of materials, large particle size and lack of colloidal stability. Calcium phosphate NanoJackets address those shortcomings as they are made of non-toxic, bioresorbable material, smaller than the commonly accepted 100nm size limit for intravenous applications, colloidally stable in physiological solutions and maintain the chemotherapeutic on the inside of the nanoparticle matrix. We believe that this combination of factors allow NanoJackets to be commercially viable where other nano-delivery systems are not. The ability to actively target the drug-containing NanoJackets directly to diseased tissue would provide the opportunity to increase the drug's efficacy while reducing unpleasant and sometimes intolerable side effects. Untargeted Doxorubicin NanoJackets are currently being produced and are at least equal to or better than treatment with Doxorubicin in preliminary in vivo experiments. We hypothesize that actively targeting NanoJacketed Doxorubicin to tumor sites will enhance efficacy while decreasing toxic side effects. To assess this hypothesis, this proposal focuses on the following specific aims: 1) identification of targets on human breast adenocarcinoma cells, 2) conjugation of antibody fragments to the surface of Doxorubicin NanoJackets with confirmation by physicochemical techniques and 3) the confirmation of antibody orientation and function by in vitro biological assays. Though Phase I of this project focuses on the feasibility of NanoJacket targeting, it is anticipated that Phase II will establish the toxicity, efficacy and biodistribution data necessary for an IND application to the FDA. While this proposal focuses on targeting Doxorubicin NanoJackets, this technology is flexible enough to allow encapsulation of many different therapeutic compounds with minimal adjustments to the synthesis procedure. The successful development of targeting strategies would permit the creation of numerous NanoJacket products with different chemotherapeutics and surface treatments from which a physician could select from to individualize treatment for optimal efficacy with minimal side effects.
Despite recent advances in the treatment options for breast cancer, there are still far too many patients who do not respond to conventional therapies. The convergence of biology, medicine, engineering and material sciences has led to the creation of nanoscale materials that have the potential to radically improve change cancer therapies and dramatically increase the number of highly effective therapeutic agents. Nanoscale constructs can serve as customizable, targeted, drug delivery vehicles capable of ferrying large doses of chemotherapeutic agents or therapeutic genes into malignant cells while sparing healthy cells, greatly reducing or eliminating the undesirable side effects that accompany many current cancer therapies.
