This Small Business Innovation Research (SBIR) Phase I project aims to develop a tumor-specific delivery technology based on the use of superparamagnetic nanoparticles as vehicles for the delivery of paclitaxel. The magnetic vectoring drug delivery platform uses external shaped magnetic field gradients to concentrate nanoparticle-drug constructs at a target site, followed by tumor extravasation. This project will focus on the treatment of superficial tumors, such as locally advanced breast cancers (LABC). These tumors pose a difficult and, as yet, unresolved clinical problem as most patients presenting with this disease will experience resistance and pronounced toxicity for current therapeutics. Therefore, a significant need exists for advanced therapies that can improve patient outcomes. A key distinguishing feature of this technology is the potential to overcome tumor interstitial pressure that normally tends to thwart free drug penetration.
The broader/commercial impact of this project will be the potential to provide localized delivery of therapeutics in a manner that improves both therapeutic and economic benefits to patients. The urgency for such advanced delivery methods is increasing as new classes of pharmaceuticals, such as siRNAs and stem cells, are being developed and brought to market. Because these new therapeutics are more effective through localized therapy, advanced delivery systems that support their full therapeutic potential must be developed. The capacity to magnetically vector therapeutics, tumor-specifically, will have a significant impact on both patient treatment strategies and outcomes.
The overall objective of the Phase I SBIR was to demonstrate the feasibility of tumor-specific targeting of the cytotoxic drug, paclitaxel, covalently linked to modified SPION carriers, and manipulated under the influence of shaped external magnetic field gradients. As proposed herein, the concentration of modified SPION-TXL prodrug constructs, and therefore toxicity, is a function of localization, and by using magnetic vectoring, one can theoretically reduce amounts of drug administered and still achieve higher concentrations at the point of tumor delivery and extravasation. Feasibility Results: The NBMI/MDACC research collaboration has successfully demonstrated the following: (1) modified SPION-TXL prodrug constructs exhibit significant anti-tumor efficacy in human breast cancer xenograft models, (2) modified SPION and SPION-TXL constructs exhibit little or no toxicity against a range of tissue types, including the liver, and (3) magnetic field gradients can be shaped to focus on a tumor site and drive the concentration/extravasation of modified SPION constructs at the tumor site . The extensive and compelling feasibility results, which distinctly separates this "nano" era technology from historical efforts, forms the basis for advancing to Phase II studies. The demonstration of tumor-specific magnetic targeting and anti-tumor efficacy of modified SPION-TXL prodrug constructs, will lead to a viable clinical modality. Of Significance – The efficacy/capacity of SPION-TXL Prodrug Constructs to Shrink Tumors was demonstrated. Of Significance – Modified SPION and SiMNP-TXL constructs, across thirty-two different tissue types, showed NO significant tissue toxicity effect. Of Significance – The capacity of configurations of permanent magnets to drive the tumor-specific concentration/extravasation of SPION constructs in Human Tumor Xenograft Models was demonstrated. Of Significance – The capacity to scale the MVU to generate a field gradient profile beyond 2 in was successfully demonstrated with a approach similar to Halbach arrays, approaching depths of 4 in or more. Of Significance – Potential for pulling SPION from dispersion at high flow, across a membrane to concentrate at a site was successfully demonstrated. Thus, we conclude: Magnetic vectoring of pro-drug constructs has the potential to significantly advance the effectiveness of systemic administration of cytotoxic drugs, raising their therapeutic index, and offering a new advanced treatment option that addresses both enhanced drug performance and quality of life.
