This application is intended to address the significant clinical problem of breast cancer metastasis to the brain via localized activation of high drug doses in these metastases, thereby potentially overcoming their notorious resistance, and minimizing normal tissue toxicity. Our concept is novel and the work is at an early stage, making it suitable for the R21 high risk high reward concept validation funding mechanism. The strategy is to concentrate toxic drug effects at breast cancer brain metastases via selective concentration at the tumor of a nontoxic, inactive complex consisting of a nanoparticle linked to doxorubicin (Dox). Dox in sufficient doses potently suppresses breast tumor cells in culture and in preclinical models, but in free form is constrained by various toxicities throughout the body. A localized, external low dose radiation beam aimed only at the tumor will activate the radiation scintillator crystal part of the nanoparticle, which will emit light to break a photosensitive linkr. Hence Dox attached to the linker will be released only at the tumor site in the active, toxic form. We feel this new strategy is feasible for three reasons (1) breast tumor brain metastases do not infiltrate the brain beyond 1mm past the primary metastatic site and so are potentially controllable, (2) these metastases retain the blood vessel morphology of the parent tumor, which is malformed, porous and leaky, and without a blood brain barrier, and (3) the literature and our own work indicates that intravenous injection of 100-150 nm liposomes bearing Dox can result in sufficient accumulation at brain tumors to exert a marked therapeutic effect. Importantly, because the radiation dose will be low and localized, and with non-toxic prodrug primarily in tumor foci, normal tissues will be relatively spared. The present proposal represents an initial feasibility study as part of a long term initiative for preclinical studies culminating clinical trials.
The specific aims to determine feasibility are;(1) assemble, physically characterize, and quantify the radiation response of the nanoscintillator - Dox platform, and (2) determine in vitro potency and in vitro efficacy of nanoparticle prodrug. We envisage our overall strategy as not necessarily a complete cure, but rather, a novel way of addressing the clinically difficult resistance of these brain metastases and as a way to significantly reduce patient tumor burden. Very low doses of radiation are well tolerated and may be used repeatedly over months and years to help control these metastases, an approach which realistically aligns with the idea of reducing cancer to a manageable, chronic condition.
This proposal aims to selectively deliver a non-toxic nanoparticle based prodrug to breast cancer brain metastases with active drug release via low dose localized radiation. The goal is to attain sufficiently high concentrations of active drug within metastates to overcome resistance mechanisms, while sparing normal tissue. This remotely activated nano-prodrug platform aligns with the mission of the NIH to improve public health, by potentially providing well-tolerated long term control of secondary brain tumors originating from breast cancers, which if successful may significantly improve the quality and duration of life for patients.