Up to 20% of treated women with early stage breast cancer will suffer from local recurrences on the chest wall (RCW). Treatment of local recurrences is problematic and surgery provides only a 33% 5-year control rate. Radiation therapy is a preferred option, but efficacy is low for larger lesions (>3 cm diameter) and additional rounds of radiation therapy are associated with other long-term risks due to cumulative ionizing radiation. POP Biotechnologies (POP BIO) is advancing a relatively unexplored tumor-treatment technique for RCW breast cancer: chemo-phototherapy (CPT). CPT involves the intravenous injection of long-circulating, doxorubicin- loaded, porphyrin-phospholipid (PoP) liposomes (NP-01) followed by tumor irradiation with a near infrared (NIR) laser resulting in the permeabilization of the liposomes and deposition of doxorubicin localized in the tumor. At present, few, if any, light-controlled systems can achieve robust, on-demand spatial and temporal control of nanovesicle permeabilization in biological environments. Unlike heat-triggered drug release approaches, NP-01 is fully stable in serum, yet rapidly release their contents when exposed to clinically-relevant NIR laser irradiation. In mouse models, a single mild laser treatment deposits large amounts of drug, leading to permanent tumor eradication. In this proposal, PoP Biotechnologies will develop scalable liposome formulation protocols using a lipid extrusion approach and evaluate the resulting NP-01 product. This project has two specific aims:
Aim 1 : Reproducibly produce and characterize doxorubicin-loaded PoP liposomes (NP-01) using a scalable approach;
and Aim 2 : Assess in vivo pharmacokinetics, efficacy and toxicity of NP-01 in rats. Pending a successful outcome of this Phase I grant application, we will put forward a Phase II grant application involving more in depth studies for treatment dosimetry and efficacy in large animals pertinent for translation to human trials.
The ability to selectively deliver drugs with precise spatial and temporal control could lead to entirely new approaches to treatments of solid tumors. We have demonstrated anti-tumor proof of principle for a new class of doxorubicin-loaded long-circulating liposomes that rapidly release drug in response to near infrared light, a safe and clinically proven stimulus. A scalable manufacturing strategy for these liposomes will be developed and preliminary pharmacokinetics, efficacy, and toxicity in rats will be assessed.
