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.
Public Health Relevance Statement: PROJECT NARRATIVE 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.
NIH Spending Category: Bioengineering; Biotechnology; Breast Cancer; Cancer; Nanotechnology; Radiation Oncology; Women's Health
Project Terms: Animal Model; Animals; Applications Grants; base; Biological; biomaterial compatibility; Biotechnology; Blood flow; Breast Cancer Model; Breast Cancer Patient; Buffaloes; Caliber; cancer therapy; Canis familiaris; Caring; Chest wall structure; Cholesterol; Clinical; Clinical Data; Clinical Treatment; Clinical Trials; clinically relevant; Communication; Cutaneous; Data; Deposition; Development; Development Plans; Dose; dosimetry; Doxorubicin; Doxorubicin Hydrochloride Liposome; Drug Kinetics; effectiveness measure; Environment; Evaluation; Exhibits; experience; Exposure to; FDA approved; Formulation; Future; Generations; Human; improved; in vivo; insight; intravenous injection; Investigational Drugs; Investigational New Drug Application; Ionizing radiation; irradiation; Lasers; Lead; Lesion; Light; Lipids; Liposomal Doxorubicin; Liposomes; malignant breast neoplasm; Mass Spectrum Analysis; Measures; Metastatic breast cancer; mid-career faculty; Modality; Modeling; mouse model; nanoparticle; nanovesicle; Nature; novel; novel strategies; Operative Surgical Procedures; orthotopic breast cancer; Outcome; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phospholipids; Photosensitivity; Phototherapy; Porphyrins; pre-clinical; Pre-Clinical Model; pressure; Production; Property; Protocols documentation; Publishing; PUVA Photochemotherapy; Quality of life; Radiation therapy; Rattus; Records; Recurrence; response; Risk; safety study; scale up; Scientist; Serum; side effect; Site; Small Business Technology Transfer Research; Solid Neoplasm; Standardization; Stimulus; Survival Rate; System; Techniques; Technology; Therapeutic; therapeutic effectiveness; Toxic effect; translation to humans; tumor; tumor ablation; tumor eradication; Tumor Volume; Universities; Vascular Permeabilities; Woman; Work
