Powerful and precise nanomedical solutions
Oncology
Development
Figure 1 | Schematic of PhotoDOX
PhotoDOX: Light-activated Chemotherapy
PhotoDOX is a revolutionary cancer therapy designed to address solid tumors which are resistant to current standards of care through the innovative benefits of the light-activated PoP-liposome drug delivery system.
PhotoDOX combines POP BIO’s proprietary photosensitive porphyrin-phospholipid (PoP) nanoparticles with the widely prescribed cancer drug doxorubicin to provide localized drug release with enhanced therapeutic benefit when activated by light. PhotoDOX provides precise targeting of Dox to tumor sites in combination with a chemotherapy with the precision of light-based treatments.
PhotoDOX’s optimized formulation combines long circulation and robust serum stability with the photodynamic enhancement of vascular permeability and light triggered doxorubicin release, allowing PhotoDOX to achieve its primary goal: targeted treatment at the tumor site with minimal systemic toxicity.
A radically different approach
Conventional light-based cancer treatment approaches, such as photodynamic therapy (PDT), have been functionally limited by the limited tumor uptake of the photosensitizing agent, as well as by the duration and intensity of light required for treatment.
Despite improvements in light delivery technology (such as interstitial probes and improved treatment planning) clinical development of PDT has been limited to topical therapies. In part, due to the fact that the PDT effect is only present during light irradiation and effective against cells by the generation of reactive oxygen species.
By integrating a nanoparticle platform that breaks through the limitations of conventional approaches such as Doxil®, with a photodynamic mechanism that transcends the functional bounds of PDT, PhotoDOX provides both localized ablation and uniquely enhanced and uniform deposition of payload drug throughout tumor tissue to provide hope to patients suffering from difficult to treat solid tumors, such as cancers of the liver, pancreas, and breast.
Therapeutic Process
PhotoDOX is a unique approach that allows for targeted ablative treatment of multiple tumor sites, maximizing the effective ability of traditional chemotherapy agents to treat tumor tissues with minimal systemic toxicity.
Therapy begins with intravenous drug administration. Red laser light (665nm) is then applied to the target tumors using a fiber-optic probe. This light activates PhotoDOX, triggering a photodynamic effect that damages the tumor and enhances the tumor drug uptake while simultaneously bursting the nanoparticle shells, driving the release of doxorubicin directly into the tumor, resulting in effective tumor ablation.
Preclinical Data
When combined with red laser light, PhotoDOX nanoparticles provide tumor ablation with exact spatial control while simultaneously substantially releasing and enhancing the deposition of encapsulated chemotherapy -- resulting in a potent and precise treatment of tumor tissues.
Preclinical evaluations of the PhotoDOX therapy have revealed light-activation of the drug provides dramatically improved drug uptake (Figure 3A) and provides a penetrating and uniform distribution of drug through the difficult tumor tissues (Figure 3B).
A
B
Figure 3 | In vivo drug uptake and tumor drug distribution of PhotoDOX treatment in an orthotopic pancreatic murine model.
A) Intratumoral Dox distribution in laser treated and untreated MIA PaCa 2 (pancreatic cancer cell line) tumor xenografts. B) Florescence imaging of tumor doxorubicin (Dox) and PhotoDOX (PoP) distributions in xenografted tumors before laser treatment (-laser) and after laser treatment (+laser).
In contrast to traditional nanoparticle drug delivery systems (e.g. Doxil®), which are limited both by the ability of the drug to accumulate at the target site and to release the drug once it has reached the target site, PhotoDOX provides focused dosing of bioavailable drug precisely to the location of treatment.
PhotoDOX has significant benefits over conventional photodynamic therapy (PDT) and chemotherapy approaches. PhotoDOX, due to the treatment's unique photodynamic release, provides effective suppression of tumor growth even when a low dose of the drug in administered.
Mice treated with light-activated PhotoDOX have higher survival rates compared to control groups (Figure 4A) and experience greater reductions in tumor volume compared to mice treated with Doxil (Figure 4C).
Figure 4 | In vivo efficacy studies in nude mice bearing MIA PaCa 2 (pancreatic cancer cell line) tumor xenografts.
A) Survival model comparing PhotoDOX (NP-01) with or without laser treatment and with or without doxorubicin; C) Comparison of PhotoDOX (NP-01) to Doxil-like liposomes and free Dox at their maximum tolerated doses.
Figure 5 | Serum concentrations over time of PhotoDOX (NP-01) compared to Doxil®-like liposomes.
Figure 6 | PhotoDOX Stability. A) Dox retention; B) Liposome size; C) liposome polydisperity; D) In vitro serum stability of loaded Dox following 6 hrs incubation at 37C in 50% bovine serum; E) Laser irradiation time for 50% release of Dox in 50% bovine serum at 37 C.
Previously developed nanoparticles for stimulated targeted release, such as the delivery of Dox using heat-triggered nanoparticles, suffer from instability in vivo and have similar pharmacokinetic and toxicity profiles (e.g., irreversible cardiotoxicity) to that of unencapsulated doxorubicin -- without the enhanced safety provided by PEGylated liposomes such as Doxil® and NP-01.
In contrast to these previous approaches, PhotoDOX exhibits similar pharmacokinetics to the long-circulating product Doxil® (Figure 5) and robust nanoparticle stability (Figure 6).