Abstract
Photosensitizers can be integrated with drug delivery vehicles to develop chemophototherapy agents with antitumor synergy between chemo- and photocomponents. Long-circulating doxorubicin (Dox) in porphyrin-phospholipid (PoP) liposomes (LC-Dox-PoP) incorporates a phospholipid-like photosensitizer (2 mole %) in the bilayer of Dox-loaded stealth liposomes. Hematological effects of endotoxin-minimized LC-Dox-PoP were characterized via standardized assays. In vitro interaction with erythrocytes, platelets, and plasma coagulation cascade were generally unremarkable, whereas complement activation was found to be similar to that of commercial Doxil. Blood partitioning suggested that both the Dox and PoP components of LC-Dox-PoP were stably entrapped or incorporated in liposomes. This was further confirmed with pharmacokinetic studies in Fischer rats, which showed the PoP and Dox components of the liposomes both had nearly identical, long circulation half-lives (25-26 hours). In a large orthotopic mammary tumor model in Fischer rats, following intravenous dosing (2 mg/kg Dox), the depth of enhanced Dox delivery in response to 665 nm laser irradiation was over 1 cm. LC-Dox-PoP with laser treatment cured or potently suppressed tumor growth, with greater efficacy observed in tumors 0.8 to 1.2 cm, compared with larger ones. The skin at the treatment site healed within approximately 30 days. Taken together, these data provide insight into nanocharacterization and photo-ablation parameters for a chemophototherapy agent.
Highlights
The delivery of anticancer agents at therapeutically relevant concentrations is a major challenge in treating solid tumors [1,2,3,4]
We previously described long-circulating Dox in porphyrin– phospholipid (LC-Dox-PoP) liposomes, a PEGylated liposomal form of Dox, co-encapsulated with a bilayer-confined and lipidlike porphyrin–phospholipid (PoP) conjugate incorporated at 2 mole %
The overall morphology is similar to the observed structure of the FDA approved liposomal doxorubicin, Doxil [14]
Summary
The delivery of anticancer agents at therapeutically relevant concentrations is a major challenge in treating solid tumors [1,2,3,4]. A PEGylated liposomal form of doxorubicin (Dox), for example, is clinically approved for the treatment of Kaposi sarcoma, ovarian cancer, and multiple melanoma [14], and is widely used for the treatment of metastatic breast cancer [15]. Its use is driven by a reduction in side-effects compared with free Dox, including cardiotoxicity [9, 17] This lack of greater efficacy, despite enhanced delivery to the tumor, is attributed to poor bioavailability of liposome-encapsulated drugs due to their slow release [9, 20].
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