title: Simultaneous delivery of cytotoxic and biologic therapeutics using nanophotoactivatable liposomes enhances treatment efficacy in a mouse model of pancreatic cancer.
abstract: A lack of intracellular delivery systems has limited the use of biologics such as monoclonal antibodies (mAb) that abrogate molecular signaling pathways activated to promote escape from cancer treatment. We hypothesized that intracellular co-delivery of the photocytotoxic chromophore benzoporphyrin derivative monoacid A (BPD) and the anti-VEGF mAb bevacizumab in a nanophotoactivatable liposome (nanoPAL) might enhance the efficacy of photodynamic therapy (PDT) combined with suppression of VEGF-mediated signaling pathways. As a proof-of-concept we found that nanoPAL-PDT induced enhanced extra- and intracellular bevacizumab delivery and enhanced acute cytotoxicity in vitro. In an in vivo subcutaneous mouse model of pancreatic ductal adenocarcinoma, nanoPAL-PDT achieved significantly enhanced tumor reduction. We attribute this to the optimal incorporation of insoluble BPD into the lipid bilayer, enhancing photocytotoxicity, and the simultaneous spatiotemporal delivery of bevacizumab, ensuring efficient neutralization of the rapid but transient burst of VEGF following PDT. From the Clinical Editor: Most patients with pancreatic ductal adenocarcinoma (PDAC) by the time present the disease it is very advanced, which unavoidably translates to poor survival. For these patients, use of traditional chemotherapy often becomes ineffective due to tumor resistance to drugs. Photodynamic therapy (PDT) can be an effective modality against chemo-resistant cancers. In this article, the authors investigated the co-delivery of a photocytotoxic agent and anti-VEGF mAb using liposomes. This combination was shown to results in enhanced tumor killing. This method should be applicable to other combination of treatments.
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Shifalika
authors.initials: S
authors.lastname: Tangutoori
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Bryan Q
authors.initials: BQ
authors.lastname: Spring
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Mai
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Akilan
authors.initials: A
authors.lastname: Palanisami
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Lawrence B
authors.initials: LB
authors.lastname: Mensah
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Harvard-MIT Division of Health Science and Technology, Boston MA, USA. Electronic address: thasan@mgh.harvard.edu.
authors.forename: Tayyaba
authors.initials: T
authors.lastname: Hasan
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000068258:Bevacizumab / Q000008:administration & dosage*; D001688:Biological Products / Q000008:administration & dosage; D003131:Combined Modality Therapy / Q000379:methods; D003692:Delayed-Action Preparations / Q000737:chemistry* / Q000528:radiation effects; D004357:Drug Synergism; D008027:Light; D051379:Mice; D008819:Mice, Nude; D053769:Nanocapsules / Q000737:chemistry* / Q000528:radiation effects / Q000648:ultrastructure; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000008:administration & dosage; D011166:Porphyrins / Q000008:administration & dosage / Q000737:chemistry; D000077362:Verteporfin
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001688:Biological Products; D003692:Delayed-Action Preparations; D053769:Nanocapsules; D017319:Photosensitizing Agents; D011166:Porphyrins; D000077362:Verteporfin; D000068258:Bevacizumab
keywords: Avastin; Benzoporphyrin derivative; Bevacizumab; Combinatorial chemotherapy; Liposomes; Nanomedicine; Nanoparticle; Pancreatic cancer; Photodynamic therapy