Simultaneous delivery of cytotoxic and biologic therapeutics using nanophotoactivatable liposomes enhances treatment efficacy in a mouse model of pancreatic cancer

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• 作者：Shifalika Tangutoori ; PhD^a ; ¹ ; Bryan Q. Spring ; PhD^a ; ² ; Zhiming Mai ; PhD^a ; ² ; Akilan Palanisami ; PhD^a ; Lawrence B. Mensah ; PhD^a ; ³ ; Tayyaba Hasan ; PhD^a ; ^b ; ^{thasan@mgh.harvard.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：mAb ; monoclonal antibody ; BPD ; benzoporphyrin derivative ; PDT ; photodynamic therapy ; nanoPAL ; nanophotoactivatable liposomes ; PDAC ; pancreatic ductal adenocarcinoma ; VEGF ; vascular endothelial growth factor ; MAPK ; mitogen activated protein kinases ; HIF ; hypoxia inducible factor ; JNK ; c-Jun NH2-terminal kinase ; MET ; hepatocyte growth factor receptor ; PDI ; polydispersity index ; DAPI ; 4&prime ; 6-diamidino-2-phenylindole ; DPPC ; 2-dipalmitoyl-sn-glycero-3-phosphocholine ; DOTAP ; 1 ; 2-dioleoyl-3-trimeth
• 刊名：Nanomedicine: Nanotechnology, Biology and Medicine
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：12
• 期：1
• 页码：223-234
• 全文大小：2069 K

文摘

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.