The modulation of tumor vessel permeability by thalidomide and its impacts on different types of targeted drug delivery systems in a sarcoma mouse model

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• 作者：Dan Wang^a ; ¹ ; Jijun Fu^a ; ¹ ; Yujie Shi^a ; Dong Peng^b ; Lan Yuan^c ; Bing He^a ; Wenbing Dai^a ; Hua Zhang^a ; Xueqing Wang^a ; Jie Tian^b ; Qiang Zhang^a ; ^{zqdodo@bjmu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Targeted drug delivery systems ; Animal model of EPR effect ; Tumor vessel permeability ; Thalidomide ; Antitumor efficacy ; Distribution
• 刊名：Journal of Controlled Release
• 出版年：2016
• 出版时间：28 September 2016
• 年：2016
• 卷：238
• 期：Complete
• 页码：186-196
• 全文大小：2150 K

文摘

The transport of nanocarriers is supposed to be based on EPR effect which is affected by diverse factors, so the modulation of EPR effect seems very significant for nanocarriers including targeted drug delivery systems (TDDSs). Besides, it is extremely unclear how the EPR effect impacts the fate of different types of TDDSs. To make the most advantage of EPR effect for TDDSs, it is definitely necessary to clarify these key issues. Here, we construct and characterize various TDDSs, including sterically-stabilized liposomes (SSL), RGD functionalized SSL (RGD-SSL) and novel 7PEP functionalized SSL (7PEP-SSL), loaded with doxorubicin (DOX), DIR or DID. Here, we modulate the permeability of tumor vessels by thalidomide (THD) in a sarcoma-bearing EPR mouse model via monitoring endogenous deoxygenated hemoglobin in circulation, and then we confirm the effect of THD on tumor vessel permeability by vessel density, vessel maturity, VEGF expression and so on. Importantly, we investigate and find the impacts of EPR effect on the antitumor efficacy, in vivo distribution and intratumoral microdistribution of the three TDDSs. Interestingly, the EPR effects affect different TDDSs differently. The elevated EPR effect enhances the tumor accumulation of SSL and RGD-SSL but fails to increase their efficacy. The RGD-SSL exhibits the best efficacy with the least fluctuation, demonstrating the advantage of angiogenesis targeted systems. 7PEP-SSL seems the biggest beneficiary of EPR effect, suggesting the significance of EPR modulation for cells targeted systems. Generally, this study demonstrates the feasibility of modulating EPR effect bidirectionally by THD as well as the impacts of EPR effect on different type of testing TDDSs based on this animal model. It certainly provides novel insight into the design and potential use of TDDSs.