Neurological Biomaterials and Cancer Therapeutics Laboratory, Wallace H Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, United States.
ACS Nano. 2011 Jun 28;5(6):4919-26. doi: 10.1021/nn201010q. Epub 2011 Jun 2.
Delivery of chemotherapeutic agents after encapsulation in nanocarriers such as liposomes diminishes side-effects, as PEGylated nanocarrier pharmacokinetics decrease dosing to healthy tissues and accumulate in tumors due to the enhanced permeability and retention effect. Once in the tumor, however, dosing of the chemotherapeutic to tumor cells is limited potentially by the rate of release from the carriers and the size-constrained, poor diffusivity of nanocarriers in tumor interstitium. Here, we report the design and fabrication of a thermosensitive liposomal nanocarrier that maintains its encapsulation stability with a high concentration of doxorubicin payload, thereby minimizing "leak" and attendant toxicity. When used synergistically with PEGylated gold nanorods and near-infrared stimulation, remote triggered release of doxorubicin from thermosensitive liposomes was achieved in a mouse tumor model of human glioblastoma (U87), resulting in a significant increase in efficacy when compared to nontriggered or nonthermosensitive PEGylated liposomes. This enhancement in efficacy is attributed to increase in tumor-site apoptosis, as was evident from noninvasive apoptosis imaging using Annexin-Vivo 750 probe. This strategy affords remotely triggered control of tumor dosing of nanocarrier-encapsulated doxorubicin without sacrificing the ability to differentially dose drugs to tumors via the enhanced permeation and retention effect.
将化疗药物封装在纳米载体（如脂质体）中后再输送，可降低副作用，因为聚乙二醇化纳米载体的药代动力学可降低对健康组织的给药剂量，并由于增强的通透性和保留效应而在肿瘤中积累。然而，一旦进入肿瘤，化疗药物对肿瘤细胞的给药量可能会受到载体从载体中释放的速度以及纳米载体在肿瘤间质中受限的尺寸和较差的扩散性的限制。在这里，我们报告了一种热敏脂质体纳米载体的设计和制造，该载体可在高浓度多柔比星载药时保持其封装稳定性，从而最大限度地减少“泄漏”和伴随的毒性。当与聚乙二醇化金纳米棒和近红外刺激联合使用时，热敏脂质体中多柔比星的远程触发释放在人胶质母细胞瘤（U87）的小鼠肿瘤模型中得以实现，与非触发或非热敏聚乙二醇化脂质体相比，疗效显著提高。这种疗效的提高归因于肿瘤部位细胞凋亡的增加，这从使用 Annexin-Vivo 750 探针进行的非侵入性细胞凋亡成像中可以明显看出。这种策略提供了对纳米载体包封的多柔比星的肿瘤给药的远程触发控制，而不会牺牲通过增强的通透性和保留效应来差异化地向肿瘤给药的能力。
