"MASKED" TARGETED NANOCARRIERS FOR IMPROVED CHEMOTHERAPY OF GLIOMAS

用于改善神经胶质瘤化疗的“蒙面”靶向纳米载体

• 批准号: 0756567
• 负责人: Ravi Bellamkonda
• 金额: $ 27.02万
• 依托单位: Georgia Tech Research Corporation
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0756567&HistoricalAwards=false
• 关键词: MASKED; TARGETED; NANOCARRIERS; IMPROVED; CHEMOTHERAPY

CBET-0756567R. Bellamkonda, Georgia Institute of TechnologyGliomas are highly invasive and diffuse; hence, surgical resection, radiation and local delivery of drugs have not been effective treatments, resulting in an extremely poor prognosis for patients diagnosed with high-grade gliomas. Nanocarrier mediated therapy of gliomas has promise because multi-functional nanocarriers can theoretically be designed not only to carry a range of chemotherapeutic or anti-invasive agents (and not just low molecular weight, uncharged lipophilic drugs), but also to both passively and actively target intracranial tumors such as gliomas. However, targeting nanocarriers to tumors has not been very effective due to increased clearance of nanocarriers from circulation due to the presence of targeting ligands compared to non-targeted nanocarriers.This project proposes an innovative strategy to use long polyethylene glycol (PEG) chains to "mask" the targeting ligands (folate, targeting the folate receptor over-expressed in gliomas) while the nanocarriers are in circulation, protecting them from accelerated clearance. PEG-lipid conjugates will be synthesized with a link that can be "cleaved" using a safe trigger such as cysteine. The targeting ligand can then be "unmasked" after the nanocarriers extravasate to the tumor using systemic administration of a safe level of exogenous cysteine to trigger active targeting of tumors. Cysteine, due to its small size, freely leaks into tumors from circulation, which has been confirmed experimentally and via mathematical modeling. Thus, the proposed strategy will exploit the advantages of active targeting which include increased tumor retention and more efficient drug uptake in the tumor, without sacrificing passive dosing of the nanocarriers to the tumor, a parameter critically dependent on circulation time of the nanocarriers. Additionally, liposomal nanocarriers can potentially carry a wide range of chemotherapeutic drugs (including doxorubicin as proposed in this study) as well as MR/CT contrast agents to facilitate real-time pharmacokinetics of systemically administered nanocarriers. The current prognosis of a mean survival time of 9 months after diagnosis of high-grade glioma, and only a 2 month extension in life after treatment of local delivery of BCNU with Gliadel wafers is unacceptable. Given its invasive and diffuse nature, systemic chemotherapy is the best route to treat gliomas; however, due to blood brain barrier imposed limitations, even with leaky blood vessels resulting from the enhanced permeation effect, a very limited range of lipophilic, low molecular weight, uncharged set of chemotherapeutics are used for systemic chemotherapy today, and their impact is limited.Multi-functional liposomal nanocarriers have the promise of delivering a wide range of chemotherapeutics, and lend themselves well to incorporation of MR and CT contrast agents for real-time pharmaco-kinetic tracking of carriers such that tumor dosing, retention time and distribution can be evaluated for patient-specific therapy. Additionally, by presenting targeting ligands to modulate the efficiency of cellular uptake, tumor retention times and distribution, liposomal nanocarriers can significantly enhance the capabilities of current generation of systemic chemotherapy options available to the clinician today. However, targeting ligands on the nanocarrier surface compromise the circulation time of nanocarriers, limiting the number of carriers that reach the tumor, offsetting any gains of active targeting. Therefore in proposing an innovative solution to preserving circulation time of nanocarriers and yet, not compromising their ability to actively target gliomas, the proposed research has implications for glioma prognosis, and for the use of nanocarriers as systemically delivered targeting agents in general. The PI's group's ability to combine contrast agents as well as chemotherapeutics in liposomal nanocarriers gives the potential to truly "personalize" systemic chemotherapy by observing tumor dosing and retention and efficacy in "real-time". Therefore, the research proposed is a functional piece of a larger effort to develop personalized, targeted nanotherapies for treating gliomas of the brain.

生态旅游- 0756567 r。胶质瘤具有高度侵袭性和弥漫性；因此，手术切除、放疗和局部给药都不是有效的治疗方法，导致高级别胶质瘤患者预后极差。纳米载体介导的胶质瘤治疗前景光明，因为从理论上讲，多功能纳米载体不仅可以携带一系列化疗或抗侵袭药物（而不仅仅是低分子量、不带电的亲脂性药物），而且可以被动或主动靶向颅内肿瘤，如胶质瘤。然而，与非靶向纳米载体相比，靶向配体的存在增加了纳米载体从循环中清除的能力，因此将纳米载体靶向肿瘤并不是非常有效。该项目提出了一种创新策略，即在纳米载体处于循环中时，使用长聚乙二醇（PEG）链“掩盖”靶向配体（叶酸，靶向胶质瘤中过度表达的叶酸受体），保护它们免受加速清除。聚乙二醇-脂质偶联物将与一个可以使用半胱氨酸等安全触发器“切割”的链接合成。靶向配体可以在纳米载体外渗到肿瘤后，通过全身给予安全水平的外源性半胱氨酸来触发肿瘤的主动靶向，从而“揭开”靶向配体。半胱氨酸由于体积小，可以从血液循环中自由地渗漏到肿瘤中，这一点已经通过实验和数学模型得到了证实。因此，所提出的策略将利用主动靶向的优势，包括增加肿瘤保留和更有效的肿瘤药物摄取，而不牺牲纳米载体对肿瘤的被动剂量，这一参数主要取决于纳米载体的循环时间。此外，脂质体纳米载体可以潜在地携带多种化疗药物（包括本研究中提出的阿霉素）以及MR/CT造影剂，以促进系统给药纳米载体的实时药代动力学。高级别胶质瘤诊断后平均生存时间为9个月，局部分娩BCNU后仅延长2个月的预后是不可接受的。鉴于其侵袭性和弥漫性，全身化疗是治疗胶质瘤的最佳途径；然而，由于血脑屏障的限制，即使渗透作用增强导致血管渗漏，目前用于全身化疗的亲脂性、低分子量、不带电的一组化疗药物的范围非常有限，其影响有限。多功能脂质体纳米载体有望提供广泛的化疗药物，并且可以很好地结合MR和CT造影剂进行实时药物动力学跟踪，从而可以评估肿瘤剂量，保留时间和分布，以进行患者特异性治疗。此外，通过提供靶向配体来调节细胞摄取的效率、肿瘤保留时间和分布，脂质体纳米载体可以显著增强当前临床医生可用的系统化疗选择的能力。然而，靶向纳米载体表面的配体损害了纳米载体的循环时间，限制了到达肿瘤的载体数量，抵消了主动靶向的任何收益。因此，提出了一种创新的解决方案，既能保持纳米载体的循环时间，又不影响其主动靶向胶质瘤的能力，该研究对胶质瘤的预后，以及纳米载体作为系统靶向药物的使用具有重要意义。PI小组将造影剂和化疗药物结合在脂质体纳米载体上的能力，通过“实时”观察肿瘤的剂量、保留和疗效，提供了真正“个性化”全身化疗的潜力。因此，这项研究提出的是一个更大的努力，以开发个性化的，有针对性的纳米治疗脑胶质瘤的功能部分。