Overcoming physical barriers arising in the drug delivery of nanomedicines to lung metastases

克服纳米药物向肺转移瘤输送药物时出现的物理障碍

• 批准号: 16F16731
• 负责人: Cabral Horacio
• 金额: $ 1.47万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for JSPS Fellows
• 财政年份: 2016
• 资助国家: 日本
• 起止时间: 2016-07-27 至 2018-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16F16731/
• 关键词: Nanomedicine; Tumor microenvironment; Tumor normalization; Tumor stffness; Lung metastasis; Breast cancer; Dexamethasone; Polymeric micelles; Liposomes

Normalizing the tumor microenvironment (TME), i.e. components of solid tumors other than cancer cells, increases oxygen and drug delivery thereby making it a treatment strategy combinable with conventional chemo-, radio-, and immune therapies. Normalizing tumor vessels increases intratumor transport of oxygen and drug delivery systems (DDS) up to 30 nanometers (nm) in diameter, while normalization of cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) increases delivery of DDS up to at least 120nm. The existence of an agent that does both types of normalization and whether such an agent would affect DDS in a size-dependent manner is unknown. We hypothesize there is a size-window of DDS that benefits from TME normalization and reduces hematological toxicity. Steroids like dexamethasone are given to patients post-chemotherapy to manage side effects, yet the potential of such drugs to normalize the TME is unclear. Here, we propose repurposing dexamethasone to a pre-chemotherapy schedule (Pre-TX DEX) to potentiate existing treatments through TME normalization. We elucidated the size-dependent changes of DDS delivery during Pre-TX DEX treatment. We found that Pre-TX DEX normalized the TEM and reduced the stiffness of the tumors, which promoted the enhanced accumulation of nanomedicines in tumors. Thus, Pre-TX DEX improved the efficacy of polymeric micelles loaded with platinum drugs in breast tumor and their lung metastasis.

使肿瘤微环境(TME)正常化，即癌细胞以外的实体肿瘤的成分，增加了氧气和药物的输送，从而使其成为一种可与传统的化疗、放射和免疫疗法相结合的治疗策略。肿瘤血管正常化可将氧和药物输送系统(DDS)的直径增加到30纳米(Nm)，而肿瘤相关成纤维细胞(CAF)和细胞外基质(ECM)的正常化将DDS的输送增加到至少120纳米。目前尚不清楚是否存在同时执行两种类型归一化的代理，以及此类代理是否会以依赖于大小的方式影响DDS。我们假设存在一个DDS的大小窗口，该窗口受益于TME正常化并降低血液毒性。地塞米松等类固醇在化疗后给患者服用以控制副作用，但此类药物使TME正常化的潜力尚不清楚。在这里，我们建议将地塞米松重新用于化疗前的时间表(Pre-TX DEX)，以通过TME标准化来加强现有的治疗。我们阐明了在Pre-TX DEX治疗期间DDS递送的大小依赖变化。我们发现，Pre-TX DEX使肿瘤的透射电子显微镜正常化，并降低了肿瘤的硬度，从而促进了纳米药物在肿瘤中的增强积累。因此，Pre-TX DEX提高了载铂药物的聚合物胶束在乳腺癌及其肺转移中的疗效。

项目成果

Proteasome inhibitor loaded micelles enhance antit8umor activity through macrophage reprograming by NF-κB inhibition,

负载蛋白酶体抑制剂的胶束通过抑制 NF-κB 来重新编程巨噬细胞，从而增强抗肿瘤活性，

• 发表时间: 2017
• 作者: Wu H;Tao A;Martin JD;Quader S;Liu X;Takahashi K;Hespel L;Miura Y;Hayakawa Y;Irimura T;Cabral H;Kataoka K
• 通讯作者: Kataoka K

Proteasome inhibitor loaded micelles enhance antitumor activity through macrophage reprogramming

负载蛋白酶体抑制剂的胶束通过巨噬细胞重编程增强抗肿瘤活性

• 发表时间: 2017
• 作者: John Martin;Horacio Cabral;Kazunori Kataoka
• 通讯作者: Kazunori Kataoka

Reengineering the tumor microenvironment to alleviate hypoxia and overcome cancer heterogeneity,” in Cancer Evolution. Charles Swanton, Alberto Bardelli, Kornelia Polyak, Sohrab Shah, and Trevor Graham, Editors.

重新设计肿瘤微环境以缓解缺氧并克服癌症异质性”，《癌症进化》编辑 Charles Swanton、Alberto Bardelli、Kornelia Polyak、Sohrab Shah 和 Trevor Graham。

• 发表时间: 2017
• 作者: Martin JD;Fukumura D;Duda DG;Boucher Y;Jain RK.
• 通讯作者: Jain RK.

Extracellular matrix remodeling after anti-VEGF therapy contributes to therapeutic resistance in colorectal cancer liver metastases

抗 VEGF 治疗后细胞外基质重塑有助于结直肠癌肝转移的治疗抵抗

• 发表时间: 2016
• 期刊: Science Translational Medicine
• 影响因子: 17.1
• 作者: Rahbari NN;Kedrin D;Incio J;Reiberger T;Liu H;Nia HT;Edrich CM;Dubroix J;Chen I;Heishi T;Martin JD;Huang Y;Reissfelder C;Weitz J;Grodzinsky A;Duda DG;Jain RK;Fukumura D.
• 通讯作者: Fukumura D.

Effective treatment of drug resistant recurrent breast tumors harboring cancer stem-like cells by staurosporine/epirubicin co-loaded polymeric micelles

• DOI: 10.1016/j.jconrel.2017.08.025
• 发表时间: 2017-10-28
• 期刊: JOURNAL OF CONTROLLED RELEASE
• 影响因子: 10.8
• 作者: Zhang, Juanjuan;Kinoh, Hiroaki;Kataoka, Kazunori
• 通讯作者: Kataoka, Kazunori