A Chemical Strategy of Developing Resistance-Proof, Immune-Friendly Drugs

开发抗耐药性、免疫友好型药物的化学策略

• 批准号: 10113275
• 负责人: PROBAL BANERJEE
• 金额: $ 41.87万
• 依托单位: COLLEGE OF STATEN ISLAND
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10113275
• 关键词: Chemical; Strategy; Developing; Resistance; Proof

Clever synthetic strategies have been used to develop highly potent drugs such as antibiotics and chemotherapeutic agents, but concurrently bacteria and cancer cells have also developed mechanisms of resistance. Such drug-resistance is proven to be devastating for patients and bewildering for the physicians. We submit the novel idea of potentiating drugs against resistant organisms and cells using simple yet reversible chemical modification. As a proof of principle, we propose to use some chemotherapeutic agents (CAs) as drugs for modification. Cancer cells develop resistance to CAs and the rarely-dividing cancer stem cells are refractory to CAs. This prompts the use of higher doses of the CAs, which results in the death of normal cells such as the immune cells, thereby exposing the patients to infections that often overpower them. Extensive studies performed by many groups including ours establish that the dietary polyphenol curcumin (CC) eliminates chemoresistance, kills cancer stem cells, and stimulates tumor-associated innate immune cells (microglia), converting them from a tumor-promoting (M2) to a tumoricidal (M1) state. However, CC per se is sparingly soluble in the aqueous body fluids and undergoes rapid degradation in vivo, which results in poor bioavailability. Capitalizing on the beneficial properties of CC, we will apply innovative, single-step chemistry to link CC to each of four prototypic CAs, Paclitaxel, Gemcitabine, Doxorubicin, and Methotrexate, through chemical bonds that would be cleaved by intracellular esterases and amidases upon entry of the adduct into cancer cells to release CA and CC. To stabilize and solubilize the adducts and enable their transit through the blood-brain barrier and other membranes, we will use our established strategy of encapsulating drugs into biocompatible chitosan-carbon dot hybrid nanogels with the capacity of smart release of adduct in the low-pH tumor micro-environment. The efficacy of the nanogel form of each adduct (named as Stomalignum) in eliminating patient-derived GBM stem cells in culture will then be compared with the cognate nanogel-encapsulated CA alone (named as Apo-Stomalignum). We expect that the Stomalignum would release CC to efficiently eliminate GBM stem cells whereas these cells should be resistant to the cognate Apo-Stomalignum. Subsequently, the anticancer efficacy of Stomalignum in vivo will be compared with that of the corresponding Apo-Stomalignum using our well-established orthotopic mouse model of GBM. We expect that each Stomalignum will be able to rescue the GBM mice at a much lower dose than required for the corresponding Apo-Stomalignum. The objective of this project is to develop a family of chemoresistance-proof, immune-friendly, new-generation, safe CAs. This project will also provide an excellent platform to train undergraduate researchers successively in three laboratories. They will synthesize each adduct, encapsulate it, and then use the Stomalignum alongside the cognate Apo-Stomalignum in biological tests for anti-cancer activity.

巧妙的合成策略已被用来开发高效药物，如抗生素和化疗药物，但同时细菌和癌细胞也产生了耐药机制。事实证明，这种耐药性对患者来说是毁灭性的，对医生来说也是令人困惑的。我们提出了利用简单但可逆的化学修饰来增强药物对抗耐药生物体和细胞的新想法。作为原理证明，我们建议使用一些化疗药物（CA）作为修饰药物。癌细胞会对 CA 产生抵抗力，并且很少分裂的癌症干细胞对 CA 具有抵抗力。这促使使用更高剂量的 CA，导致免疫细胞等正常细胞死亡，从而使患者面临感染，而这些感染常常压倒他们。包括我们在内的许多团体进行的广泛研究表明，膳食多酚姜黄素 (CC) 可以消除化疗耐药性，杀死癌症干细胞，并刺激肿瘤相关的先天免疫细胞（小胶质细胞），将其从促肿瘤 (M2) 状态转变为杀肿瘤 (M1) 状态。然而，CC本身难溶于水性体液，并且在体内快速降解，导致生物利用度差。利用 CC 的有益特性，我们将应用创新的单步化学方法，通过化学键将 CC 与四种原型 CA（紫杉醇、吉西他滨、多柔比星和甲氨蝶呤）连接起来，加合物进入癌细胞后，这些化学键将被细胞内酯酶和酰胺酶裂解，释放 CA 和 CC。为了稳定和溶解加合物并使其能够通过血脑屏障和其他膜，我们将使用我们既定的策略将药物封装到生物相容性壳聚糖-碳点杂化纳米凝胶中，该凝胶具有在低pH肿瘤微环境中智能释放加合物的能力。然后将每种加合物的纳米凝胶形式（称为 Stomalignum）消除培养物中患者来源的 GBM 干细胞的功效与单独的同源纳米凝胶封装的 CA（称为 Apo-Stomalignum）进行比较。我们预计 Stomalignum 将释放 CC 以有效消除 GBM 干细胞，而这些细胞应该对同源 Apo-Stomalignum 具有抵抗力。随后，我们将使用我们完善的 GBM 原位小鼠模型，将 Stomalignum 的体内抗癌功效与相应的 Apo-Stomalignum 进行比较。我们预计每个 Stomalignum 都能够以比相应 Apo-Stomalignum 所需剂量低得多的剂量来拯救 GBM 小鼠。该项目的目标是开发一系列抗化学耐药性、免疫友好型、新一代安全 CA。该项目还将为三个实验室相继培养本科生研究人员提供良好的平台。他们将合成每种加合物，将其封装，然后将 Stomalignum 与同源 Apo-Stomalignum 一起用于抗癌活性的生物测试。