Encapsulation and delayed release of gemcitabine by aluminum metal-organic frameworks

铝金属有机框架对吉西他滨的封装和延迟释放

• 批准号: 10396032
• 负责人: Alexandr Samokhvalov
• 金额: $ 11.33万
• 依托单位: MORGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10396032
• 关键词: Affect; AlamarBlue; Aluminum; Anions; Antimetabolites; Binding Sites; Biological Assay; Biopolymers; Books; Buffers; Carmustine; Cations; Cells; Chemicals; Combined Modality Therapy; Complex; Crystallization; Devices; Diagnosis; Disease; Encapsulated; FDA approved; Gliadel Wafers; Goals; Implant; In Vitro; Intravenous; Kinetics; Knowledge; Laws; Lead; Learning; Maintenance Therapy; Malignant Neoplasms; Malignant neoplasm of pancreas; Metals; Methods; Molecular; Nanostructures; Oral; Pancreas; Persons; Pharmaceutical Preparations; Phosphate Buffer; Polymers; Porosity; Powder dose form; Publishing; Pyrimidine; Reporting; Research; Sodium Chloride; Solid; Solid Neoplasm; Structure; Temperature; Testing; Time; Toxic effect; United States; Vesicle; Water; Work; anti-cancer; aqueous; base; cancer recurrence; chemical kinetics; chemical property; chemical stability; chemical synthesis; chemotherapy; cytotoxicity; design; gemcitabine; gemzar; innovation; insight; intravenous administration; materials science; nano; nanoparticle; novel therapeutics; pancreatic cancer cells; prototype; side effect; small molecule; tumor

PROJECT SUMMARY This proposal seeks to study encapsulation of gemcitabine to complexes with aluminum metal-organic frameworks (Al-MOFs), mechanism of bonding, chemical kinetics of delayed release, and cytotoxicity to pancreatic cancer and healthy cells. Standard chemotherapy of solid tumors is systemic (oral or intravenous). Gemcitabine is FDA-approved pyrimidine drug to treat pancreatic cancer. Systemic administration shows “burst” effect with quick increase of drug concentration, which leads to severe side effects. Systemic chemotherapy often uses large amount of drug (grams), which is undesirable for prolonged treatments. Alternative administration is by local delayed release with drug-eluting implant. The only FDA-approved anticancer implant is Gliadel wafer, where polymer matrix holds small amount (mg) of carmustine for prolonged release. Common encapsulation matrices are polymers and vesicles, which form weak bonds with drug molecules, and a moderately slow release. Metal-organic frameworks (MOFs) emerged as promising matrix for drug encapsulation and delayed release. Recently, PI of this SC-3 proposal published book on interactions of MOFs with small molecules. MOFs contain organic linkers and metal cations. Certain MOFs show stronger bonds with drug molecules and slower release than other matrices. Mainly, nano-MOFs and chemically unstable solid MOFs with substantial toxicity were studied for drug release. Al-MOFs are water-insoluble, structurally versatile, have porosity and high stability, and low toxicity. The overall goal of this project is to study selected Al-MOFs as new matrix for encapsulation and prolonged release of gemcitabine. Our goals are to study fundamental chemical properties of complexes of gemcitabine with Al-MOFs, kinetics of delayed release, and cytotoxicity. The goals will be accomplished by the following specific Aims. Aim I. Synthesize complexes of gemcitabine with Al-MOFs which contain archetypal linkers, and determine bonding mechanism. Each Al-MOF has archetypal linker with or without (hetero)aromatic group as binding site. We will determine structure of complexes, and mechanism of bonding of encapsulated gemcitabine to groups in Al-MOFs by the complementary methods of instrumental analysis. Aim II. Study kinetics of time-delayed release of gemcitabine to buffer solution. We will establish the relationships between kinetic parameters of release, bonding mechanism, and structure of archetypal linkers. Aim III. Study short- and long-term in-vitro cytotoxicity of complexes to pancreatic cancer and healthy cells. We will draw conclusions how numeric parameters of the time-dependent cytotoxicity are related to bonding mechanism in complexes. This research will determine the connections between bonding mechanism, kinetic release parameters, and time-dependent cytotoxicity. In summary, this study will reveal Al-MOFs as new promising materials for prolonged local chemotherapy of pancreatic cancer.

项目总结 本方案旨在研究吉西他滨与铝金属有机络合物的包封性。 骨架(Al-MOF)，键合机制，延迟释放的化学动力学，以及对 胰腺癌和健康细胞。实体肿瘤的标准化疗是全身化疗(口服或静脉注射)。 吉西他滨是FDA批准的治疗胰腺癌的嘧啶类药物。系统性管理显示 “爆发性”效应，药物浓度快速增加，副作用严重。系统性 化疗通常使用大量的药物(克)，这对于长期治疗是不可取的。 替代给药方式是局部延迟释放和药物洗脱植入物。唯一获得FDA批准的 抗癌植入物是Garia del晶片，其中聚合物基质可长时间保持少量(Mg)的卡莫司汀 放手。常见的包囊基质是聚合物和囊泡，它们与药物形成弱结合 分子，以及适度缓慢的释放。金属有机骨架(MOF)是一种很有前途的有机骨架材料 药物包封性和缓释性。最近，这个SC-3提案的PI出版了一本关于 具有小分子的MOF。MOF含有有机连接物和金属阳离子。某些MOF表现出更强的 与药物分子结合，与其他骨架相比释放较慢。主要是纳米MOF和化学上的 对具有较大毒性的不稳定固体MOF进行了药物释放研究。Al-MOF不溶于水， 结构多样，具有多孔性和高稳定性，毒性低。这个项目的总体目标是研究 选用Al-MOF作为吉西他滨的包封剂和缓释片。我们的目标是 研究了吉西他滨-Al-MOF络合物的基本化学性质、缓释动力学 和细胞毒性。这些目标将通过以下具体目标来实现。 目的I.合成含原型连接物的吉西他滨与Al-MOF的配合物，并测定 结合机制。每个Al-MOF都有带或不带(杂环)芳基的原型连接子作为结合位点。 我们将确定络合物的结构，以及包封吉西他滨与基团的键合机制 在Al-MOF中，通过仪器分析的补充方法。 目的II.吉西他滨缓释缓冲液的时延释放动力学研究。我们将建立 释放动力学参数、键合机制和原型连接体结构之间的关系。 目的III.研究络合物对胰腺癌细胞和健康细胞的短期和长期体外细胞毒性。我们 我将得出结论，依赖时间的细胞毒性的数值参数与结合是如何相关的 络合物中的作用机理。本研究将确定键合机制、动力学之间的联系 释放参数和时间依赖的细胞毒性。总而言之，这项研究将揭示Al-MOF是新的 胰腺癌长期局部化疗有希望的材料。

项目成果

Hygroscopic metal-organic framework MIL-160(Al): In-situ time-dependent ATR-FTIR and gravimetric study of mechanism and kinetics of water vapor sorption.

• DOI: 10.1016/j.saa.2021.120550
• 发表时间: 2022-02-15
• 期刊: Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy
• 作者: Henry B;Samokhvalov A
• 通讯作者: Samokhvalov A

Characterization of tautomeric forms of anti-cancer drug gemcitabine and their interconversion upon mechano-chemical treatment, using ATR-FTIR spectroscopy and complementary methods.

使用 ATR-FTIR 光谱和补充方法表征抗癌药物吉西他滨的互变异构形式及其在机械化学处理后的相互转化。

• DOI: 10.1016/j.jpba.2023.115243
• 发表时间: 2023
• 期刊: Journal of pharmaceutical and biomedical analysis
• 影响因子: 3.4
• 作者: Henry,Barrington;Samokhvalov,Alexander
• 通讯作者: Samokhvalov,Alexander