Development of stimuli deformable lipid/polymer hybrid nano-materials for drug delivery applications

开发用于药物输送应用的刺激可变形脂质/聚合物混合纳米材料

• 批准号: RGPIN-2019-05979
• 负责人: Lavasanifar, Afsaneh
• 金额: $ 3.35万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=762131
• 关键词: Development; stimuli; deformable; lipid; polymer

The main aim of this research is to develop nano-materials that can adequately solubilize drugs, and release them in an appropriate rate/location, and be safe for human use. This NSERC funded project, has previously led to the development and global intellectual protection of a library of safe, and degradable block copolymers based on poly(ethylene oxide) (PEO) and functionalized poly(ester)s such as poly(caprolactone) (PCL). The copolymers within this library were utilized to form core/shell nanocarries, namely polymeric micelles, capable of encapsulating a number of drugs, gene therapeutics and imaging probes through physical or chemical means, stabilizing them in the biological environment, reducing their exposure to healthy tissues while directing them towards target sites. This has enhanced the performance of the incorporated cargo in treating or imaging of cancerous or inflammatory sites. To improve the performance of this novel library for additional roles in drug delivery, we propose development of liposomes enveloping polymeric micelles and nano-gels from this polymer family. This approach is expected to: i) enhance the safety of polycationic or polyanionic PEO-poly(ester)s for gene/drug delivery, ii) expand the application of functionalized PEO-poly(ester)s in the co-delivery of small molecules drugs, proteins and genes of various hydrophilic/hydrophobic profile; and iii) lead to the development of nano-delivery systems that can change their shape and firmness and, as a result, show different cell interaction or drug release profiles in response to stimuli. Our specific goals are: 1. To develop lipid vesicles containing PEG-(functionalized)PCL based polymeric micelles (namely lipocells) or nano-gels (namely lipogels). 2. To investigate the effect of lipid structure, encapsulation method, polymer structure as well as stimuli (temperature, pH, reducing agents) on the characteristics (size, morphology, polymer encapsulation and leakage) of lipocells and lipogels. 3. To assess the capacity of lipocells and lipogels for the co-encapsulation and release of model hydrophilic and hydrophobic molecules in comparison to parent liposomal or polymeric nanocarriers. 4. To assess the in vitro protein adsorption, cell uptake and toxicity of lipocells and lipogels in cancer and normal cells, under physiological conditions and in response to stimuli. 5. To investigate the in vivo biodistribution of lipocells and lipogels compared to their parent liposomal or polymeric nanocarriers in mice bearing orthotropic breast tumors. The results of this research can lead to the development of novel nano-materials with improved safety profile and performance for the solubilisation, controlled and/or targeted (co-)delivery of different drugs, gene therapeutics and diagnostics. The proposed architectures, may be adopted  to develop artificial cells, in future, mimicking natural cells in terms of incorporation of different subcellular organelles and elasticity.

这项研究的主要目的是开发能够充分溶解药物并以适当的速率/位置释放它们并且对人类安全使用的纳米材料。这项由国家环保研究中心资助的项目此前已经开发了一系列安全的、可降解的嵌段共聚物库，这些嵌段共聚物基于聚环氧乙烷(PEO)和官能化聚(酯)S，如聚己内酯(PCL)。该文库中的共聚物被用来形成核/壳纳米载体，即聚合物胶束，能够通过物理或化学手段包裹一些药物、基因疗法和成像探针，在生物环境中稳定它们，减少它们对健康组织的暴露，同时将它们定向到靶点。这增强了所结合的货物在癌症或炎症部位的治疗或成像方面的性能。为了提高这种新型文库的性能，以便在药物输送中发挥更多的作用，我们建议开发包裹该聚合物家族的聚合物胶束和纳米凝胶的脂质体。这一方法有望：i)提高聚阳离子或聚阴离子聚氧乙烯醚聚(酯)S用于基因/药物输送的安全性；ii)扩大功能化聚氧化乙烯聚(酯)S在小分子药物、蛋白质和各种亲水/疏水基因共输送中的应用；iii)开发能够改变其形状和坚固性的纳米给药系统，从而根据刺激显示不同的细胞相互作用或药物释放谱。我们的具体目标是：1.开发含有聚乙二醇化的PCL聚合物胶束(即脂肪细胞)或纳米凝胶(即脂凝胶)的脂泡。2.研究脂类结构、包埋方法、聚合物结构以及刺激因素(温度、pH、还原剂)对脂细胞和脂凝胶的大小、形态、聚合物包封率和渗漏特性的影响。3.与亲本脂质体或聚合物纳米载体相比，评价脂细胞和脂凝胶共包裹和释放模型亲水分子和疏水分子的能力。4.评价在生理条件和刺激反应下，脂肪细胞和脂凝胶对肿瘤细胞和正常细胞的体外蛋白质吸附、细胞摄取和毒性。5.研究脂细胞和脂凝胶在荷正交异性乳腺肿瘤小鼠体内的分布，并与其亲本脂质体或聚合物纳米载体进行比较。这项研究的结果可以导致新型纳米材料的开发，这些材料具有更好的安全性和性能，用于增溶、受控和/或靶向(共同)输送不同的药物、基因治疗和诊断。建议的架构可能会被采用来开发人工细胞，在未来通过合并不同的亚细胞细胞器和弹性来模仿自然细胞。