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可以充分可溶性药物的纳米材料，并以适当的速度/位置释放它们，并可以安全地使用人类。该NSERC资助的项目以前已导致基于聚（乙烷氧化乙烷）（PEO）（PEO）和功能化的聚（酯）S，例如聚（caprolactone）（PCL）的安全性和可降解共聚物的库的发展和全球智力保护。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方法封装多种药物，基因治疗和成像问题，在生物学环境中稳定它们，将其降低到健康组织的暴露范围，同时将其引导到目标位置。这已经提高了综合货物在处理或成像取消或炎症部位的成像中的性能。为了提高这个新颖的文库在药物输送中的额外作用，我们提议开发该聚合物家族的聚合物胶束和纳米凝胶的脂质体。预计这种方法是：i）提高多阳离子或聚苯基Peo-Poly（酯）对基因/药物递送的安全性，ii）扩展了在小分子药物的共同传递中的功能化PEO-POLY（ESTER）S的应用； iii）导致可以改变其形状和固件的纳米递送系统的发展，结果，对响应刺激显示出不同的细胞相互作用或药物释放曲线。我们的具体目标是：1。开发含有PEG-（功能化的）基于PCL的聚合物胶束（即Lipocells）或纳米凝胶（即Lipocells）的脂质蔬菜。 2。研究脂质结构，封装方法，聚合物结构以及刺激（温度，pH，还原剂）对Lipocells和Lipogels的特征（大小，形态，聚合物封装和泄漏）的影响。 3。评估Lipocells和Lipogels的能力，用于与母体脂质体或聚合物纳米载体相比，与亲水性和疏水分子的共囊化和释放。 4。在生理条件下，在生理条件下，对癌症和正常细胞中Lipocells和lipodogels的细胞摄取和毒性的毒性和毒性评估。 5。研究Lipocells和Lipogels的体内生物分布，与携带正性乳腺肿瘤的小鼠中的母体脂质体或聚合物纳米载体相比。这项研究的结果可以导致新型纳米材料的发展，并改善了安全性和性能，以溶解，受控和/或有针对性的（共同）递送不同药物，基因治疗和诊断。在将来，可以采用提出的体系结构来发展人造细胞，以不同的亚细胞器细胞器和弹性的收入来模仿自然细胞。