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

本研究的主要目的是开发能够充分溶解药物的纳米材料，并以适当的速率/位置释放药物，并且对人类使用安全。该NSERC资助的项目之前已经导致了基于聚（环氧乙烷）（PEO）和官能化聚（酯）（如聚（己内酯）（PCL））的安全和可降解嵌段共聚物库的开发和全球知识保护。该文库中的共聚物用于形成核/壳纳米载体，即聚合物胶束，其能够通过物理或化学手段包封许多药物、基因治疗剂和成像探针，使它们在生物环境中稳定，减少它们对健康组织的暴露，同时将它们导向靶位点。这增强了掺入的货物在治疗或成像癌性或炎性部位中的性能。* 为了提高这种新型库在药物递送中的额外作用的性能，我们提出了开发包封来自该聚合物家族的聚合物胶束和纳米凝胶的脂质体。这一办法预计将：i）增强聚阳离子或聚阴离子PEO-聚（酯）用于基因/药物递送的安全性，ii）扩大官能化PEO-聚（酯）在各种亲水/疏水分布的小分子药物、蛋白质和基因的共递送中的应用;和iii）导致可以改变其形状和坚固性的纳米递送系统的发展，结果，显示不同的细胞相互作用或药物释放曲线响应刺激。我们的具体目标是：**1。开发含有基于PEG-（官能化）PCL的聚合物胶束（即脂质细胞）或纳米凝胶（即脂质凝胶）的脂质囊泡。2.研究脂质结构、包封方法、聚合物结构以及刺激（温度、pH、还原剂）对脂质细胞和脂质凝胶的特性（大小、形态、聚合物包封和渗漏）的影响。*3。评估与母体脂质体或聚合物纳米载体相比，脂质细胞和脂质凝胶共包封和释放模型亲水性和疏水性分子的能力。* 4.评估在生理条件下和对刺激的反应中，脂质细胞和脂质凝胶在癌细胞和正常细胞中的体外蛋白质吸附、细胞摄取和毒性。*5。研究与其母体脂质体或聚合物纳米载体相比，脂质细胞和脂质凝胶在荷有正交异性乳腺肿瘤的小鼠中的体内生物分布。*这项研究的结果可以导致开发具有改善的安全性和性能的新型纳米材料，用于溶解，控制和/或靶向（共）递送不同的药物，基因治疗和诊断。所提出的架构，可能会被采用来开发人工细胞，在未来，模仿自然细胞在不同的亚细胞器和弹性方面的结合。

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.*****