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，并以适当的速度/位置释放药物，并且可以安全用于人体。这个NSERC资助的项目，之前已经导致了基于聚环氧乙烷（PEO）和功能化聚（酯）如聚己内酯（PCL）的安全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封装许多药物、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，同时引导它们走向目标位点。这提高了合并货物在治疗或成像癌症或炎症部位的性能。为了提高这个新文库的性能，使其在药物传递中发挥更多的作用，我们建议从该聚合物家族中开发包膜聚合物胶束和纳米凝胶的脂质体。该方法有望：i)提高聚阳离子或聚阴离子peo -聚（酯）s用于基因/药物递送的安全性，ii)扩大功能化peo -聚（酯）s在小分子药物、蛋白质和各种亲疏水基因的共递送中的应用；iii)导致纳米递送系统的发展，可以改变它们的形状和硬度，因此，在响应刺激时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：开发含有PEG（功能化）PCL基聚合物胶束（即脂细胞）或纳米凝胶（即脂凝胶）的脂质囊泡。2. 探讨脂质结构、包封方式、聚合物结构以及刺激因素（温度、pH、还原剂）对脂细胞和脂凝胶特性（大小、形态、聚合物包封和渗漏）的影响。3. 与亲本脂质体或聚合纳米载体相比，评估脂细胞和脂凝胶共包封和释放模型亲水和疏水分子的能力。4. 在生理条件下和对刺激的反应下，评估癌症细胞和正常细胞中脂细胞和脂凝胶的体外蛋白质吸附、细胞摄取和毒性。5. 目的：比较脂细胞和脂凝胶与其母体脂质体或聚合纳米载体在小鼠原位乳腺肿瘤中的体内生物分布。这项研究的结果可以导致新型纳米材料的发展，这些材料具有更好的安全性和性能，用于不同药物的增溶、控制和/或靶向（共同）递送，基因治疗和诊断。所提出的结构，可能被用来开发人造细胞，在未来，模仿自然细胞在不同的亚细胞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.