Engineering Starch-Based Nanoparticles and Nanoparticle Clusters for Improving Local Drug Delivery to Tumour Cores and the Brain

使用纳米颗粒给药已在多个案例中被证明可以提高药物到达靶点的能力，特别是在药物必须在细胞内转运才能发挥作用和/或药物必须从血液通过难以穿透的生物屏障(例如进入大脑或通过致密组织，如肿瘤)转运的情况下。我们的合作伙伴EcoSynthetix开发的淀粉纳米颗粒(SNPs)具有在制造过程中直接载药的能力、极小的尺寸、凝胶状特性(以及在压力下变形的潜力)和生物惰性，因此在这方面具有特殊的药物输送潜力。然而，使用SNPs进行药物传递有两个固有的局限性：(1)由于SNPs的多孔结构，药物从SNPs中释放非常快；(2)SNPs的小尺寸，虽然对于渗透到大脑或肿瘤深处是理想的，但也会导致SNPs从正常循环中相对较快地清除，限制了SNPs将药物运送到靶点的能力。在这项提议中，我们的目标是通过以下方式来应对这些挑战：(1)设计SNPs的表面，以将药物租赁率调整到所需的值；(2)开发制造具有良好循环性能的受控SNPs簇的方法，这些SNPs簇可以在需要药物释放的地方选择性地降解(通过目标位置的特定化学作用或特定时间后的外部激活)。我们预计，这种基于SNP的材料将显着改善药物的输送，不仅在肿瘤深处，而且在大脑内和大脑中(我们的两个概念验证演示)，而且还将改善有效治疗受到药物输送限制的其他疾病。这种能力预计将改善患有此类疾病的加拿大人的健康状况，并为EcoSynthetix提供一个新的增值市场，将促进加拿大创造新的就业机会。

Delivering drugs using nanoparticles has been demonstrated in multiple cases to improve theability of drugs to get to their target sites, particularly in cases in which drugs must betransported inside cells to be functional and/or drug must be transported from the bloodthrough hard-to-penetrate biological barriers (e.g. into the brain or through dense tissues suchas tumour masses). Starch nanoparticles (SNPs), developed by our partner EcoSynthetix,have particular potential for drug delivery in this context given their capacity for direct loadingof drug during fabrication, their extremely small sizes, their gel-like properties (and thuspotential to deform under stress), and their biological inertness. However, there are twoinherent limitations to using SNPs for drug delivery: (1) drug release from SNPs is very fastgiven their porous structures and (2) the small size of SNPs, while ideal for penetrating intothe brain or deep into tumours, also induces relatively fast clearance of SNPs from normalcirculation, restricting the capacity of SNPs to transport drugs to target sites. In this proposal,we aim to address these challenges by (1) engineering the surface of SNPs to adjust drugrelease rates to desired values and (2) developing methods of fabricating controlled clustersof SNPs with good circulation properties that can be selectively degraded where drug releaseis desired (either by specific chemistry at the target site or by external activation after aspecific time). We anticipate that such SNP-based materials will significantly improve thedelivery of drugs not only deep inside tumours and both into and within the brain (our twoproof-of-concept demonstrations) but also other diseases in which effective therapy is limitedby drug transport. Such capacity is anticipated to both improve health outcomes forCanadians suffering from such diseases as well as provide a new, value-added market toEcoSynthetix that will promote new job creation in Canada.