Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Koch Institute for Integrative Cancer Research, 500 Main Street, Cambridge, MA 02142, USA.
Sci Transl Med. 2018 Nov 28;10(469). doi: 10.1126/scitranslmed.aat8800.
Osteoarthritis is a debilitating joint disease affecting nearly 30 million people for which there are no disease-modifying therapies. Several drugs that have failed clinical trials have shown inefficient and inadequate delivery to target cells. Anabolic growth factors are one class of such drugs that could be disease-modifying if delivered directly to chondrocytes, which reside deep within dense, anionic cartilage tissue. To overcome this biological barrier, we conjugated a growth factor to a cationic nanocarrier for targeted delivery to chondrocytes and retention within joint cartilage after direct intra-articular injection. The nanocarrier uses reversible electrostatic interactions with anionic cartilage tissue to improve tissue binding, penetration, and residence time. Amine terminal polyamidoamine (PAMAM) dendrimers were end functionalized with variable molar ratios of poly(ethylene glycol) (PEG) to control surface charge. From this small family of variably PEGylated dendrimers, an optimal formulation showing 70% uptake into cartilage tissue and 100% cell viability was selected. When conjugated to insulin-like growth factor 1 (IGF-1), the dendrimer penetrated bovine cartilage of human thickness within 2 days and enhanced therapeutic IGF-1 joint residence time in rat knees by 10-fold for up to 30 days. In a surgical model of rat osteoarthritis, a single injection of dendrimer-IGF-1 rescued cartilage and bone more effectively than free IGF-1. Dendrimer-IGF-1 reduced width of cartilage degeneration by 60% and volumetric osteophyte burden by 80% relative to untreated rats at 4 weeks after surgery. These results suggest that PEGylated PAMAM dendrimer nanocarriers could improve pharmacokinetics and efficacy of disease-modifying osteoarthritis drugs in the clinic.
骨关节炎是一种使人虚弱的关节疾病，影响近 3000 万人，目前尚无针对这种疾病的疗法。许多在临床试验中失败的药物显示出对靶细胞的低效和不足的传递。合成代谢生长因子是此类药物的一种，如果直接递送到软骨细胞中，就可以成为一种治疗疾病的药物，而软骨细胞存在于致密的阴离子软骨组织深处。为了克服这种生物屏障，我们将生长因子与阳离子纳米载体缀合，用于靶向递送到软骨细胞，并在直接关节内注射后保留在关节软骨中。该纳米载体利用与阴离子软骨组织的可逆静电相互作用来改善组织结合、穿透和停留时间。胺端聚酰胺-胺（PAMAM）树枝状大分子用不同摩尔比的聚（乙二醇）（PEG）进行末端功能化，以控制表面电荷。从这个具有不同 PEG 化树枝状大分子的小家族中，选择了一种最佳配方，该配方显示出 70%的摄取进入软骨组织和 100%的细胞活力。当与胰岛素样生长因子 1（IGF-1）缀合时，树枝状大分子在 2 天内穿透了牛的人类厚度的软骨，并将 IGF-1 在大鼠膝关节中的治疗性关节停留时间延长了 10 倍，长达 30 天。在大鼠骨关节炎的手术模型中，与游离 IGF-1 相比，单次注射树枝状大分子-IGF-1 更有效地挽救了软骨和骨骼。与未治疗的大鼠相比，在手术后 4 周时，树枝状大分子-IGF-1 使软骨退变的宽度减少了 60%，体积性骨赘负担减少了 80%。这些结果表明，PEG 化 PAMAM 树枝状大分子纳米载体可改善临床治疗疾病的骨关节炎药物的药代动力学和疗效。
