Predicting transport of intra-articularly injected growth factor fusion proteins into human knee joint cartilage.
Predicting transport of intra-articularly injected growth factor fusion proteins into human knee joint cartilage.
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DOI：
10.1016/j.actbio.2022.09.032
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发表时间：
2022-09
影响因子：
9.7
通讯作者：
Y. Krishnan;Y. Yang;Sieun K. Barnes;H. Hung;B. Olsen;P. Hammond;A. Grodzinsky
中科院分区：
文献类型：
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作者：
Y. Krishnan;Y. Yang;Sieun K. Barnes;H. Hung;B. Olsen;P. Hammond;A. Grodzinsky
目前还没有已知的药物或治疗方法可以预防创伤后骨关节炎 (PTOA)，这是一种由创伤性关节损伤引发的骨关节炎 (OA)，占全球近 6 亿 OA 病例的 12%。缺乏有效的药物递送技术仍然是开发临床有效治疗方法的主要挑战，但阳离子递送载体可以帮助克服这一挑战。扩大在体外模型中有效的治疗，以在临床前体内模型和临床试验中取得成功也是该领域的一个具有挑战性的问题。在这里，我们使用阳离子绿色荧光蛋白 (GFP) 作为载体来递送胰岛素样生长因子 1 (IGF-1)，这种药物被认为是 PTOA 的潜在治疗药物。 GFP-IGF-1 缀合物首先被合成为具有不同多肽接头的融合蛋白，并在人软骨外植体中表征了它们的转运特性。体外实验数据用于开发预测数学运输模型，并使用独立的体外实验数据集进行验证。该模型用于预测这些融合蛋白在关节内注射到人类膝关节后的转运。预测包括融合蛋白渗透到软骨中的速率和程度的结果，以及通过关节囊逃逸到体循环中的融合蛋白的最大水平。总之，我们的运输测量和模型为此类外植体培养研究转化为体内临床前研究和潜在的临床应用奠定了基础。意义陈述 软骨中缺乏血液供应以及注射到人体膝盖中的药物的快速清除对开发临床上有效的骨关节炎治疗方法提出了重大挑战。阳离子递送载体可以靶向带负电的软骨并帮助克服这个问题。扩大体外有效的治疗以在体内取得成功也具有挑战性。在这里，我们使用阳离子绿色荧光蛋白 (GFP) 将胰岛素样生长因子-1 (IGF-1) 输送到软骨中。测量人软骨外植体中 GFP-IGF-1 融合蛋白转运的实验用于开发和验证数学模型，以预测注入人膝关节后融合蛋白的转运。这项工作将此类外植体培养研究转化为体内临床前研究和潜在的临床应用。
There are no drugs or treatment methods known to prevent the development of post-traumatic osteoarthritis (PTOA), a type of osteoarthritis (OA) that is triggered by traumatic joint injuries and accounts for∼ 12% of the nearly 600 million OA cases worldwide. Lack of effective drug delivery techniques remains a major challenge in developing clinically effective treatments, but cationic delivery carriers can help overcome this challenge. Scaling up treatments that are effective in in vitro models to achieve success in preclinical in vivo models and clinical trials is also a challenging problem in the field. Here we use a cationic green fluorescent protein (GFP) as a carrier to deliver Insulin-Like Growth Factor 1 (IGF-1), a drug considered as a potential therapeutic for PTOA. GFP-IGF-1 conjugates were first synthesized as fusion proteins with different polypeptide linkers, and their transport properties were characterized in human cartilage explants. In vitro experimental data were used to develop a predictive mathematical transport model that was validated using an independent in vitro experimental data set. The model was used to predict the transport of these fusion proteins upon intra-articular injection into human knee joints. The predictions included results for the rate and extent of fusion protein penetration into cartilage, and the maximum levels of fusion proteins that would escape into systemic circulation through the joint capsule. Together, our transport measurements and model set the stage for translation of such explant culture studies to in vivo preclinical studies and potentially clinical application. Statement of significance The lack of blood supply in cartilage and rapid clearance of drugs injected into human knees presents a major challenge in developing clinically effective treatments for osteoarthritis. Cationic delivery carriers can target negatively charged cartilage and help overcome this problem. Scaling up treatments that are effective in vitro to achieve success in vivo is also challenging. Here, we use a cationic green fluorescent protein (GFP) to deliver Insulin-Like Growth Factor-1 (IGF-1) into cartilage. Experiments measuring transport of GFP-IGF-1 fusion proteins in human cartilage explants were used to develop and validate a mathematical model to predict fusion protein transport upon injection into human knee joints. This work translates such explant culture studies to in vivo preclinical studies and potentially clinical application.