Department of Materials Science and Engineering, Stanford University, Stanford, CA 94305, USA.
Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.
Biomater Sci. 2023 Mar 14;11(6):2065-2079. doi: 10.1039/d2bm00819j.
Prolonged maintenance of therapeutically-relevant levels of broadly neutralizing antibodies (bnAbs) is necessary to enable passive immunization against infectious disease. Unfortunately, protection only lasts for as long as these bnAbs remain present at a sufficiently high concentration in the body. Poor pharmacokinetics and burdensome administration are two challenges that need to be addressed in order to make pre- and post-exposure prophylaxis with bnAbs feasible and effective. In this work, we develop a supramolecular hydrogel as an injectable, subcutaneous depot to encapsulate and deliver antibody drug cargo. This polymer-nanoparticle (PNP) hydrogel exhibits shear-thinning and self-healing properties that are required for an injectable drug delivery vehicle. drug release assays and diffusion measurements indicate that the PNP hydrogels prevent burst release and slow the release of encapsulated antibodies. Delivery of bnAbs against SARS-CoV-2 from PNP hydrogels is compared to standard routes of administration in a preclinical mouse model. We develop a multi-compartment model to understand the ability of these subcutaneous depot materials to modulate the pharmacokinetics of released antibodies; the model is extrapolated to explore the requirements needed for novel materials to successfully deliver relevant antibody therapeutics with different pharmacokinetic characteristics.
为了实现传染病的被动免疫，有必要使治疗相关水平的广泛中和抗体（bnAbs）长时间维持。不幸的是，只要这些 bnAbs 在体内保持足够高的浓度，保护作用就会持续。为了使 bnAbs 的预防和暴露前及暴露后预防变得可行和有效，需要解决药代动力学差和给药负担重这两个挑战。在这项工作中，我们开发了一种超分子水凝胶作为可注射的皮下储库，用于封装和输送抗体药物。这种聚合物-纳米颗粒（PNP）水凝胶具有可注射药物输送载体所需的剪切稀化和自修复特性。药物释放实验和扩散测量表明，PNP 水凝胶可以防止突释并减缓封装抗体的释放。将针对 SARS-CoV-2 的 bnAbs 从 PNP 水凝胶中递送到临床前小鼠模型中，并与标准给药途径进行了比较。我们开发了一个多隔室模型来了解这些皮下储库材料调节释放抗体药代动力学的能力；该模型被外推以探索新型材料成功输送具有不同药代动力学特征的相关抗体治疗药物所需的条件。
