Department of Bioengineering, Northeastern University, Boston, Massachusetts.
Department of Bioengineering, Northeastern University, Boston, Massachusetts; Department of Mechanical Engineering, Northeastern University, Boston, Massachusetts.
Biophys J. 2022 Sep 20;121(18):3542-3561. doi: 10.1016/j.bpj.2022.06.024. Epub 2022 Jun 27.
Cationic nanocarriers offer a promising solution to challenges in delivering drugs to negatively charged connective tissues, such as to articular cartilage for the treatment of osteoarthritis (OA). However, little is known about the effects that cationic macromolecules may have on the mechanical properties of cartilage at high interstitial concentrations. We utilized arginine-rich cationic peptide carriers (CPCs) with varying net charge (from +8 to +20) to investigate the biophysical mechanisms of nanocarrier-induced alterations to cartilage biomechanical properties. We observed that CPCs increased the compressive modulus of healthy bovine cartilage explants by up to 70% and decreased the stiffness of glycosaminoglycan-depleted tissues (modeling OA) by 69%; in both cases, the magnitude of the change in stiffness correlated with the uptake of CPC charge variants. Next, we directly measured CPC-induced osmotic deswelling in cartilage tissue due to shielding of charge repulsions between anionic extracellular matrix constituents, with magnitudes of reductions between 36 and 64 kPa. We then demonstrated that electrostatic interactions were required for CPC-induced stiffening to occur, evidenced by no observed increase in tissue stiffness when measured in hypertonic bathing salinity. We applied a non-ideal Donnan osmotic model (under triphasic theory) to separate bulk modulus measurements into Donnan and non-Donnan components, which further demonstrated the conflicting charge-shielding and matrix-stiffening effects of CPCs. These results show that cationic drug carriers can alter tissue mechanical properties via multiple mechanisms, including the expected charge shielding as well as a novel stiffening phenomenon mediated by physical linkages. We introduce a model for how the magnitudes of these mechanical changes depend on tunable physical properties of the drug carrier, including net charge, size, and spatial charge distribution. We envision that the results and theory presented herein will inform the design of future cationic drug-delivery systems intended to treat diseases in a wide range of connective tissues.
阳离子纳米载体为解决向带负电荷的结缔组织（如治疗骨关节炎（OA）的关节软骨）输送药物的挑战提供了有希望的解决方案。然而，对于阳离子大分子可能对高细胞间隙浓度下软骨机械性能的影响知之甚少。我们利用具有不同净电荷（从+8 到+20）的精氨酸丰富的阳离子肽载体（CPC）来研究纳米载体引起的软骨生物力学特性变化的生物物理机制。我们观察到 CPC 使健康牛软骨外植体的压缩模量增加了高达 70%，并使糖胺聚糖耗竭组织（模拟 OA）的刚度降低了 69%；在这两种情况下，刚度变化的幅度与 CPC 电荷变体的摄取量相关。接下来，我们直接测量了由于带负电荷的细胞外基质成分之间的电荷排斥而屏蔽引起的 CPC 诱导的软骨组织渗透压肿胀，降低幅度在 36 和 64kPa 之间。然后，我们证明了静电相互作用是 CPC 诱导变硬发生所必需的，这从在高渗浴盐度下测量时观察到组织刚度没有增加这一事实中得到证明。我们应用非理想的 Donnan 渗透模型（在三相理论下）将体积模量测量值分离为 Donnan 和非 Donnan 分量，这进一步证明了 CPC 的相互冲突的电荷屏蔽和基质变硬作用。这些结果表明，阳离子药物载体可以通过多种机制改变组织机械性能，包括预期的电荷屏蔽以及由物理连接介导的新型变硬现象。我们提出了一个模型，用于说明这些机械变化的幅度如何取决于药物载体的可调物理性质，包括净电荷、大小和空间电荷分布。我们设想本文提出的结果和理论将为设计旨在治疗各种结缔组织疾病的未来阳离子药物输送系统提供信息。
