Effects of polycationic drug carriers on the electromechanical and swelling properties of cartilage
Effects of polycationic drug carriers on the electromechanical and swelling properties of cartilage
复制标题
聚阳离子药物载体对软骨机电和溶胀性能的影响
DOI：
10.1016/j.bpj.2022.06.024
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发表时间：
2022
影响因子：
3.4
通讯作者：
Bajpayee, Ambika G.
中科院分区：
文献类型：
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作者：
Warren, Matthew R.;Vedadghavami, Armin;Bhagavatula, Sanjana;Bajpayee, Ambika G.
阳离子纳米载体为负电荷结缔组织的药物输送提供了一个有希望的解决方案，例如治疗骨关节炎(OA)的关节软骨。然而，在高间质浓度下，阳离子大分子对软骨力学性能的影响还知之甚少。我们利用不同净电荷(从+8到+20)的富含精氨酸的阳离子多肽载体(CPC)来研究纳米载体诱导软骨生物力学特性变化的生物物理机制。我们观察到，CPC使健康牛软骨移植的压缩模数增加了70%，而糖胺多糖耗竭组织(模拟骨性关节炎)的硬度降低了69%；在这两种情况下，硬度变化的幅度与CPC电荷变量的摄取有关。接下来，我们直接测量了由于屏蔽了阴离子细胞外基质成分之间的电荷斥力而导致的软骨组织中CPC诱导的渗透消胀，减少的幅度在36到之间。然后，我们证明了静电相互作用是CPC诱导的僵硬发生所必需的，当在高渗浴盐中测量时，没有观察到组织僵硬的增加。我们应用一个非理想的Donnan渗透模型(在三相理论下)将体积弹性模量的测量结果分离为Donnan和非Donnan分量，这进一步证明了CPC相互冲突的电荷屏蔽和基质硬化效应。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的力学性质，包括预期的电荷屏蔽以及由物理连接介导的一种新的僵硬现象。我们介绍了一个模型，说明这些机械变化的大小如何依赖于药物载体的可调物理属性，包括净电荷、大小和空间电荷分布。我们预见，本文提出的结果和理论将为未来阳离子药物输送系统的设计提供参考，旨在治疗广泛结缔组织中的疾病。
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.