Department of Bioengineering, Northeastern University, Boston, MA 02115, USA.
Department of Bioengineering, Northeastern University, Boston, MA 02115, USA; Department of Mechanical Engineering, Northeastern University, Boston, MA 02115, USA.
Acta Biomater. 2022 Oct 1;151:278-289. doi: 10.1016/j.actbio.2022.08.010. Epub 2022 Aug 11.
Charge-based drug delivery has proven to be effective for targeting negatively charged cartilage for the treatment of osteoarthritis. Cartilage is surrounded by synovial fluid (SF), which is comprised of negatively charged hyaluronic acid and hydrophobic proteins that can competitively bind cationic carriers and prevent their transport into cartilage. Here we investigate the relative contributions of charge and hydrophobic effects on the binding of cationic carriers within healthy and arthritic SF by comparing the transport of arginine-rich cartilage targeting cationic peptide carriers with hydrophilic (CPC +14N) or hydrophobic property (CPC +14A). CPC +14N had significantly greater intra-cartilage uptake in presence of SF compared to CPC +14A in-vitro and in vivo. In presence of individual anionic SF constituents, both CPCs maintained similar high intra-cartilage uptake while in presence of hydrophobic constituents, CPC +14N had greater uptake confirming that hydrophobic and not charge interactions are the dominant cause of competitive binding within SF. Results also demonstrate that short-range effects can synergistically stabilize intra-cartilage charge-based binding - a property that can be utilized for enhancing drug-carrier residence time in arthritic cartilage with diminished negative fixed charge density. The work provides a framework for the rational design of cationic carriers for developing targeted therapies for another complex negatively charged environments. STATEMENT OF SIGNIFICANCE: This work demonstrates that hydrophobic and not charge interactions are the dominant cause of the binding of cationic carriers in synovial fluid. Therefore, cationic carriers can be effectively used for cartilage targeting if they are made hydrophilic. This can facilitate clinical translation of various osteoarthritis drugs for cartilage repair that have failed due to a lack of effective cartilage targeting methods. It also demonstrates that short-range hydrogen bonds can synergistically stabilize electrostatic binding in cartilage offering a method for enhancing the targeting and residence time of cationic carriers within arthritic cartilage with reduced charge density. Finally, the cartilage-synovial fluid unit provides an excellent model of a complex negatively charged environment and allows us to generalize these findings and develop targeted therapies for other charged tissue-systems.
基于电荷的药物递送已被证明可有效靶向带负电荷的软骨，用于治疗骨关节炎。软骨周围环绕着滑液（SF），SF 由带负电荷的透明质酸和疏水性蛋白组成，这些物质可以竞争性结合阳离子载体并阻止其进入软骨。在这里，我们通过比较富含精氨酸的靶向软骨阳离子肽载体与亲水性（CPC +14N）或疏水性（CPC +14A）的阳离子载体在健康和关节炎 SF 中的结合情况，研究电荷和疏水性效应对阳离子载体结合的相对贡献。在 SF 存在的情况下，CPC +14N 在体外和体内的软骨内摄取量明显大于 CPC +14A。在存在单个阴离子 SF 成分的情况下，两种 CPC 都保持了相似的高软骨内摄取量，而在存在疏水性成分的情况下，CPC +14N 的摄取量更高，这证实了疏水性而不是电荷相互作用是 SF 中竞争结合的主要原因。结果还表明，短程相互作用可以协同稳定软骨内基于电荷的结合-这一特性可用于增强具有降低的固定负电荷密度的关节炎软骨中药物载体的停留时间。该工作为阳离子载体的合理设计提供了一个框架，用于开发针对另一种复杂带负电荷环境的靶向治疗方法。
这项工作表明，在滑液中，阳离子载体的结合主要是疏水性而不是电荷相互作用。因此，如果阳离子载体亲水化，它们可以有效地用于软骨靶向。这可以促进各种骨关节炎药物向软骨修复的临床转化，这些药物由于缺乏有效的软骨靶向方法而失败。它还表明，短程氢键可以协同稳定软骨中的静电结合，提供一种方法来增强具有降低的电荷密度的关节炎软骨中阳离子载体的靶向性和停留时间。最后，软骨-滑液单元提供了一个复杂带负电荷环境的极好模型，并允许我们推广这些发现并为其他带电荷的组织系统开发靶向治疗方法。
