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Cartilage penetrating cationic peptide carriers for applications in drug delivery to avascular negatively charged tissues.
Acta Biomaterialia ( IF 9.7 ) Pub Date : 2018-12-06 , DOI: 10.1016/j.actbio.2018.12.004
Armin Vedadghavami 1 , Erica K Wagner 1 , Shikhar Mehta 1 , Tengfei He 1 , Chenzhen Zhang 1 , Ambika G Bajpayee 2
Affiliation  

Drug delivery to avascular, negatively charged tissues like cartilage remains a challenge. The constant turnover of synovial fluid results in short residence time of administered drugs in the joint space and the dense negatively charged matrix of cartilage hinders their diffusive transport. Drugs are, therefore, unable to reach their cell and matrix targets in sufficient doses, and fail to elicit relevant biological response, which has led to unsuccessful clinical trials. The high negative fixed charge density (FCD) of cartilage, however, can be used to convert cartilage from a barrier to drug entry into a depot by making drugs positively charged. Here we design cartilage penetrating and binding cationic peptide carriers (CPCs) with varying net charge, spatial distribution and hydrophobicity to deliver large-sized therapeutics and investigate their electro-diffusive transport in healthy and arthritic cartilage. We showed that CPC uptake increased with increasing net charge up to +14 but dropped as charge increased further due to stronger binding interactions that hindered CPC penetrability and uptake showing that weak-reversible binding is key to enable their penetration through full tissue thickness. Even after 90% GAG depletion, while CPC +14 uptake reduced by over 50% but still had a significantly high value of 148× showing that intra-tissue long-range charge-based binding is further stabilized by short-range H-bond and hydrophobic interactions. The work presents an approach for rational design of cationic carriers based on tissue FCD and properties of macromolecules to be delivered. These design rules can be extended to drug delivery for other avascular, negatively charged tissues. STATEMENT OF SIGNIFICANCE: Osteoarthritis (OA) remains an untreatable disease partly due to short joint residence time of drugs and a lack of delivery methods that can effectively target the dense, avascular, highly negatively charged cartilage tissue. In this study, we designed cartilage penetrating and binding cationic peptide carriers (CPCs) that, due to their optimal charge provide adequate electrical driving force to rapidly transport OA drugs into cartilage and reach their cell and matrix targets in therapeutic doses before drugs exit the joint space. This way cartilage is converted from being a barrier to drug entry into a drug depot that can provide sustained drug release for several weeks. This study also investigates synergistic effects of short-range H-bond and hydrophobic interactions in combination with long-range electrostatic interactions on intra-cartilage solute transport. The work provides rules for rational design of cartilage penetrating charge-based carriers depending on the net charge of tissue (normal versus arthritic), macromolecule to be delivered and whether the application is in drug delivery or tissue imaging.

中文翻译:

渗透软骨的阳离子肽载体,用于将药物输送到无血管带负电的组织中。

将药物输送到无血管的,带负电荷的组织(如软骨)仍然是一个挑战。滑液的不断转换导致所用药物在关节腔内的停留时间短,并且软骨的带负电荷的密集基质阻碍了它们的扩散运输。因此,药物无法以足够的剂量达到其细胞和基质靶标,并且无法引起相关的生物学反应,这导致了临床试验的失败。但是,软骨的高负固定电荷密度(FCD)可用于通过使药物带正电来将软骨从屏障转化为药物进入储库。在这里,我们设计了具有不同净电荷的软骨穿透和结合阳离子肽载体(CPC),空间分布和疏水性,以提供大型治疗剂并研究其在健康和关节炎软骨中的电扩散转运。我们显示,CPC的吸收随着净电荷的增加而增加,直至+14,但由于电荷相互作用的增强阻碍了CPC的渗透性和吸收,电荷随着电荷的进一步增加而下降,这表明弱的可逆结合是使其能够穿透整个组织厚度的关键。即使在90%的GAG耗竭后,CPC +14的吸收减少了50%以上,但仍然具有很高的148x值,表明组织内基于远程电荷的结合通过短程H键和疏水相互作用。这项工作提出了一种基于组织FCD和要传递的大分子特性合理设计阳离子载体的方法。这些设计规则可以扩展到其他无血管,带负电荷的组织的药物输送。重大意义声明:骨关节炎(OA)仍然是一种无法治愈的疾病,部分原因是药物的关节滞留时间短和缺乏可以有效靶向致密,无血管,带负电荷的软骨组织的递送方法。在这项研究中,我们设计了软骨穿透和结合阳离子肽载体(CPC),由于它们的最佳电荷提供了足够的电驱动力,可以在药物离开关节之前以治疗剂量快速将OA药物转运到软骨中并到达其细胞和基质靶标。空间。通过这种方式,软骨从对药物进入的障碍转变为可以持续释放药物数周的药物仓库。这项研究还研究了短程H键和疏水相互作用与远程静电相互作用对软骨内溶质运输的协同作用。这项工作根据组织的净电荷(正常与关节炎),要输送的大分子以及应用是在药物输送还是在组织成像中,为基于软骨的电荷基载体的合理设计提供了规则。
更新日期:2019-07-05
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