Electrospun poly-l-lactide scaffold for the controlled and targeted delivery of a synthetically obtained Diclofenac prodrug to treat actinic keratosis.
Electrospun poly-l-lactide scaffold for the controlled and targeted delivery of a synthetically obtained Diclofenac prodrug to treat actinic keratosis.
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DOI：
10.1016/j.actbio.2016.11.002
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发表时间：
2017-04
影响因子：
9.7
通讯作者：
Germano Piccirillo;B. Bochicchio;A. Pepe;K. Schenke-Layland;Svenja Hinderer
中科院分区：
文献类型：
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作者：
Germano Piccirillo;B. Bochicchio;A. Pepe;K. Schenke-Layland;Svenja Hinderer
光化性角化病(AKs)是一种与长期日晒损伤有关的小皮肤病变，如果不治疗，可能会发展为浸润性鳞癌(SCC)。治疗AKs的有效、特异和耐受性好的治疗方法仍然是人们非常感兴趣的。就成本、有效性、副作用和耐受性而言，双氯芬酸(DCF)是目前AKS局部治疗的黄金标准。在这项工作中，电纺聚乳酸(PLA)支架负载了合成的DCF前药并对其进行了表征。具体来说，通过固相肽合成(SPPS)将DCF结合到甘氨酸残基上，然后将其结合到静电纺丝的聚乳酸支架中，成功地合成了前药。用多光子显微镜(MPM)验证药物包封率，用分光光度法监测支架释放，并用MPM进行确认。通过扫描电子显微镜(SEM)、拉伸测试和接触角测量对支架进行了进一步表征。通过细胞增殖实验验证其生物相容性，并与含有等量DCF钠盐(DCFONa)的聚乳酸支架进行比较。最后，结合MPM和荧光寿命成像显微镜，研究了电纺支架对人真皮成纤维细胞(HDFS)形态和代谢的影响。研究结果表明，所制得的支架可用于控制和靶向地给药治疗AK的合成前体药物。在这项工作中，一种含有人工合成的双氯芬酸前体药物的电纺聚乳酸支架被提出作为局部治疗光化性角化病的新型底物。以感兴趣区域为靶点的受控给药可以提高治疗效果并有利于愈合过程。该前药是通过固相合成的，采用一种清洁和通用的方法来获得双氯芬酸衍生物。在这里，我们使用多光子显微镜对纤维支架中的药物胶囊进行成像，并使用荧光寿命成像显微镜来研究双氯芬酸的作用和潜在的作用机制。
Actinic Keratosis’ (AKs) are small skin lesions that are related to a prolonged sun-damage, which can develop into invasive squamous cell carcinoma (SCC) when left untreated. Effective, specific and well tolerable therapies to cure AKs are still of great interest. Diclofenac (DCF) is the current gold standard for the local treatment of AKs in terms of costs, effectiveness, side effects and tolerability. In this work, an electrospun polylactic acid (PLA) scaffold loaded with a synthetic DCF prodrug was developed and characterized. Specifically, the prodrug was successfully synthetized by binding DCF to a glycine residue via solid phase peptide synthesis (SPPS) and then incorporated in an electrospun PLA scaffold. The drug encapsulation was verified using multiphoton microscopy (MPM) and its scaffold release was spectrophotometrically monitored and confirmed with MPM. The scaffold was further characterized with scanning electron microscopy (SEM), tensile testing and contact angle measurements. Its biocompatibility was verified by performing a cell proliferation assay and compared to PLA scaffolds containing the same amount of DCF sodium salt (DCFONa). Finally, the effect of the electrospun scaffolds on human dermal fibroblasts (HDFs) morphology and metabolism was investigated by combining MPM with fluorescence lifetime imaging microscopy (FLIM). The obtained results suggest that the obtained scaffold could be suitable for the controlled and targeted delivery of the synthesized prodrug for the treatment of AKs.Statement of SignificanceElectrospun scaffolds are of growing interest as materials for a controlled drug delivery. In this work, an electrospun polylactic acid scaffold containing a synthetically obtained Diclofenac prodrug is proposed as a novel substrate for the topical treatment of actinic keratosis. A controlled drug delivery targeted to the area of interest could enhance the efficacy of the therapy and favor the healing process. The prodrug was synthesized via solid phase, employing a clean and versatile approach to obtain Diclofenac derivatives. Here, we used multiphoton microscopy to image drug encapsulation within the fibrous scaffold and fluorescence lifetime imaging microscopy to investigate Diclofenac effects and potential mechanisms of action.