Electrospun poly-l-lactide scaffold for the controlled and targeted delivery of a synthetically obtained Diclofenac prodrug to treat actinic keratosis.
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.



Electrospun 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.
Dept. of Science, University of Basilicata, 85100 Potenza (PZ), Italy; Dept. of Women's Health, Research Institute for Women's Health, Eberhard-Karls-University Tübingen, 72076 Tübingen, Germany.
Germano
G
Piccirillo
Dept. of Science, University of Basilicata, 85100 Potenza (PZ), Italy.
Brigida
B
Bochicchio
Dept. of Science, University of Basilicata, 85100 Potenza (PZ), Italy.
Antonietta
A
Pepe
Dept. of Women's Health, Research Institute for Women's Health, Eberhard-Karls-University Tübingen, 72076 Tübingen, Germany; Dept. of Cell and Tissue Engineering, Fraunhofer-Institute for Interfacial Engineering and Biotechnology (IGB), 70569 Stuttgart, Germany; Dept. of Medicine/Cardiology, Cardiovascular Research Laboratories, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Katja
K
Schenke-Layland
Dept. of Women's Health, Research Institute for Women's Health, Eberhard-Karls-University Tübingen, 72076 Tübingen, Germany; Dept. of Cell and Tissue Engineering, Fraunhofer-Institute for Interfacial Engineering and Biotechnology (IGB), 70569 Stuttgart, Germany. Electronic address: svenja.hinderer@igb.fraunhofer.de.
Svenja
S
Hinderer
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000737:chemistry; D002478:Cells, Cultured; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000737:chemistry; D004008:Diclofenac / Q000008:administration & dosage* / Q000737:chemistry; D004058:Diffusion; D016503:Drug Delivery Systems / Q000379:methods; D004595:Electroplating / Q000379:methods*; D006801:Humans; D055623:Keratosis, Actinic / Q000188:drug therapy* / Q000473:pathology; D011091:Polyesters / Q000737:chemistry*; D011355:Prodrugs / Q000008:administration & dosage; D017768:Skin, Artificial; D054457:Tissue Scaffolds; D016896:Treatment Outcome
D000894:Anti-Inflammatory Agents, Non-Steroidal; D003692:Delayed-Action Preparations; D011091:Polyesters; D011355:Prodrugs; D004008:Diclofenac; C033616:poly(lactide)
Actinic keratosis; Diclofenac; Electrospinning; FLIM; Multiphoton imaging