Hollow microneedle assisted intradermal delivery of hypericin lipid nanocapsules with light enabled photodynamic therapy against skin cancer
Photodynamic therapy (PDT) to manage non-melanoma skin cancers has garnered great attention over the past few years. Hypericin (Hy) is a potent lipid-soluble photosensitiser with promising anticancer therapeutic activities. Nevertheless, its poor water-solubility, aggregation in biological systems and insufficient skin penetration restricted its effective exploitation. Herein, we report for the first-time encapsulation of Hy into lipid nanocapsules (Hy-LNCs), and then application of an AdminPen™ hollow microneedles (Ho-MNs) array and an in-house fabricated Ho-MN to enable efficient intradermal delivery. The physicochemical properties, photoactivity, ex vivo drug distribution and cellular uptake were evaluated. Results showed that Hy-LNCs were successfully formed with a particle size of 47.76 ± 0.49 nm, PDI of 0.12 ± 0.02, high encapsulation efficiency (99.67% ± 0.35), 396 fold higher photoactivity, 7 fold higher skin drug deposition, significantly greater cellular uptake and higher photocytotoxicity compared to free Hy. The therapeutic effect of Hy-LNCs was finally assessed in vivo using a nude mouse model with transplanted tumours. Interestingly, Hy-LNCs delivered by Ho-MN exhibited remarkable anti-tumour destruction (85.84%) after irradiation with 595 nm. This study showed that Ho-MNs-driven delivery of Hy-LNCs followed by irradiation could form a promising minimally invasive, effective and site-specific approach for managing non-melanoma skin cancers.
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Hypericin was purchased from Planta Natural Products GmbH, Austria. Labrafac® WL 1349 (caprylic-capric acid triglycerides) was provided by Gattefossé S.A., Saint-Priest, France. Solutol® HS 15, Kolliphor® HS 15, Macrogol (15) – hydroxystearate, Polyethylene glycol (15) hydroxystearate, Polyoxyethylated 12 – hydroxystearic acid (a mixture of free polyethylene glycol 660 and polyethylene glycol 660 hydroxystearate) were obtained from Sigma Aldrich, Dorset, UK. Lipoid® S 100 (a soybean lecithin at 97% of phosphatidylcholine) was a kind gift from Lipoïd GMBH Ludwigshafen, Germany. Poly lactic acid (PLA 3D850) biopolymer was purchased from Nature Works LCC, Minnetonka, MN, USA. Dimethyl sulfoxide, DMSO, >99.5%, was obtained from Honeywell Specialty Chemicals Seelze GmbH, Wunstorfer Strabe, Seelze, Germany. Light-emitting diode (LED) with 595 ± 10 nm, 445 mW and 700 mA mounted with adjustable collimation optic was purchased from Thorlabs GmbH, Germany. AdminPen™ device was purchased from NanoBioSciences LLC, USA. Matrigel® was obtained from Corning, UK. Isoflurane inhaled anaesthetic agent was purchased from AbbVie Ltd., Maidenhead, UK. Only ultra-pure water (Milli-Q Millipore, USA) was used. All other chemical reagents were commercially obtained as reagent-grade products.
Heba Abd-El-Azim, Ismaiel A. Tekko, Ahlam Ali, Alyaa Ramadan, Noha Nafee, Nawal Khalafallah, Taifur Rahman, William Mcdaid, Rania G. Aly, Lalitkumar K. Vora, Steven J. Bell, Fiona Furlong, Helen O. McCarthy, Ryan F. Donnelly,
Hollow microneedle assisted intradermal delivery of hypericin lipid nanocapsules with light enabled photodynamic therapy against skin cancer,
Journal of Controlled Release, Volume 348, 2022, Pages 849-869, ISSN 0168-3659,