Gold nanorods-loaded hydrogel-forming needles for local hyperthermia applications: Proof of concept.

Basal cell carcinoma (BCC) is the most common form of skin cancer and responsible for most of the cancer related morbidities and pose a significant public health concern worldwide. Surgery treatment modality is able to clear the BCC, yet it mostly leads to scar formation. Plasmonic photothermal therapy (PPTT) which involves using gold nanostructures and near-infrared (NIR) light to kill the BCC cells by local heating is associated with excellent tissue preservation and healing without scarring. Parenteral administration of such gold nanostructures suffers from off-target delivery and side effects. Delivering such phototherapeutics directly to the BCC proved to be an attractive alternative route of administration yet encountered with penetration limitations due to the stratum corneum (SC) fierce barrier. In the current study, we developed and optimised a novel NIR light-responsive hydrogel-forming long needle (HFLN) loaded with Gold nanorods (GNRs) as a potential plasmonic photothermal device for localised treatment of nodular BCC. The HFLN was prepared from Gantrez® S-97 and poly(ethylene glycol) (PEG) 200 Da and characterized in terms of swelling, insertion and mechanical properties. GNRs were synthesised and tunned using seed-mediated growth method. The integrated devices developed could revolutionise BCC treatment benefiting both patients and healthcare providers.

Development and characterisation of novel poly (vinyl alcohol)/poly (vinyl pyrrolidone)-based hydrogel-forming microneedle arrays for enhanced and sustained transdermal delivery of methotrexate.

Methotrexate (MTX) is one of the mainstays of treatment for rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) and it is mainly administered either orally or by subcutaneous (SC) injection, which are not so satisfactory. While orally administered MTX is associated with variable bioavailability and causes gastrointestinal side effects, including nausea and vomiting, SC injection is painful and produces high peak blood levels of MTX. Transdermal delivery presents an attractive alternative administration route. However, MTX passive permeation through the skin is hindered by the skin barrier and MTX physicochemical properties. To address these issues, hydrogel-forming microneedle arrays (HFMN) and a patch-like reservoir loaded with MTX (MTX-RV) were developed and combined to form a minimally invasive patch to deliver MTX transdermally in a sustained manner. HFMN were prepared from an aqueous blend of poly (vinyl alcohol) (PVA) and poly (vinyl pyrrolidone) (PVP) which was crosslinked chemically with citric acid (CA) at 130˚C. MTX-RV was prepared from hydroxypropyl methylcellulose (HPMC) and glycerol. Both the HFMN and MTX-RV were fully characterised and then combined to form an integrated patch, which was evaluated ex vivo and in preclinical studies. The HFMN demonstrated a satisfactory mechanical strength and insertion capability into excised neonatal porcine skin, as well as moderate swelling properties. The MTX-RV incorporated a high dose of MTX (150.3 ± 5.3 µg/mg) without precipitation. The integrated patch delivered MTX at a steady-state flux of 506.8 ± 136.9 µg.cm2/h in an ex vivo setup. Furthermore, in preclinical studies performed in Sprague Dawley rats, MTX appeared in blood after 1 h from patch application at a concentration of 7.6 ± 2.0 nM. MTX blood level increased gradually to reach its peak, Cmax = 35.1 ± 5.1 nM, at 24 h. Importantly, the HFMN were removed intact from the skin with only mild erythema, despite the cytotoxic nature of MTX. Accordingly, the integrated patch produced in this work represents a promising minimally invasive transdermal drug delivery system that can overcome the skin barrier and deliver MTX in a sustained manner. This may help in minimising or even avoiding the nausea and vomiting, associated with the conventional administration routes.

Intradermal Delivery of a Near-Infrared Photosensitizer Using Dissolving Microneedle Arrays.

Nodular basal cell carcinoma is a deep skin lesion and one of the most common cancers. Conventional photodynamic therapy is limited to treatment of superficial skin lesions. The parenteral administration of near-IR preformed photosensitizers suffers from poor selectivity and may result in prolonged skin photosensitivity. Microneedles (MNs) can provide localized drug delivery to skin lesions. Intradermal delivery of the preformed near-IR photosensitizer; 5,10,15,20-tetrakis(2,6-difluoro-3-N-methylsulfamoylphenyl bacteriochlorin (Redaporfin™) using dissolving MN was successful in vitro and in vivo. MN demonstrated complete dissolution 30 min after skin application and showed sufficient mechanical strength to penetrate the skin to a depth of 450 µm. In vitro deposition studies illustrated that the drug was delivered and detected down to 5 mm in skin. In vivo biodistribution studies in athymic nude mice Crl:NU(NCr)-Foxn1nu showed both fast initial release and localized drug delivery. The MN-treated mice showed a progressive decrease in the fluorescence intensity at the application site over the 7-day experiment period, with the highest and lowest fluorescence intensities measured being 9.2 × 1010 ± 2.5 × 1010 and 3.8 × 109 ± 1.6 × 109 p/s, respectively. By day 7, there was some migration of fluorescence away from the site of initial MN application. However, the majority of the body surfaces showed fluorescence levels that were comparable to those seen in the negative control group. This work suggests utility for polymeric MN arrays in minimally invasive intradermal delivery to enhance photodynamic therapy of deep skin lesions.