Browsing by Author "Statts, Larry"

Leishmaniasis is a neglected disease presenting cutaneous, mucosal and visceral forms and affecting an estimated 12 million mostly low-income people. Treatment of cutaneous leishmaniasis (CL) is recommended to expedite healing, reduce risk of scarring, prevent parasite dissemination to other mucocutaneous (common with New World species) or visceral forms and reduce the chance of relapse, but remains an unmet need. Available treatments are painful, prolonged (>20 days) and require hospitalisation, which increases the cost of therapy. Here we present the development of optimised topical self-nanoemulsifying drug delivery systems (SNEDDS) loaded with buparvaquone (BPQ, a hydroxynapthoquinone from the open Malaria Box) for the treatment of CL from New World species. The administration of topical BPQ-SNEDDS gels for 7 days resulted in a reduction of parasite load of 99.989 ± 0.019 % similar to the decrease achieved with intralesionally administered Glucantime® (99.873 ± 0.204 %) in a L. amazonensis BALB/c model. In vivo efficacy was supported by ex vivo permeability and in vivo tape stripping studies. BPQ-SNEDDS and their hydrogels demonstrated linear flux across non-infected CD-1 mouse skin ex vivo of 182.4 ± 63.0 μg cm-2 h-1 and 57.6 ± 10.8 μg cm-2 h-1 respectively localising BPQ within the skin in clinically effective concentrations (227.0 ± 45.9 μg and 103.8 ± 33.8 μg) respectively. These levels are therapeutic as BPQ-SNEDDS and their gels showed nanomolar in vitro efficacy against L. amazonensis and L. braziliensis amastigotes with excellent selectivity index toward parasites versus murine macrophages. In vivo tape stripping experiments indicated localisation of BPQ within the stratum corneum and dermis. Histology studies confirmed the reduction of parasitism and indicated healing in animals treated with BPQ-SNEDDS hydrogels. These results highlight the potential clinical capability of nano-enabled BPQ hydrogels towards a non-invasive treatment for CL.

Cutaneous fungal and parasitic diseases remain challenging to treat, as available therapies are unable to permeate the skin barrier. Thus, treatment options rely on systemic therapy, which fail to produce high drug local concentrations but can lead to significant systemic toxicity. Amphotericin B (AmB) is highly efficacious in the treatment of both fungal and parasitic diseases such as cutaneous leishmaniasis, but is only reserved for parenteral administration in patients with severe pathophysiology. Here, we have designed and optimised AmB-transfersomes [93.5 % encapsulation efficiency, size of 150 nm, and good colloidal stability (-35.02 mV)] that can remain physicochemically stable (>90 % drug content) at room temperature and 4 °C over 6 months when lyophilised and stored under desiccated conditions. AmBtransfersomes possessed good permeability across mouse skin (4.91 ± 0.41 μg/cm2/h) and 10-fold higher permeability across synthetic Strat-M® membranes. In vivo studies after a single topical application in mice showed permeability and accumulation within the dermis (>25 μg AmB /g skin at 6 h post-administration) indicating the delivery of therapeutic amounts of AmB for mycoses and cutaneous leishmaniasis, while a single daily administration in Leishmania (Leishmania) amazonensis infected mice over 10 days resulted in excellent efficacy (98 % reduction in Leishmania parasites). Combining the application of AmB-transfersomes with metallic microneedles in vivo increased levels in the SC and dermis but is unlikely to elicit transdermal levels. In conclusion, AmB-transfersomes are promising and stable topical nanomedicines that can be readily translated for parasitic and fungal infectious diseases.