Intranasal Delivery Of Polymer-Anchored Lipid Nanoconstructs Of Artemether-Lumefantrine In Plasmodium Berghei Anka Murine Model

Cerebral malaria is a serious plasmodial infection that calls for immediate treatment for parasitic clearance from brain. Oral regimen of cerebral malaria is an impracticable option, it being often associated with problems like impaired consciousness, nausea and anorexia. The current research studies were, accordingly, undertaken to develop a patient-friendly non-invasive and rapid therapy via intranasal delivery of artemether (AM) and lumefantrine (LMF) employing their surface-modified lipidic nanocarriers (LNCs) using N, N, N trimethyl chitosan (TMC) as the polymer. Systematically developed employing Quality-by-Design (QbD) principles, LNCs and TMC-LNCs exhibited particle size of 63.7 and 80.8 nm, polydispersity of 0.19 and 0.28, respectively, along with modulated drug release profile for a period of 48 h. TMC-LNCs indicated nearly 2- and 7-folds enhancement in the mucoadhesive strength and nasal mucosal permeation vis-a-vis conventional LNCs and pure drug(s) suspension, respectively. In vitro nitric oxide assay unraveled the potential of both TMC-LNCs and LNCs to trigger macrophages for stimulating innate immune response against the parasites. Brain biodistribution studies in female C57BL/6 mice indicated higher drug concentrations in mice brain with intranasally delivered TMC-LNCs over intranasal and peroral AM-LMF suspension. Further, the speed and effectiveness of TMC-LNCs and LNCs in eradicating Plasmodium berghei ANKA strain in the murine model was also evaluated. Intranasal TMC-LNC demonstrated considerable in vivo anti-plasmodial efficacy with over 95% parasite suppression on day 7, followed by intranasal LNCs (82.5%), intranasal AM-LMF (79.1%) and peroral AM-LMF (46.3%). Overall, the surface-modified formulation, i.e., intranasal TMC-LNCs demonstrated markedly superior efficacy and parasitic suppression in brain.