This study was executed to mitigate imiquimod (IMQ)-side effects and promote its anticancer potential against skin cancer via encapsulation in hyaluronic acid-coated lipid nanocapsules (HA-LNCs) for targeted topical delivery. The LNCs were prepared using the phase inversion technique. Optimized LNCs formulation was gained following 22 factorial design experiment to adjust the IMQ and CTAB concentrations. The two variables were found to significantly influence the dependent responses. The encapsulation efficiency of IMQ exceeded 97%. HA coating provided a sustained release of IMQ from LNCs, with 63.81±2.45% of IMQ released after 24h. Moreover, the ex-vivo human skin permeation study showed that 7.9-fold more IMQ was localized in all skin layers than that permeated. In vitro anticancer activity indicated that IMQ-HA-LNCs had higher cytotoxicity (IC50=22.39μg/mL) compared to free IMQ (IC50=97.94μg/mL). Further, in vivo studies revealed that encapsulation of IMQ in HA-LNCs enhanced its immunostimulatory potential and promoted its anti-tumor activity in competing skin cancer even in low doses compared to the untreated group and group treated with a brand product with no topical or systemic toxicity. The present study suggested that HA-LNCs with their mixed polymeric/lipophilic nature epitomize a promising strategy for safe topical delivery of poorly water-soluble candidates.
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