Development and optimization of solvent-assisted gradient active loading technique (SGALT) to improve the encapsulation efficiency and ulcerative colitis efficacy of liposomal andrographolide derivatives

Andrographolide and its derivatives have demonstrated significant anti-inflammatory properties, making them potential candidates for treating ulcerative colitis (UC). However, the clinical application of andrographolide injection via intravenous injection is often limited due to poor water solubility, severe adverse reactions, and poor targeting efficacy. This study developed a solvent-assisted gradient activity loading technique (SGALT) to improve the clinical application of dehydrated andrographolide succinate sesquiterpenes (DAS). DAS formed insoluble salt complexes in the interior of liposomes. The "lock-in" loading strategy exhibited a high encapsulation efficiency (89.78 ± 2.81 %) and sufficient DAS retention ability. There was 84.13 % of liposomal DAS that remained stable in plasma for 24 h, and the drug release was accelerated in the acidic environment of colitis. Moreover, the accumulation of DAS liposomes (DAS-Lip) was 3.3 times greater than that of free drugs in 24 h in colitis mice but not in normal mice due to extravasation through leaky vasculature and subsequent inflammatory cell-mediated sequestration (ELVIS) effect. Pharmacodynamic studies further demonstrated that DAS-Lip effectively improved anti-colitis efficacy in mice with higher disease activity index (DAI), lower inflammatory cytokine levels, and less toxicity. In conclusion, SGALT-mediated intra-liposomal drug locking facilitates the drugability of DAS and will provide a new idea for the treatment of UC.