Abstract
pH-responsive nanoparticles enable the selective delivery of a chemotherapeutic agent to tumours while reducing adverse effects. Herein we synthesised four novel aminolipids and developed pH-responsive nanostructured lipid nanoparticles (LNP), which exhibited a slow-releasing hexagonal structure (H(2)) at physiological pH and quick release bicontinuous cubic phase (Q(2)) at the acidic tumour pH. The nanoparticles were used to encapsulate and control the release of the chemotherapeutic agent SN-38. High-throughput formulation techniques were employed to fabricate LNP by mixing various amounts of aminolipid with monoolein (MO). The effect of aminolipids on MO self-assembled structures was studied using small-angle X-ray scattering (SAXS) at various pH values. Out of the four studied aminolipid-MO LNP systems, the nanoparticles containing N-(Pyridin-4-ylmethyl) oleamide (OAPy-4) or N-(2(piperidin-1yl)ethyl) oleamide (OAPi-1) exhibited a pH-induced H(2) to Q(2) phase transition in a tumour-relevant pH range (pH 5.5-7.0). SN-38 is 1000 times more efficacious than the commercially available prodrug irinotecan. However, low solubility in water and instability at physiological pH makes it unsuitable for clinical use. SN-38 was loaded into LNP containing MO and aminolipid OAPy-4. The drug loading and entrapment efficiency were determined, and the results indicated that the aqueous solubility of SN-38 loaded in LNP dispersions was ~100 times higher compared to the solubility of the pure drug in aqueous solution. Furthermore, we demonstrated that the in vitro SN-38 release rate from LNPs was faster at lower pH (pH 5) than at neutral pH. Therefore, pH-responsive LNPs developed in this study can potentially be employed in delivering and controlling the release of the potent drug SN-38 to tumour sites.