Novel pH-Responsive Cubosome and Hexosome Lipid Nanocarriers of SN-38 Are Prospective for Cancer Therapy

• Main Authors: Sarigama Rajesh (Author), Jiali Zhai (Author), Calum J. Drummond (Author), Nhiem Tran (Author)
• Format: Book
• Published: MDPI AG, 2022-10-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/pharmaceutics14102175; 1999-4923
• Keywords: pH-responsive; cubosomes; hexosomes; lipid-nanoparticles (LNPs); SN-38; ionisable lipids; Pharmacy and materia medica; RS1-441
• Source: Pharmaceutics, Vol 14, Iss 10, p 2175 (2022)

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 (H₂) at physiological pH and quick release bicontinuous cubic phase (Q₂) 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 H₂ to Q₂ 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.