A prospective class of materials for drug delivery is lyotropic liquid crystalline (LLC) nanoparticles, such as cubosomes and hexosomes. Efforts are being made to generate a pH-dependent system that exhibits slow release hexosomes (H2) at physiological pH and relatively fast release cubosomes (Q2) at acidic disease sites such as in various cancers and bacterial infections (pH ~5.5–6.5). Herein, we report the synthesis of nine ionizable aminolipids, which were doped into monoolein (MO) lipid nanoparticles. Using high-throughput formulation and synchrotron small-angle X-ray scattering (SAXS), the effects of aminolipid structure and concentration on the mesophase of MO nanoparticles at various pH levels were determined. As the pH changed from neutral to acidic, mesophases could be formed in an order of L2 (inverse micelles) → H2 → Q2. Specifically, systems with heterocyclic oleates exhibited the H2 to Q2 transition at pH 5.1223397-11-2 MedChemExpress 5–6.5. Furthermore, the phase transition pH could be fine-tuned by incorporating two aminolipids into the nanoparticles. Nanoparticles with a pH-dependent phase transition as described in this study may be useful as drug delivery carriers for the treatment of cancers and certain bacterial infections.
Nine novel ionizable aminolipids were synthesized and formulated into stable MO-based nanoparticles. These aminolipids consist of a hydrophobic oleyl tail and a hydrophilic headgroup containing a tertiary amine, linked via an ester bond. The synthesis was carried out using oleic acid and various tertiary aminoalcohols through an esterification reaction, followed by purification using flash chromatography. The structures were confirmed via 1H NMR and GC-MS analysis. The resulting aminolipids were categorized into pyridinyl-oleates, heterocyclic-oleates, aniline-oleate, and di-oleates, each differing in molecular architecture and pKa values.158966-92-8 Molecular Weight
The nanoparticles were prepared using a high-throughput method, where varying amounts of aminolipids (RMO = 0.05 to 0.5) were mixed with MO and stabilized with Pluronic F127 or F108. Dynamic light scattering (DLS) revealed average particle sizes ranging from 176 to 298 nm with low polydispersity indices (PDI < 0.23), indicating monodisperse and stable formulations. Particle size remained consistent over 30 days, confirming long-term stability. Synchrotron SAXS was employed to analyze the internal mesophase structure across a pH range of 2.5 to 10. At neutral pH, increasing aminolipid content induced a phase sequence from bicontinuous cubic (Q2) to inverse hexagonal (H2) and finally to inverse micellar (L2). This transformation was attributed to increased effective critical packing parameter (CPP) due to the lipophilic nature of the aminolipids. However, upon lowering pH, protonation of the tertiary amine led to charge development and electrostatic repulsion, increasing the effective headgroup area and reducing CPP. This resulted in a reversible transition from H2 to Q2, particularly observed in systems containing heterocyclic-oleates (Lipid-5 and Lipid-6), which exhibited a sharp H2 → Q2 transition between pH 5.PMID:30855858 5 and 6.5—within the pathologically relevant range for solid tumors and infected tissues.
The phase transition pH could be precisely tuned by co-doping two aminolipids. For example, mixing Lipid-2 (pyridinyl-oleate) and Lipid-6 (heterocyclic-oleate) yielded a transition at pH ~5.5, demonstrating the ability to engineer responsiveness around desired therapeutic pH windows. This tunability offers significant potential for targeted delivery systems.
Moreover, the choice of stabilizer influenced nanoparticle behavior. While both F127 and F108 stabilized the dispersions, F108 preserved the Q2 phase better than F127, which favored a primitive cubic (QIm3m) structure. Despite this, both stabilizers allowed for pH-responsive transitions, confirming the robustness of the system.
In conclusion, this study presents a library of synthetic ionizable aminolipids capable of inducing pH-dependent phase transitions in MO nanoparticles. The ability to switch from slow-release H2 nanoparticles at physiological pH to fast-release Q2 nanoparticles at acidic disease sites enables smart, stimuli-responsive drug delivery. These findings open new avenues for designing next-generation nanomedicines targeting cancer and infection with enhanced specificity and reduced systemic toxicity.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com
