The development of smart drug delivery systems that respond to physiological cues remains a key challenge in nanomedicine. This study focuses on the precise engineering of pH-responsive lyotropic liquid crystalline nanoparticles based on monoolein (MO), where the phase transition from inverse hexagonal (H2) to bicontinuous cubic (Q2) is strategically tuned through the use of mixed aminolipids. While single aminolipid-doped MO nanoparticles exhibited pH-dependent transitions, the range and sharpness of these transitions were often limited by the intrinsic pKa values and molecular structure of individual components. To overcome this, we explored co-doping two distinct aminolipids—Lipid-2 (a pyridinyl-oleate) and Lipid-6 (a heterocyclic-oleate)—at a 1:1 weight ratio into MO nanoparticles stabilized with Pluronic F127.
The rationale behind this approach lies in the principle of averaging pKa values in mixed amphiphile systems. Lipid-2 has a lower pKa (~3.5), leading to H2 → Q2 transition at very low pH, while Lipid-6 exhibits a higher pKa (~6.0), enabling transition within the biologically relevant range of 5.5–6.5. By blending them, we aimed to achieve an intermediate pKa behavior, thereby shifting the phase transition to the desired acidic microenvironment of tumors and infected tissues. Synchrotron SAXS analysis confirmed this hypothesis: the mixed lipid system displayed a clear H2 → Q2 transition occurring at pH ~5.5, with minimal hysteresis and high sensitivity—observed within just a 0.5 pH unit change.
Partial phase diagrams revealed that the transition pH decreased slightly as the total aminolipid content (RMO) increased, consistent with trends seen in single-component systems.59-05-2 MedChemExpress However, the critical difference was the broadened operational window. At RMO = 0.15, for instance, the H2 phase remained stable up to pH 5.8, transitioning abruptly to Q2 at pH 5.5. This sharp, reversible switch ensures minimal premature release in healthy tissues and maximal payload delivery at disease sites.
Importantly, lattice parameter measurements showed a significant increase in the Q2 phase upon acidification, confirming structural expansion due to electrostatic repulsion between protonated headgroups. For example, at RMO = 0.1, the lattice parameter rose from 91 Å at pH 7 to 108 Å at pH 4, indicating effective swelling of the aqueous channels—key for enhanced drug release kinetics.
Cryogenic transmission electron microscopy (cryo-TEM) imaging further validated the phase changes, revealing well-defined cubic structures at low pH and hexagonal arrangements at neutral pH. The absence of aggregation or instability even after prolonged storage underscores the robustness of the formulation.611168-24-2 medchemexpress
This work demonstrates a powerful strategy to fine-tune the responsiveness of lipid nanoparticles without synthesizing new molecules.PMID:28722873 By mixing existing aminolipids with complementary pKa profiles, researchers can rapidly engineer materials tailored to specific therapeutic applications. Such systems are particularly promising for intracellular delivery, where endosomal escape (pH ~5.5–6.0) is crucial, and for siRNA or protein therapeutics requiring membrane fusion facilitated by the more fusogenic cubic phase.
In summary, codoping two aminolipids provides a versatile, scalable method to control the onset and sensitivity of pH-triggered phase transitions in MO-based nanoparticles. This approach not only expands the design space for stimuli-responsive nanocarriers but also accelerates the path toward clinical translation by enabling precise targeting of diseased microenvironments. Future studies will focus on encapsulating model drugs such as doxorubicin and evaluating release profiles under simulated physiological conditions, paving the way for next-generation targeted therapies.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