Development of Robust Cationic Light-Activated Thermosensitive Liposomes: Choosing the Right Lipids.

Extensive research has been conducted on cationic light-activated thermosensitive liposomes (CLTSLs) as a means for site-specific and controlled drug release; however, less attention has been given to the stability of these nanoparticles. Selecting the appropriate lipids is crucial for the development of a stable and responsive system. In this study, we investigated the impact of various lipids on the physical properties of cationic light-activated liposomes. Incorporating poly(ethylene glycol) PEG molecules resulted in uniform liposomes with low polydispersity index, while the addition of unsaturated lipid (DOTAP) resulted in extremely leaky liposomes, with almost 80% release in just 10 min of incubation at body temperature. Conversely, the inclusion of cholesterol in the formulation increased liposome stability too much and decreased their sensitivity to stimuli-responsive release, with only 14% release after 2 min of light exposure. To achieve stable and functional CLTSL, we substituted an equivalent amount of unsaturated lipid with a saturated lipid (DPTAP), resulting in stable liposomes at body temperature that were highly responsive to light, releasing 90% of their content in 10 s of light exposure. We also conducted two atomistic molecular dynamics simulations using lipid compositions with saturated and unsaturated lipids to investigate the effect of lipid composition on the dynamical properties of the liposomal lipid bilayer. Our findings suggest that the nature of lipids used to prepare liposomes significantly affects their properties, especially when the drug loading needs to be stable but triggered drug release properties are required at the same time. Selecting the appropriate lipids in the right amount is therefore essential for the preparation of liposomes with desirable properties.

Mechanistic Insight into How PEGylation Reduces the Efficacy of pH-Sensitive Liposomes from Molecular Dynamics Simulations.

Liposome-based drug delivery systems composed of DOPE stabilized with cholesteryl hemisuccinate (CHMS) have been proposed as a drug delivery mechanism with pH-triggered release as the anionic form (CHSa) is protonated (CHS) at reduced pH; PEGylation is known to decrease this pH sensitivity. In this manuscript, we set out to use molecular dynamics (MD) simulations with a model with all-atom resolution to provide insight into why incorporation of poly(ethyleneglycol) (PEG) into DOPE-CHMS liposomes reduces their pH sensitivity; we also address two additional questions: (1) How CHSa stabilizes DOPE bilayers into a lamellar conformation at a physiological pH of 7.4? and (2) how the change from CHSa to CHS at acidic pH triggers the destabilization of DOPE bilayers? We found that (A) CHSa stabilizes the DOPE lipid membrane by increasing the hydrophilicity of the bilayer surface, (B) when CHSa changes to CHS by pH reduction, DOPE bilayers are destabilized due to a reduction in bilayer hydrophilicity and a reduction in the area per lipid, and (C) PEG stabilizes DOPE bilayers into the lamellar phase, thus reducing the pH sensitivity of the liposomes by increasing the area per lipid through penetration into the bilayer, which is our main focus.

Promoting effect of nano hydroxyapatite and vitamin D3 on the osteogenic differentiation of human adipose-derived stem cells in polycaprolactone/gelatin scaffold for bone tissue engineering.

Tissue engineering knowledge is a step towards the treatment of irreversible damages to human beings. In the present study, PCL/Gel, PCL/Gel/nHA, PCL/Gel/Vit D3 and PCL/Gel/nHA/Vit D3 (Polycaprolactone/Gelatin/Nanohydroxyapatite/Vitamin D3) composite scaffolds were successfully constructed using electrospinning method. The proliferation and differentiation of hADSCs into the bone phenotype were determined using MTT method, ALP activity, Von Kossa and Alizarin red staining, and qRT-PCR test. The simultaneous presence of nHA and vitamin D3 led to the increased activity of ALP in the early stages (on the 14th day) and increased mineralization in the late stages (on the 21st day) in differentiated hADSCs. Further, it was found that the use of nHA and vitamin D3 resulted in increased expression of BGLAP and COLL I and reduced expression of ALP and RUNX2 in hADSCs for 21 days. The results indicated that nHA and vitamin D3 have a synergistic effect on the osteogenic differentiation of hADSCs.

Interactions between Chloramphenicol, Carrier Polymers, and Bacteria-Implications for Designing Electrospun Drug Delivery Systems Countering Wound Infection.

Antibacterial drug-loaded electrospun nano- and microfibrous dressings are of major interest as novel topical drug delivery systems in wound care. In this study, chloramphenicol (CAM)-loaded polycaprolactone (PCL) and PCL/poly(ethylene oxide) (PEO) fiber mats were electrospun and characterized in terms of morphology, drug distribution, physicochemical properties, drug release, swelling, cytotoxicity, and antibacterial activity. Computational modeling together with physicochemical analysis helped to elucidate possible interactions between the drug and carrier polymers. Strong interactions between PCL and CAM together with hydrophobicity of the system resulted in much slower drug release compared to the hydrophilic ternary system of PCL/PEO/CAM. Cytotoxicity studies confirmed safety of the fiber mats to murine NIH 3T3 cells. Disc diffusion assay demonstrated that both fast and slow release fiber mats reached effective concentrations and had similar antibacterial activity. A biofilm formation assay revealed that both blank matrices are good substrates for the bacterial attachment and formation of biofilm. Importantly, prolonged release of CAM from drug-loaded fibers helps to avoid biofilm formation onto the dressing and hence avoids the treatment failure.

Elucidation of Molecular Mechanisms Behind the Self-Assembly Behavior of Chitosan Amphiphilic Derivatives Through Experiment and Molecular Modeling.

PURPOSE: Chitosan-based polymeric micelles (CBPMs) are considered as promising carriers for delivery of anticancer drugs, imaging agents and genes. To optimize the physicochemical, pharmaceutical and biological properties of CBPMs, the molecular mechanisms behind the self-assembly behavior of chitosan (CHI) amphiphilic derivatives are elucidated. METHODS: This study has two stages. In the experimental stage, dexamethasone (DEX) as a hydrophobic group is grafted to CHI in three degrees of substitution in order to obtain CHI derivatives with different degrees of hydrophobicity. These new CHI amphiphilic derivatives (CHI_DEXs) form micelles in water where their critical aggregation concentration (CAC), size and zeta potential are measured. Through comparing the results of these measurements, the change of self-assembly behavior of CHI_DEXs in response to increasing their hydrophobicity is evaluated. Correlating this evaluation with the results of the 13 MD simulations conducted on CHI_DEXs in atomistic molecular dynamics (MD) simulation stage, reveals the molecular mechanisms behind the self-assembly behavior of CHI_DEXs. RESULTS: Our evaluation of the experimental results reveals that increasing hydrophobicity of a CHI amphiphilic derivative would not necessarily cause it to form micelles with lower CAC value, smaller size and lower zeta potential. The MD simulations reveal that there exists a balance between intra- and inter-chain interactions which is responsible for the self-assembly behavior of CHI amphiphilic derivatives. CONCLUSION: An increase in DS of the hydrophobic group triggers a cascade of molecular events that shifts the balance between intra- and inter-chain interactions leading to changes in the CAC, size and zeta potential of the CBPMs.

Physicochemical, pharmaceutical and biological approaches toward designing optimized and efficient hydrophobically modified chitosan-based polymeric micelles as a nanocarrier system for targeted delivery of anticancer drugs.

Hydrophobically modified chitosan-based polymeric micelles (CBPMs) are formed through self-aggregation of chitosan amphiphilic derivatives. Their core-shell structure, diversity and the fact that all of their properties are adjustable through reconciling the interactions among their three main constituents: chitosan, hydrophilic segment and hydrophobic segment as well as with the outside medium through changing the ratio and chemical structure of each component's, chemical structure distinguish them from other chitosan-based drug delivery systems (DDSs) and give rise to these promising candidates for targeted delivery of lipophilic anticancer drugs. The majority of review articles conducted previously on chitosan-based DDSs have only made simple differential comparisons between such systems and the anticancer drugs that have been delivered through them. In this review article, all the basic properties of CBPMs including physicochemical, pharmaceutical and biological properties are technically detailed and discussed. The intention of this article is to outline and discuss salient features of CBPMs to contribute to the understanding of optimized strategies for the design of stable and efficient CBPMs.