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Relevant academic research and scientific papers

Self-aggregates of cholesterol-modified carboxymethyl konjac glucomannan conjugate: Preparation, characterization, and preliminary assessment as a carrier of etoposide

Various cholesterol (CH) bearing carboxymethyl konjac glucomannan (CKGM) amphiphilic conjugates (denoted CHCKGM) were synthesized using CKGM as hydrophilic segments and CH as hydrophobic parts. Structural characteristics of these CHCKGM conjugates were in

Engineering liposomal nanoparticles of cholesterol-tethered amphiphilic Pt(iv) prodrugs with prolonged circulation time in blood

Cisplatin is a platinum-based chemotherapeutic agent widely used in the treatment of various solid tumors. However, a major challenge in the use of cisplatin and in the development of cisplatin derivatives, namely Pt(iv) prodrugs, is their premature reduction in the bloodstream before reaching cancer cells. To circumvent this problem, we designed liposomal nanoparticles coupled with a cholesterol-tethered amphiphilic Pt(iv) prodrug. The addition of cholesterol served to stabilize the formation of the liposome, while selectively incorporating cholesterol as the axial ligand also allowed the Pt(iv) prodrug to readily migrate into the liposomal bilayer. Notably, upon embedding into the nanoparticles, the Pt(iv) prodrug showed marked resistance against premature reduction in human plasma in vitro. Pharmacokinetic analysis in a mouse model also showed that the nanoparticles significantly extend the half-life of the Pt(iv) prodrug to 180 min, which represents a >6-fold increase compared to cisplatin. Importantly, such lipid modification did not compromise the genotoxicity of cisplatin, as the Pt(iv) prodrug induced DNA damage and apoptosis in ovarian cancer cell lines efficiently. Taken together, our strategy provides a novel insight as to how to stabilize a platinum-based compound to increase the circulation time in vivo, which is expected to enhance the efficacy of drug treatment. This journal is

Synthesis and gelation behaviors of five new dimeric cholesteryl derivatives

Five new diacid amides of di-cholesteryl l-glycinates were designed and prepared. The compounds with linkers containing 0, 1, 2, 3, or 4 methylene units are denoted as 1, 2, 3, 4, and 5, respectively. Their gelation behaviors in 25 solvents were tested as novel low-molecular-mass organic gelators (LMOGs). It was shown that the length of the linker connecting the two-cholesteryl residues in a gelator plays a crucial role in the gelation behavior of the compound. 1 gels 11 of the 25 solvents tested at a concentration lower than 1.0%, while 2 gels 17 of the solvents tested. 4 and 5, however, gel only 2 and 4 of them, respectively. SEM observation reveals that the lengths of the linkers and the identity of the solvents are the main factors affecting the structures of the aggregates in the gels. Experimentally, a clear linker effect on the microstructures of the gels was observed. As example, the aggregates of 1, 2 and 3 in benzene or 1-heptanol adopt structures of thin fibers, rods or lamellas, respectively. Furthermore, it was found that the gelation and aggregation behaviors of 2, 3, 4, and 5 in DMSO showed an even-odd effect.

Metabolism-based brain-targeting system for a thyrotropin-releasing hormone analogue

Gln-Leu-Pro-Gly, a progenitor sequence for the thyrotropin-releasing hormone (TRH) analogue [Leu2]TRH (pGlu-Leu-Pro-NH2), was covalently and bioreversibly modified on its N- and C-termini (by a 1,4-dihydrotrigonellyl and a cholesteryl group, respectively) to create lipoidal brain-targeting systems for the TRH analogue. The mechanism of targeting and the recovery of the parent peptide at the target site involve several enzymatic steps, including the oxidation of the 1,4-dihydropyridine moiety. Due to the lipid insolubility of the peptide pyridinium conjugate obtained after this reaction, one of the rudimentary steps of brain targeting (i.e., trapping in the central nervous system) can be accomplished. Our design also included spacer amino acid(s) inserted between the N-terminal residue of the progenitor sequence and the dihydrotrigonellyl group to facilitate the posttargeting removal of the attached modification. The release of the TRH analogue in the brain is orchestrated by a sequential metabolism utilizing esterase/lipase, peptidyl glycine α-amidating monooxygenase (PAM), peptidase cleavage, and glutaminyl cyclase. In addition to in vitro experiments to prove the designed mechanism of action, the efficacy of brain targeting for [Leu2]TRH administered in the form of chemical-targeting systems containing the embedded progenitor sequence was monitored by the antagonistic effect of the peptide on the barbiturate-induced anesthesia (measure of the activational effect on cholinergic neurons) in mice, and considerable improvement was achieved over the efficacy of the parent peptide upon using this paradigm.

Hyaluronic acid-glycine-cholesterol conjugate-based nanoemulsion as a potent vaccine adjuvant for T cell-mediated immunity

Clinical cases of allergic reaction that are due to excipients containing polyethylene glycol (PEG), a hydrophilic molecule commonly used in drug/vaccine formulations, has attracted much attention in recent years. In order to develop PEG-free adjuvants, we investigated the feasibility of natural ingredients in the human body such as hyaluronic acid in the form of hyaluronic acid-glycine cholesterol (HACH) conjugate as an excipient for vaccine formulation. Interestingly, HACH grafted with ~13 wt.% cholesterol has good water dispersity and can serve as an emulsifier to stabilize the squalene/water interfaces, yielding a milky white and isotropic emulsion (SQ@HACH) after being passed through a high-shear microfluidizer. Our results show that SQ@HACH particles possessed a unimodal average hydrodynamic diameter of approximately 190 nm measured by dynamic light scattering and exhibited good stability upon storage at 4?C and 37?C for over 20 weeks. The results of immunogenicity using a mouse model with ovalbumin (OVA) as the antigen revealed that SQ@HACH significantly enhanced antigen-specific immune responses, including the polarization of IgG antibodies, the cytokine secretions of T cells, and enhancement of cytotoxic T lymphocyte (CTL) activation. Moreover, SQ@HACH revealed lower local inflammation and rapidly absorbing properties compared with AlPO4 after intramuscular injection in vivo, indicating the potential functions of the HA-derived conjugate as an excipient in vaccine formulations for enhancement of T cell-mediated immunity.

The self-assembly and chiroptical properties of tetraphenylethylene dicycle tetracholesterol with an AIE effect

The immobilized propeller-like conformation of tetraphenylethylene (TPE) can be used to emit strong circularly polarized luminescence (CPL) light, but the immobilized propeller-like conformation must be resolved. A single-handed helical conformation of TPE units induced by chiral group(s) that do not need resolution can also enable CPL emission, but related research is very rare. In this paper, TPE dicycle tetracholesterol is synthesized which could self-assemble into nano-tubes with a double molecule-layer shell, and which showed a fluorescence quantum yield of >76%. One film composed of nano-tubes displayed an enhanced first positive circular dichroism (CD) effect and emitted strong positive CPL light. A suspension or solution of the TPE dicycle tetracholesterol in DCE had a first negative CD band and negative CPL emission. In contrast, TPE tetracholesterol without intramolecular cyclization self-assembled into very soft "noodle-like" aggregations and showed very weak CD signals and CPL emission. The TPE dicycle tetracholesterol had a large CPL dissymmetric factor (≤3.0 × 10-3), which was 30 times larger than the TPE tetracholesterol without cycles. Due to the strong bisignate band in the CD spectrum of TPE dicycle tetracholesterol and the absence of a helical structure in aggregates, the CD and CPL signals of the TPE dicycle tetracholesterol could be ascribed to the prevailing single-handed propeller-like conformation of TPE units induced by chiral cholesterol groups.

Naphthalene-cholesterol conjugate as simple gelator for selective sensing of CN– ion

Cholesterol-based Schiff base 1 has been designed and synthesised. The Schiff base 1 forms yellow coloured gel in DMF:H2O (2:1, v/v) and the gel is anion responsive. Among different anions, the gel phase of 1 is selectively transformed into sol in the presence of CN– ions and validates its visual sensing. 1H NMR, FTIR and HRMS spectroscopic techniques were adopted to study the gelation of 1 and its responsive behaviour towards anions.

Development of streptavidin-based nanocomplex for siRNA delivery

In our previous study, we have identified a PCBP2 siRNA that exhibits antifibrotic activity in rat hepatic stellate cells (HSCs) by inhibition of αCP2, a protein responsible for stabilization of the collagen α1 (I) mRNA in alcoholic liver fibrosis. This study aims to develop a streptavidin-based nanocomplex that can efficiently deliver the PCBP2 siRNA to HSCs. Biotin-siRNA and biotin-cholesterol were mixed with streptavidin to form the streptavidin-biotin complex, which was further condensed electrostatically with positively charged protamine to form the final multicomponent siRNA nanocomplex in the size range of 150-250 nm. The siRNA nanocomplex does not induce cytotoxicity in rat HSCs as compared to commercially available transfection agents. The cellular uptake efficiency of the siRNA nanocomplex is higher in rat HSCs than other cell lines, such as Caco-2 and PC-3, indicating that receptor-mediated endocytosis mainly contributes to the cellular uptake of the siRNA nanocomplex. The siRNA nanocomplex exhibits more than 85% silencing effect on the PCBP2 mRNA in HSCs. Stability study indicates that the nanocomplex can efficiently protect siRNA from degradation in the serum. The streptavidin-based multicomponent siRNA nanocomplex provides a promising strategy to deliver the PCBP2 siRNA to HSCs. Moreover, the nanocomplex can be used as a platform for other diseases by changing the siRNA sequence and targeting ligand.