Xiaohui Li

Effect of Cationic Cyclopeptides on Transdermal and Transmembrane Delivery of Insulin

Poor permeability of stratum corneum limits the transportation of insulin across the skin. A transdermal peptide has exhibited enhancement activity on insulin transdermal delivery. A series of cationic cyclopeptides based on the sequence of TD-1 (ACSSSPSKHCG) were designed by the partial arginine or lysine scan method. Among these peptides, TD-34 (ACSSKKSKHCG) with bis-substituted lysine in N-5 and N-6 showed the best transdermal enhancement activity, with the blood glucose level lowered to about 26% of initial after administrating 2.1 IU insulin with 0.5 μmol of TD-34 in 100 μL of saline for 8 h to diabetic rats in vivo. In addition, the transmembrane permeability in Caco-2 cell monolayers (BL→AP) exhibited preferable correlation with percutaneous absorption of insulin (R(2) = 0.73). It can be concluded that the appropriate content and position of cationic group in cyclopeptides may improve percutaneous absorption and transmembrane ability of insulin, and Caco-2 cell monolayers (BL→AP) might be applied to predict the percutaneous absorption of insulin chaperoned by a transdermal peptide in vivo.

Discovery of Potent HDAC Inhibitors Based on Chlamydocin with Inhibitory Effects on Cell Migration

The histone deacetylase (HDAC) family is a promising drug target class owing to the importance of these enzymes in a variety of cellular processes. Docking studies were conducted to identify novel HDAC inhibitors. Subtle modifications in the recognition domain were introduced into a series of chlamydocin analogues, and the resulting scaffolds were combined with various zinc binding domains. Remarkably, cyclo(L‐Asu(NHOH)‐L‐A3mc6c‐L‐Phe‐D‐Pro, compound 1u2009b), with a methyl group at positionsu20053 or 5 on the aliphatic ring, exhibited better antiproliferative effects than trichostatinu2005A (TSA) against MCF‐7 and K562 cell lines. In addition to cell‐cycle arrest and apoptosis, cell migration inhibition was observed in cells treated with compound 1u2009b. Subsequent western blot analysis revealed that the balance between matrix metalloproteinaseu20052 (MMP2) and tissue inhibitors of metalloproteinaseu20051 (TIMP1) determines the degree of metalloproteinase activity in MCF‐7 cells, thereby regulating cell migration. The improved inhibitory activity imparted by altering the hydrophobic substitution pattern at the bulky cap group is a valuable approach in the development of novel HDAC inhibitors.

Selective Inhibition of Bicyclic Tetrapeptide Histone Deacetylase Inhibitor on HDAC4 and K562 Leukemia Cell

Histone deacetylase (HDAC) inhibitors of cyclic peptide have been proved to be the most complex but the most stable and relative efficient inhibitors because of their large cap region. In this paper, a series of studies were carried out to evaluate the efficacy of synthetic bicyclic tetrapeptide inhibitors 1-5 containing hydroxamic acid referring molecular docking, anti-proliferation, morphology and apoptosis. Docking analysis, together with enzyme inhibitory results, verified the selective capability of inhibitor 4 to HDAC4, which might closely related to haematological tumorigenesis, with Phe227, Asp115, Pro32, His198 and Ser114 participating into hydrophobic interactions and Van der Waals force which was familiar with former study. Moreover, inhibitor 4 inhibited K562 cell line at the IC50 value of 1.22 μM which was 51-67 times more efficient than that for U937 and HL60 cell lines. Inhibitor 4 exhibited the cell cycle-arrested capability to leukemia at S phase or G2/M phase as well as apoptosis-induced ability in different degrees. Finally, we considered that bicyclic tetrapeptide inhibitors were promising inhibitors used in cancer treatment and inhibitor 4 could prevent K562 cell line well from proliferation, arrest cell cycle and induce K562 towards apoptosis to achieve the goals of reversing cancer cells which could become a potential leukemia therapeutic agent in the future.

Pharmacokinetics and pharmacodynamics of glycyrrhetinic acid with Paeoniflorin after transdermal administration in dysmenorrhea model mice

BACKGROUNDnGlycyrrhetinic acid (GA) and paeoniflorin (PF) are the main active ingredients in Chinese peony- Liquorice Decoction, a widely used Traditional Chinese Medicine.nnnHYPOTHESIS/PURPOSEnThe aim of this work was to investigate the combinatory analgesic effect of GA and PF after percutaneous administration and to define their pharmacokinetic/pharmacodynamic (PK/PD) characteristics.nnnSTUDY DESIGN AND METHODSnGA and PF were produced to transdermal patches based on previous research, and the permeation parameters of GA and PF in the patches were investigated with in vitro experiments. Dysmenorrhea model mice were then produced to compare the analgesic effects of the patches with different proportions of GA-PF. In the in vivo assessment, the number of writhes exhibited by the dysmenorrhea mice was recorded at designated time points, and skin, muscle under skin and plasma samples were collected, for assessments of drug distribution, pharmacokinetics parameters and PK/PD characteristics.nnnRESULTS AND CONCLUSIONnIn dysmenorrhea mice, GA-PF and meloxicam (the positive control drug) could relieve pain to equal degrees. Specifically, a single dose of the optimized patches (10%GA-10%PF, wt) exerted a steady analgesic effect for 48h in dysmenorrhea mice, but this effect lagged behind the changes in the plasma concentration. Evaluation with the Bliss Independence criterion revealed that the two ingredients displayed a synergistic effect. Then the PK/PD relationship of GA in this compound preparation was defined with this synergistic effect. The preparation might be suitable for topical spasmolysis and anti-inflammatory therapy.

Over-Expression of Beclin-1 Facilitates Acquired Resistance to Histone Deacetylase Inhibitor-Induced Apoptosis

Apoptotic cell death plays a predominant role in histone deacetylase (HDAC) inhibitor-induced cytotoxicity. Nuclear morphological changes and activation of apoptotic executors are involved in CTS203-induced cell death. However, emerging issues of HDAC inhibitor-resistance have been observed in patients. Herein, MCF-7 cells were continuously exposed to CTS203 until the derived cells could proliferate normally in its presence. The newly obtained CTS203-resistant cells were nominated as MCF-7/203R. Compared to MCF-7 original cells, the MCF-7/203R cells were less sensitive to CTS203-induced apoptosis, with a minimal 6-fold higher IC50 value. In contrast, the expression of Beclin-1 was dramatically up-regulated, positively correlated to the acquisition of CTS203-resistance. Our results revealed the participation of autophagy in acquired HDAC inhibitor-resistance and further identified Beclin-1 as a promising target for anti-drug resistance.

Development of a Prolonged-Release Pramipexole Transdermal Patch: In Vitro and In Vivo Evaluation

The current study aimed to develop a prolonged-release pramipexole (PPX) transdermal patch for the treatment of Parkinson’s disease. Permeation parameters of PPX were investigated using human cadaver skin. Pramipexole patches were prepared using DURO-TAK® pressure-sensitive-adhesive (PSA) and evaluated for drug stability, drug loading, in vitro drug release, and in vitro permeation through mouse skin. The results indicated that blends of DURO-TAK® 87-2852 and DURO-TAK® 87-2510 were suitable for creating a prolonged-release PPX patch due to their advantages in drug release, drug loading, and stability. The final formulation consisted of 87-2852/87-2510 (70:30), 10% PG, and 15% PPX and showed a cumulative permeation amount of 1497.19u2009±u2009102.90xa0μg/cm2 with a continuous flux over 6.0xa0μg/(cm2·h) across human cadaver skin for 7xa0days. In vivo studies in rats indicated that PPX patch produced a significantly longer (pu2009<u20090.001) half-life (t1/2, 75.16u2009±u200917.37xa0h) and mean residence time (MRT, 135.89u2009±u200924.12 h) relative to oral tablets (Sifrol®) and had a relative bioavailability of 51.64u2009±u200921.32%. Therefore, this study demonstrated the feasibility of developing a prolonged-release PPX patch, which proposed the potential to serve as an alternate to conventional oral tablets and may therefore improve patient compliance.

Effect of glycyrrhizic acid on the oral absorption of paeoniflorin in rats in vivo

Paeoniflorin (PF) and glycyrrhizic acid (GL) are the major active components in the peony liquorice decoction, which has been widely used clinically in China for more than one thousand years. The available reports on the pharmacokinetic behaviour of the two compounds in the presence of each other still are not consistent and are sometimes even contradictory. The aim of this study was to investigate the effect of GL on the absorption of PF administrated orally with or without pre- or co-administration of GL at different dosages in rats. The results indicated that GL has effects on the absorption extent of PF, however, without any significant impact on the absorption rate and excretion of PF. Furthermore, the effect of GL on the absorption of PF was GL dosage dependent and the concentration of GL in the small intestinal tissue should be a decisive factor for the effect. GL (300 or 900 mg kg−1 BW) showed an inhibition effect on the absorption of PF (300 mg kg−1 BW) when the two drugs were co-administrated orally, while the effect was reversed when GL at a higher dosage of 2700 mg kg−1 BW. The present study explained the contradiction of varying reports on the effect of GL on the absorption of PF and will provide important information for the rational design of peony and liquorice based formula in TCM.

Studies on In Vitro Release Performance of Hydrophilic Drugs and Lipophilic Drugs in Amphiphilic SIS-Based Hot-Melt Pressure Sensitive Adhesives

In order to fabricate a kind of amphiphilic hot-melt pressure sensitive adhesives (HMPSAs) suitable for transdermal drug delivery systems (TDDS) of natural medicines, SIS-based hot-melt pressure sensitive adhesives were modified by a melt-blending method, in which a kind of hydrophilic poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) (RLPO) and polyethylene glycol 2000 (PEG2000) were utilized. Functional RLPO and its plasticizer PEG2000 worked as a hydrophilic skeleton of amphiphilic HMPSAs. SEM and FT-IR results indicated that RLPO and SIS were partially compatible with each other through n-π complex between the n electrons of the carbonyl group of RLPO and the π electrons of the benzene rings of SIS and their compound had a good thermal stability. The phase microscope images showed that PEG could improve the compatibility between RLPO phase and SIS phase. As the ratio of SIS/RLPO/PEG equaled to 1/2/1.6, their compounds obtained bi-continuous structures. Geniposide (logP<0) and oleanic acid (logP=9.0) were chosen as representatives of hydrophilic drugs and lipophilic drugs, respectively. It was observed that both hydrophilic drugs and lipophilic drugs had a continuous release in the optimized amphiphilic HMPSAs. In addition, the release behavior of hydrophilic geniposide could be controlled by adjusting the ratio of RLPO to PEG.