Conjugates of TAT and folate with DOX-loaded chitosan micelles offer effective intracellular delivery ability.

The key for better antitumor efficacy is to improve the specificity of antitumor drugs for tumor cells and diminish their cytotoxicity to normal tissues. Targeted nanoparticles as antitumor drug delivery system can resolve this problem. In this study, we prepared folate and TAT (arginine-rich cell-penetrating peptide) modified N-PEG-N'-octyl-chitosan to form the folate/TAT-PEG-OC micelles. Then, the molecular structure, morphology, size distribution and bio-safety of the micelles were characterized. In order to investigate the drug-loading capacity of folate/TAT-PEG-OC micelles, doxorubicin (DOX) was used as model drug to prepare DOX-loaded chitosan micelles. Here, the confocal microscopy was used to evaluate the cellular uptake of DOX/folate/TAT-PEG-OC micelles, while the self-built NIR imaging system was used to evaluate the dynamic behavior of ICG-Der-01/folate/TAT-PEG-OC micelles in vivo. Our results demonstrate that the dual-modified PEG-OC micelles not only have good morphology, uniform size distribution and excellent drug loading capacity, but also show a strong capability for the efficient intracellular uptake and enhanced targeting behaviors in a folate receptor positive tumor model (Bel-7402 human hepatocellular cells). All these results suggest the potential application of folate/TAT-PEG-OC micelles in the targeted diagnosis and therapy to different kinds of folate receptor positive tumors.

N-Demethylsinomenine, an active metabolite of sinomenine, attenuates chronic neuropathic and inflammatory pain in mice.

Chronic pain is a significant public health problem that afflicts nearly 30% of the global population, but current pharmacotherapies are insufficient. Previous report indicated that N-demethylsinomenine, an active metabolite of sinomenine, is efficacious against postoperative pain. The present study investigated whether N-demethylsinomenine is effective for chronic painful conditions or whether repeated treatment alters its effect. Both chronic constriction injury (CCI) surgery and complete Freund's adjuvant (CFA) intraplantar injection induced significant and reliable mechanical allodynia at least for 7 days. Acute treatment with N-demethylsinomenine (10-40 mg/kg, i.p.) dose-dependently attenuated the mechanical allodynia both in CCI-induced neuropathic pain and CFA-induced inflammatory pain in mice. The potency of N-demethylsinomenine for reducing CFA-induced mechanical allodynia was slightly higher than sinomenine. During the period of repeated treatment, N-demethylsinomenine maintained its anti-allodynic effect against both neuropathic and inflammatory pain without producing carry-over effect. Pretreatment with bicuculline, a selective γ-aminobutyric acid type A (GABAA) receptor antagonist, almost completely blocked the anti-allodynia of N-demethylsinomenine (40 mg/kg) both in CCI and CFA-treated mice. Our findings indicated that N-demethylsinomenine exhibits GABAA receptor-mediated anti-allodynic effects in mouse models of neuropathic and inflammatory pain, suggesting it may be a useful novel pharmacotherapy for the control of chronic pain.

Effective management of acute postoperative pain using intravenous emulsions of novel ketorolac prodrugs: in vitro and in vivo evaluations.

The aim was to prepare intravenous fat emulsions (IFEs) of ketorolac (KTL) ester prodrugs and to investigate the pharmacokinetics and pharmacodynamics of these formulations. Three prodrugs of KTL (KTL-IS, KTL-AX and KTL-BT) were synthesized as a means to increase the lipid solubility of KTL. All KTL prodrugs with higher Log P values presented increased tendency to partition into a blank IFE using extemporaneous addition method - the encapsulation efficiency of KTL-IS IFE and KTL-BT IFE was more than 97%. The particle sizes and zeta potentials of these two formulations were comparable to that of the blank IFE. PK studies in rabbits showed significant larger AUC0-8h (646.969 ± 154.326 mg/L•h-1 for KTL-IS IFE and 559.426 ± 103.057 mg/L•h-1 for KTL-BT IFE) than that of ketorolac tromethamine (KTL-T) injectable (286.968 ± 63.045 mg/L•h-1) and approximately 2-fold increases in the elimination t1/2 over KTL-T. In a rat postoperative pain model, the paw withdrawal thresholds and the paw withdrawal latency after I.V. KTL prodrug IFEs were significantly higher than that after I.V. KTL-T at 3~4 h. Effective controlling of acute postoperative pain in a longer duration can be achieved by using non-addictive ketorolac derivatives intraveneous emulsions.