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Aim: To evaluate the association between SLCO1B1 polymorphisms and elimination/toxicities of high-dose methotrexate (MTX). Methods: SLCO1B1 rs11045879 and rs4149056 polymorphisms were retrospectively genotyped in 301 children with newly diagnosed acute lymphoblastic leukemia. MTX concentration, doses of leucovorin rescue and toxicities were recorded. Results: SLCO1B1 rs11045879C carriers (CC + CT) had higher plasma MTX levels at 96 hr, and longer MTX elimination time. The number of leucovorin rescue doses in rs4149056C carriers (CC + CT) was more than those in TT ones. Moreover, SLCO1B1 polymorphisms were associated with HDMTX toxicities including thrombocytopenia, renal toxicity and anal mucositis, but not associated with MTX level at other time points or delayed elimination. Conclusions: Our data demonstrate that genotyping of SLCO1B1 might be useful to optimize MTX therapy.

Background: Compounds that target tumor epigenetic events are likely to constitute a prominent strategy for anticancer treatment. Histone deacetylase inhibitors (HDACis) have been developed as prospective candidates in anticancer drug development, and currently, many of them are under clinical investigation. We assessed the anticancer efficacy of a now hydroxamate-based HDACi, YF-343, in triple-negative breast cancer development and studied its potential mechanisms. Methods: YF-343 was estimated as a novel HDACi by the HDACi drug screening kit. The biological effects of YF-343 in a panel of breast cancer cell lines were analyzed by Western blot and flow cytometry. YF-343 exhibited notable cytotoxicity, promoted apoptosis, and induced cell cycle arrest. Furthermore, it also induced autophagy, which plays a pro-survival role in breast cancer cells. Results: The combination of YF-343 with an autophagy inhibitor chloroquine (CQ) significantly suppressed breast tumor progression as compared to the YF-343 treatment alone both in vitro and in vivo. Mechanistically, the molecular mechanism of YF-343 on autophagy was elucidated by gene chip expression profiles, qPCR analysis, luciferase reporter gene assay, chromatin immunoprecipitation assays, immunohistochemical analysis, and other methods. E2F7, a transcription factor, promoted the expression of ATG2A via binding to the ATG2A promoter region and then induced autophagy in triple-negative breast cancer cells treated with YF-343. Conclusion: Our studies have illustrated the mechanisms for potential action of YF-343 on tumor growth in breast cancer models with pro-survival autophagy. The combination therapy of YF-343 and CQ maybe a promising strategy for breast cancer therapy.

Bone marrow transplantation is regarded as the most effective immunotherapy for hematologic cancer, but it generally faces difficulties in matching. Aberrant expression of histone deacetylases (HDACs) is closely related to the occurrence and development of hematological cancer. Recent studies suggested that HDACs might play a critical role in initiating anti-cancer immune response or enhancing anti-cancer immunotherapy. Besides, combining HDAC inhibition and immunotherapy could prevent immunotherapy resistance in some degree and reach an extended treatment window. This review summarized the relationship between HDACs and immune and described the current understanding of HDACs in immunotherapy for hematologic cancer.

Xiao Hu,1 Feifei Yang,2 Yonghong Liao,2 Lin Li,1 Guoguang Zhao,3 Lan Zhang1 1Department of Pharmacy, Xuanwu Hospital of Capital Medical University, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing 100053, People’s Republic of China; 2Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, People’s Republic of China; 3Department of Neurosurgery, Xuanwu Hospital of Capital Medical University, Beijing 100053, People’s Republic of ChinaCorrespondence: Guoguang Zhao; Lan Zhang Email ggzhao@vip.sina.com; lanizhg@126.comBackground and Aim: Polymeric nanoparticles (NPs) have received much attention as promising carrier systems in lung cancer and brain metastases.Methods: Here, for the first time, we investigated the feasibility of using inhaled cholesterol-PEG co-modified poly (n-butyl) cyanoacrylate NPs (CLS-PEG NPs) of docetaxel (DTX) for sustained pulmonary drug delivery in cancer metastasis.Results: Spray-dried or freeze-dried NPs yielded sustained drug release in vitro. In vitro inhalation evaluation data indicated that the inhalation formulation had better inhalability. Compared with intravenous (IV) administration, pharmacokinetic data suggested that the inhalation formulation prolonged plasma concentration of DTX for greater than 24 h and is more quickly and completely absorbed into the rat lung after intratracheal (IT) administration. Furthermore, freeze-dried powders were found to increase the t1/2 and area under curve (AUC) by 2.3 and 6.5 fold compared to the free drug after IT administration, and spray-dried powders were found to increase the t1/2 and AUC by 3.4 and 8.8 fold, respectively. After pulmonary administration of the inhalation formulation, DTX appeared to prolong the pulmonary absorption time. In addition, the inhalation formulation was distributed to the brain in a sustained release manner.Conclusion: These experimental results demonstrated that freeze- and spray-dried powders have the potential for pulmonary sustained release, and they also have the potential to be used as a novel treatment for the delivery of drugs that pass through the air–blood barrier and enter the brain and are efficient carriers for the treatment of brain metastasis.Keywords: pulmonary delivery, docetaxel, lung cancer, spray-drying, dry powder

Myocardial injury is a nonnegligible problem in cardiovascular diseases and cancer therapy. The functional feature of N-containing heterocycles in the cardiovascular field has attracted much attention in recent years. Herein, we discovered a lead compound 12a containing 1,3,4-oxadiazole by extensive screening of anticancer derivatives containing nitrogen-heterocycle, which exhibited potential protective activity against oxidative stress in cardiomyocytes. Follow-up structure-activity relationship (SAR) studies also highlighted the role of substitution sites and bisamide moiety in enhancing the protective activity against oxidative stress. Specifically, compound 12d exhibited low cytotoxicity under high concentration and potent myocardial protection against oxidative stress in H9c2 cells. Preliminary mechanistic studies showed compound 12d could decrease the expression of cardiac hypertrophy and oxidative stress-related proteins/genes and reduce mitochondria-mediated cell apoptosis, thereby enhancing the cell vitality of injured cardiomyocytes. In this study, 1,3,4-oxadiazole may represent a novel pharmacophore that possesses potential myocardial protection and provides more choices for future optimization of cardiovascular drugs, especially for the treatment of onco-cardiology.

Due to intestinal cytochrome P450 (CYP450)-mediated metabolism and P-glycoprotein (P-gp) efflux, poor oral bioavailability hinders ginsenoside-Rh1 (Rh1) and ginsenoside-Rh2 (Rh2) from clinical application. In this study, Rh1 and Rh2 were incorporated into two self-microemulsions (SME-1 and SME-2) to improve oral bioavailability. SME-1 contained both CYP450 and P-gp inhibitory excipients while SME-2 only consisted of P-gp inhibitory excipients. Results for release, cellular uptake, transport, and lymph node distribution demonstrated no significant difference between either self-microemulsions in vivo, but were elevated significantly in comparison to the free drug. The pharmaceutical profiles in vivo showed that the bioavailability of Rh1 in SME-1 (33.25%) was significantly higher than that in either SME-2 (21.28%) or free drug (12.92%). There was no significant difference in bioavailability for Rh2 between SME-1 (48.69%) or SME-2 (41.73%), although they both had remarkable increase in comparison to free drug (15.02%). We confirmed that SME containing CYP450 and P-gp inhibitory excipient could distinctively improve the oral availabilities of Rh1 compared to free drug or SME containing P-gp inhibitory excipient. No notable increase was observed between either SME for Rh2, suggesting that Rh2 undergoes P-gp-mediated efflux, but may not undergo distinct CYP450-mediated metabolism.

The main objective of this study was to test the hypothesis that inhaled nanocrystals of a highly lipophilic drug could be used as a novel approach for producing sustained pulmonary delivery. Curcumin acetate, an ester prodrug of curcumin, was utilized as a highly lipophilic model drug. Curcumin acetate was subjected to wet ball milling to produce different particle sizes of nanocrystals and microparticles, and the milled curcumin acetate was spray-dried to yield similar inhalable microparticles. Following intrapulmonary administration in rats, pharmacokinetic experiments indicated that curcumin acetate significantly extended the pulmonary absorption time by 7.2-fold compared to curcumin, possibly due to the high lipophilicity of the former. The biodistribution data showed that aerosolized curcumin acetate nanocrystals 123.7 nm in size not only prolonged pulmonary retention, with the AUC value of curcumin acetate being 7.62-fold higher than that of the microparticles 1120 nm in size, but also increased the local in vivo release rate by 3.3-fold and the local availability of converted curcumin by 25.1-fold. In addition, the improved local availability resulted in better pharmacological efficacy in a monocrotaline-induced rat model of pulmonary arterial hypertension. This study was the first to demonstrate that inhalable nanocrystals are a feasible means for the sustained pulmonary delivery of highly lipophilic drugs.

The aim of this study was to produce fine particles with different corrugated degree of surface by spray-drying and to investigate the effect of surface morphology on in vitro aerosol performance of the particles within HFA 134a based metered dose formulations. Compositions of rizatriptan and scutellarin were spray-dried using different spray-drying parameters, and particles were suspended within HFA 134a. The surface morphology were determined using scanning electron microscopy (SEM), while the aerodynamic performance of MDIs was evaluated using a next generation pharmaceutical impactor. The surface morphology of spray-dried particles could vary from smooth to moderately corrugated, and to raisin-like depending upon spray-drying parameters and preparation compositions. In general, increasing inlet temperature, decreasing feed concentration and/or adding leucine to the feed solution tended to increase the corrugated degree of particle surface. Deposition results indicated that raisin-like particle based MDIs for all compositions of the two drugs produced significantly better aerodynamic performance in terms of fine particle fractions and mass median aerodynamic diameters relative to the formulations of the corresponding smooth or slightly corrugated particles when the particle compositions were the same. The present results demonstrated that wrinkled particles increased fine particle fractions within surfactant-free MDI formulations.

Cajaninstilbene acid (CSA) exerts wide pharmacological activities, such as anti-inflammation, hypoglycaemic activity, analgesic effect and cognition improvement. However, it underwent severe phase II metabolism mediated by UDP-glucuronosyltransferase (UGT) in the gastrointestinal (GI) tract after oral administration, affecting its oral bioavailability. In the present study, we utilize UGT inhibitory excipient containing self-microemulsion (SME) delivery system to reduce the production of glucuronide metabolites and increase its oral bioavailability. The present results showed that although similar properties in physiochemical, cytotoxicity, cellular uptake, absorption and transport across rat everted gut sacs between SME-1 (inhibitory excipient containing SME) and SME-2 (control SME, without inhibitory excipient), an improved absolute bioavailability of 57.3 % was conferred by SME-1, significantly higher than the value of 35.4 % by SME-2 and 34.0 % by free CSA. Noticeably, the significantly lower AUC value of CSA glucuronide was determined in rats treated with SME-1 than those either treated with SME-2 or free CSA. Thus, the ability of SME-1 to enhance oral bioavailability of CSA is mainly attributed to the inhibition of phase II metabolism in the GI tract.

This study intended to investigate the in vivo pulmonary fate of intratracheally dosed nanosuspensions of fluticasone propionate (FP). Three FP suspensions, including a microsuspension and two nanosuspensions with different dissolution profiles, were prepared and they exhibited comparable aerodynamic performances after nebulization via a jet nebulizer. Following intratracheal administration to rats, the microsuspension underwent extensive mucociliary clearance, leading to a limited absorption time whereas the nanosuspensions decreased the mucociliary clearance and allowed dissolution rate-limiting and extended pulmonary absorption, resulting in prolonged pulmonary retention and long-acting anti-inflammatory efficacy in a lipopolysaccharide induced lung injury model. Delaying the FP dissolution of a nanosuspension by phospholipid coating increased AUC value in lung tissues to 1.72-fold of a conventional nanosuspension, but led to a decreased pharmacological efficacy. This study demonstrated that inhalable nanosuspensions were a feasible means for the sustained pulmonary delivery of FP and the local anti-inflammatory efficacy was highly dependent on the dissolution profiles.

Polymeric micelles represent interesting delivery systems for pulmonary sustained release. However, little is known about their in vivo release and translocation profile after delivery to the lungs. In the present study, curcumin acetate (CA), which is an ester prodrug of curcumin, or the mixture of CA and Nile red was encapsulated into PEG–PLGA micelles by a solvent evaporation method. The micellar formulation increased the stability of CA in water and physiologically relevant fluids and led to a sustained drug release in vitro. Following intratracheal (IT) administration to rats, CA loaded micelles achieved not only prolonged pulmonary retention with AUC values almost 400-fold higher than by IV route, but also local sustained release up to 24 h. In addition, IT delivery of micelles appeared to facilitate the uptake into the pulmonary vascular endothelium and efficiently translocate across the air–blood barrier and penetrate into the brain. Co-localization of CA and Nile red confirmed that micelles in lung and brain tissue were still intact. This study is the first to demonstrate that aerosolized PEG–PLGA micelles are a promising carrier for both pulmonary and non-invasive systemic sustained release of labile drugs.

Self-microemulsifying (SME) drug delivery system has been developed to increase oral bioavailabilities, and inhibitory excipients are capable of improving oral bioavailability by inhibiting enzyme mediated intestinal metabolism. However, the potential of enzyme inhibitory excipients containing SME in boosting resveratrol bioavailability remains largely uninvestigated. In this study, we set out to prepare SME-1 with UGT inhibitory excipients (excipients without inhibitory activities named SME-2 as control) to increase the bioavailability of RES by inhibiting intestinal metabolism. Results demonstrated that similar physicochemical properties such as size, polydistribution index and in vitro release, cellular uptake and permeability in Caco-2 cells as well as in vivo lymphatic distribution between inhibitory SME-1 and non-inhibitory SME-2 were observed. In vivo study demonstrated that the molar ratios of RES-G/RES were 7.25±0.48 and 5.06±2.42 for free drug and SME-2, respectively, and the molar ratio decreased to 0.36±0.10 in SME-1 group. Pharmacokinetic study confirmed that the inhibitory excipients containing SME demonstrated potential in increasing bioavailability of RES from 6.5% for the free RES and 12.9% for SME-2 to 76.1% in SME-1 through modulating the glucuronidation by UGT inhibitory excipients.

Herb extracts were shown to inhibit the activity of UDP-glucuronosyltransferases (UGTs) in vitro. However, the actual in vivo effect of the inhibitory ability on oral bioavailability is yet verified. In this study, resveratrol (RES) was used as a model drug to study the effect of three Chinese herb extracts, Ganoderma, Rhodiola and grape seed, on the in vitro and in vivo inhibition of glucuronidation and the in vivo bioavailability of RES. Overall, although herb extracts might show inhibition on glucuronidation of RES in vitro and in vivo, the inhibition of glucuronidation did not necessarily mean to improve the in vivo bioavailability of RES.

Protopanaxatriol and protopanaxadiol exhibit limited oral bioavailability due to the poor solubility and intestinal cytochromes P450-mediated metabolism. This study set out to develop a novel cytochromes P450 inhibitory excipient(s)-based self-microemulsion to encapsulate protopanaxatriol and protopanaxadiol so as to enhance the in vivo bioavailability by inhibiting intestinal metabolism. After screening the inhibitory effect of pharmaceutical excipients on the cytochromes P450-mediated metabolism, two self-microemulsions, SME-1 and SME-2, with similar physicochemical properties were prepared by using either active inhibitory excipients or corresponding inactive excipients. The results showed that no significant difference existed in the profiles of in vitro release, cellular uptake, and permeability in Caco-2 cells, and in vivo lymphatic transport between self-microemulsion-1 and self-microemulsion-2. The in vivo pharmacokinetic experiments indicated that self-microemulsion-1 conferred to significantly higher absolute bioavailability of protopanaxatriol (19.55 %) and protopanaxadiol (100.07 %) than those of the free drug (2.21 % and 23.70 %, respectively) or of self-microemulsion-2 (4.95 % and 45.35 %, respectively). The present work demonstrated that the presence of cytochromes P450 inhibitory excipients in self-microemulsion-1 tended to inhibit intestinal cytochromes P450-mediated metabolism and subsequently improved the oral bioavailability of protopanaxatriol and protopanaxadiol.

Background Systemic pulmonary delivery is considered to have advantages over oral or intravenous administration for certain drugs. Methods In this article, we review the effects of intrinsic drug properties and drug loading carriers on the pharmacokinetic parameters of inhaled drugs in the context of use in systemic pulmonary delivery. Results The delivery of drugs via inhalation can be advisable to achieve a fast onset of action; enhance the systemic bioavailability of drugs with poor oral absorption, including peptides and proteins; avoid invasive administration and improve patient compliance. To optimize the functioning of this delivery system, there is high demand for a systematic understanding of the pharmacokinetic characteristics, which are closely related to the pharmacodynamic and toxicological effects. Conclusion The pharmacokinetic parameters of inhaled drug products are affected by many factors, including physiological and pathological variables and the intrinsic drug and formulation properties.

Nanoemulsions have been developed for the oral delivery of poorly bioavailable phenolic compounds that are sensitive to intestinal glucuronidation. However, little is known about the contribution of UDP-glucuronosyltransferase (UGT) inhibitory excipients in nanoemulsions toward the inhibition of intestinal glucuronidation and the consequent enhanced bioavailability. In this study, Labrasol but not poloxamer 188 (F68) was found to inhibit the glucuronidation of resveratrol (RES), a model phenolic compound, in an inhibition assay with rat microsomes. Subsequently, two nanoemulsions, Lab-N and F68-N, were prepared with similar particle size distribution, zeta potentials, and entrapment efficiency by coemulsifying with Labrasol or F68, respectively. Although Lab-N exhibited inferior or comparable profiles of in vitro release, cellular uptake in Caco-2 cells, and lymphatic transport in rats to F68-N, the in vitro absorption study with everted sacs suggested that Labrasol containing formulations significantly and dose-dependently increased the transport of RES relative to free RES or F68-N by decreasing the amount of permeated metabolite, RES-3-glucuronide (RES-G). The in vivo pharmacokinetic experiments indicated that Lab-N exhibited increments in the maximum plasma concentration and the bioavailability of RES by 1098% and 560%, respectively, and significant decreases in those of RES-G, compared to F68-N. The overall results demonstrated that the improved oral bioavailability of RES by Lab-N was mainly attributable to the inhibition of intestinal glucuronidation by the presence of UGT inhibitory excipient.

The solvent dependence of this domino cyclization is discussed and a reaction mechanism is given.