Mesoporous silica nanoparticles: synthesis,classification, drug loading,pharmacokinetics, biocompatibility,and application in drug delivery

Introduction: Mesoporous silica nanoparticles (MSNs) feature a high surface area and large pore volume, uniform and tunable pore size, and stable framework; thus, they have been used extensively as drug carriers.

Areas covered: The synthesis, classification, and the latest generation of MSNs, drug loading methods, modification of MSNs, pharmacokinetic studies, biocompatibility, and toxicity of MSNs, and their application in drug delivery systems (DDS) are covered in this review.

Expert opinion: It is crucial to uncover the mechanism for the formation of MSNs. Before drug loading, the characteristics of MSNs should be taken into consideration. In addition, the porosity, particle size and morphology, surface oxidation and surface functionalization can also influence the in vivo fate of MSNs, which is worthy of further study. Coating MSNs with novel materials may improve their biocompatibility, control the release of drugs loaded into the MSNs or enhance the uptake of the coated MSNs by tumor cells. MSNs can also be used as carriers for combination therapy in the treatment of cancer. Despite the rapid development of MSNs, the biological effects of these biomaterials remain relatively less understood.     

Secondary cannabis use among London drug treatment service clients

Background: Cannabis is the second most commonly used substance after alcohol among people seeking treatment for other drug use, but no statistics are available regarding secondary cannabis use among drug treatment clients.

Objectives: To investigate levels of secondary cannabis use among drug treatment clients and perceived need for support addressing this use among clients and staff.

Methods: Cross-sectional surveys of clients (N?=?295) and staff (N?=?33) were conducted in 2015 at four London drug and alcohol treatment services. Client measures included recent drug use, type of cannabis used, Severity of Dependence Scale for cannabis, and views on secondary cannabis use treatment. Staff measures included definition of problem cannabis use, importance and timing for addressing secondary cannabis use.

Results: Among clients, 39.7% reported recent secondary cannabis use, with 30.8% of these clients meeting criteria for problem use. Problem users were more likely to be interested in receiving treatment for cannabis use than non-problem users (51.4% versus 10.8%, p?<?.001). Nearly half of staff (48.5%) thought secondary cannabis use should be addressed early in treatment.

Conclusions: Two out of five drug treatment clients used cannabis and a third experienced cannabis-related problems. Many are willing to address cannabis use, but defined treatment pathways are needed.     

Magnetic iron oxide nanoparticles for drug delivery: applications and characteristics

Introduction: For many years, the controlled delivery of therapeutic compounds has been a matter of great interest in the field of nanomedicine. Among the wide amount of drug nanocarriers, magnetic iron oxide nanoparticles (IONs) stand out from the crowd and constitute robust nanoplatforms since they can achieve high drug loading as well as targeting abilities stemming from their remarkable properties (magnetic and biological properties). These applications require precise design of the nanoparticles regarding several parameters which must be considered together in order to attain highest therapeutic efficacy.

Areas covered: This short review presents recent developments in the field of cancer targeted drug delivery using magnetic nanocarriers as drug delivery systems.

Expert opinion: The design of nanocarriers enabling efficient delivery of therapeutic compounds toward targeted locations is one of the major area of research in the targeted drug delivery field. By precisely shaping the structural properties of the iron oxide nanoparticles, drugs loaded onto the nanoparticles can be efficiently guided and selectively delivered toward targeted locations. With these goals in mind, special attention should be given to the pharmacokinetics and in vivo behavior of the developed nanocarriers.     

Preclinical pharmacokinetics of a novel anti-c-Met antibody–drug conjugate,SHR-A1403, in rodents and non-human primates

1. The in vivo pharmacokinetics (PK) profiles of a novel c-Met antibody–drug conjugate (ADC), SHR-A1403, were investigated and characterized in mice, rats and monkeys.

2. Serum concentrations of ADC and total antibody were detected using validated ELISA methods. The results showed low systemic clearance of both ADC and total antibody in all three species as reflected by gradual decrease in serum concentrations. Half-life (t_1/2) of ADC ranged from 4.6 to 11.3?days in the three species.

3. Tissue distribution study in tumor-bearing mice showed high accumulation of ¹²⁵I-SHR-A1403 in tumor tissues over the other organs/tissues, indicating the favorable safety of SHR-A1403 and characteristics of an ADC drug.

4. Relatively low grade of anti-drug antibody (ADA) in monkeys had no impact on PK profile of the ADC.

5. During discovery stage, undesirable exposure and/or ADA incidence were observed for SHR-A1403 with high or low drug-antibody ratio (DAR), which was DAR?=?5 to 6 and DAR?=?1, respectively, and therefore prompted selection of an appropriate DAR value (DAR?=?2) for SHR-A1403 used in preclinical development and clinical trials.

6. In conclusion, our work demonstrated favorable PK characterization of SHR-A1403, and supported for investigational new drug application (IND) and the ongoing first-in-human trial in the US.     

An evaluation of peripapillar choroidal thickness in patients receiving systemic isotretinoin treatment

Purpose: Oral isotretinoin (13-cis retinoic acid, 13-cis RA) was approved for severe acne treatment by the FDA in 1982. The ocular side effects associated with oral isotretinoin use are mostly dose-dependent. Numerous ocular pathologies affect peripapillary choroidal layer primarily or indirectly.

Objective: Evaluation of the peripapillary choroidal layer in the patients receiving oral isotretinoin therapy may aid in explaining the pathophysiology of ocular side effects.

Methods: In this study, peripapillary choroidal thickness was assessed in the patients receiving oral isotretinoin treatment via optical coherent tomography technique.

Results: Significant difference was found in the superotemporal and temporal areas.

Conclusion: Oral isotretinoin treatment may affect the thickness of the peripapillary choroidal layer.     

A tearable dissolving microneedle system for shortening application time

Objectives: A tearable dissolving microneedle system (TD-MN system) was developed for shortening the time required to administer drugs into the skin through the dissolving microneedles.

Methods: TD-MN system consisted of an array of tearable dissolving microneedles (TD-MN) and micro-pillars. The microneedle tips had a female part to integrate with the micro-pillars. The micro-pillars exerted a vertical force to cause the separation of the tips from the base. The separation force exerted by six TD-MN arrays with different thicknesses of separation region was measured. The TD-MN system with trypan blue was inserted into porcine skin to observe the separation of the microneedle tips, and then calcein was added separately to observe drug diffusion into the skin.

Results: The thickness of the tearable region and the depth of the female part were a function of the concentration and volume of the molding solution. The separation force increased as the thickness of the tearable region increased. Nine tips were successfully separated from the base by applying a force of through the micro-pillars.

Conclusions: The TD-MN system could provide immediate administration of a drug, resulting in improved patient convenience as well as delivery of the correct drug dose.     

Smart thermosensitive chitosan hydrogel for nasal delivery of ibuprofen to treat neurological disorders

Background: The in-situ gelation of thermosensitive nasal formulations with desirable spray characteristics at room temperature and ability to undergo a phase change to a semi-solid state with mucoadhesive behavior at physiological temperature has the potential to efficiently deliver therapeutics to brain. However, their application in nasal spray generation with favorable characteristics has not been investigated.

Methods: Thermosensitive chitosan (CS)-based formulations with different viscosities were prepared for intranasal delivery of ibuprofen using CS of various molecular weights. The formulation developed was optimized with regards to its physicochemical, rheological, biological properties and the generated aerosol characteristics.

Results: The formulations showed rapid gelation (4–7 min) at 30–35°C, which lies in the human nasal cavity temperature spectrum. The decrease in CS molecular weight to 110–150 kDa led to generation of optimum spray with lower Dv₅₀, wider spray area, and higher surface area coverage. This formulation also showed improved ibuprofen solubility that is approximately 100× higher than its intrinsic aqueous solubility, accelerated ibuprofen transport across human nasal epithelial cells and transient modulation of tight junctions.

Conclusions: A thermosensitive CS-based formulation has been successfully developed with suitable rheological properties, aerosol performance and biological properties that is beneficial for nose-to-brain drug delivery.     

Efficacy of istradefylline for gait disorders with freezing of gait in Parkinson’s disease: A single-arm,open-label,prospective, multicenter study

Background: Gait disorders are common in Parkinson’s disease patients who respond poorly to dopaminergic treatment. Blockade of adenosine A_2A receptors is expected to improve gait disorders. Istradefylline is a first-in-class selective adenosine A_2A receptor antagonist with benefits for motor complications associated with Parkinson’s disease.

Research design and methods: This multicenter, open-label, single-group, prospective interventional study evaluated changes in total gait-related scores of the Part II/III Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and Freezing of Gait Questionnaire (FOG-Q) in 31 Parkinson’s disease patients treated with istradefylline. Gait analysis by portable gait rhythmogram was performed.

Results: MDS-UPDRS Part III gait-related total scores significantly decreased at Weeks 4–12 from baseline with significant improvements in gait, freezing of gait, and postural stability. Significant decreases in MDS-UPDRS Part II total scores and individual item scores at Week 12 indicated improved daily living activities. At Week 12, there were significant improvements in FOG-Q, new FOG-Q, and overall movement per 48 h measured by portable gait rhythmogram. Adverse events occurred in 7/31 patients.

Conclusions: Istradefylline improved gait disorders in Parkinson’s disease patients complicated with freezing of gait, improving their quality of life. No unexpected adverse drug reactions were identified.

Trial registration: UMIN-CTR (UMIN000020288).     

Combining stem cell-derived hepatocytes with impedance sensing to better predict human drug toxicity

Background: The liver plays a central role in human drug metabolism. To model drug metabolism, the major cell type of the liver, the hepatocyte, is commonly used. Hepatocytes can be derived from human and animal sources, including pluripotent stem cells. Cell-based models have shown promise in modeling human drug exposure. The assays used in those studies are normally ‘snap-shot’ in nature, and do not provide the complete picture of human drug exposure.

Research design and methods: In this study, we employ stem cell-derived hepatocytes and impedance sensing to model human drug toxicity. This impedance-based stem cell assay reports hepatotoxicity in real time after treatment with compounds provided by industry.

Results: Using electric cell-substrate impedance Sensing (ECIS), we were able to accurately measure drug toxicity post-drug exposure in real time and more quickly than gold standard biochemical assays.

Conclusions: ECIS is robust and non-destructive methodology capable of monitoring human drug exposure with superior performance to current gold standard ‘snapshot’ assays. We believe that the methodology presented within this article could prove valuable in the quest to better predict off-target effects of drugs in humans.     

Optimisation of the microencapsulation of lavender oil by spray drying

Background: Lavender oil consists of around 100 components and is susceptible to volatilisation and degradation reactions.

Aim: Microencapsulate lavender oil by spray drying using a biocompatible polymeric blend of gum acacia and maltodextrin to protect the oil components. Effect of total polymer content, oil loading, gum acacia, and maltodextrin proportions on the size, yield, loading, and encapsulation efficiency of the microparticles was investigated.

Methods: Morphology and oil localisation within microparticles were assessed by confocal laser scanning electron microscope. Structural preservation and compatibility were assessed using Fourier transform infra-red spectroscopy, differential scanning calorimetry, and gas chromatography–mass spectrometry.

Results: Lavender microparticles of size 12.42?±?1.79?µm prepared at 30 w/w% polymer concentration, 16.67 w/w% oil loading, and 25w/w% gum acacia showed maximum oil protection at high loading (12?mg w/w%), and encapsulation efficiency (77.89 w/w%).

Conclusion: Lavender oil was successfully microencapsulated into stable microparticles by spray drying using gum acacia/maltodextrin polymeric blend.     

Insulin-like growth factor-1 (IGF-1) poly (lactic-co-glycolic acid) (PLGA) microparticles – development,characterisation, and in vitro assessment of bioactivity for cardiac applications

Aim: The aim of this study was to evaluate the formulation of a synthetic IGF-1 (pIGF-1) in PLGA microparticles (MP).

Methods: Poly (lactic-co-glycolic acid) (PLGA) MPs loaded with pIGF-1 were prepared, characterised and evaluated using double emulsion solvent evaporation method.

Results: Spherical MPs showed an average particle size of 2?µm, encapsulation efficiency (EE) of 67% and 50% degradation over 15?days. With a view to enhancing retention in the myocardium, the MP formulation was encapsulated in a cross-linked hyaluronic acid hydrogel. pIGF-1 released from MPs and from MPs suspended in hyaluronic acid hydrogel remained bioactive, determined by a significant increase in cellular proliferation of c-kit⁺ cells.

Conclusion: This formulation has potential for loco-regional delivery to damaged myocardium to promote the survival of cardiomyocytes.     

Routine care interventions with the parents of adult drug and alcohol users

Introduction and aims: To explore routine care interventions which enable parents to support the therapeutic effort of their adult child in drug and alcohol treatment.

Design and methods: Inductive content analysis was used to analyze the experiences of 31 Greek addiction professionals who participated in focus groups.

Findings: Professionals adopted various interventions which included (a) respond to parents quest for help, (b) involvement of the distant parent in treatment, (c) boundary setting, (d) facilitation of parent-child communication, and (e) support of parental changes. These interventions were perceived as necessary, both for motivating and sustaining the client’s change, and for alleviating the parents’ chronic grief and distress over their child’s addiction.

Conclusion: Overall, addiction professionals perceived low intensity interventions, information giving, and non- judgmental informal interactions as catalysts for the parents involvement in addiction treatment.     

Functional genetic evaluation of DNA house-cleaning enzymes in the malaria parasite: dUTPase and Ap4AH are essential in Plasmodium berghei but ITPase and NDH are dispensable

Background: Cellular metabolism generates reactive oxygen species. The oxidation and deamination of the deoxynucleoside triphosphate (dNTP) pool results in the formation of non-canonical, toxic dNTPs that can cause mutations, genome instability, and cell death. House-cleaning or sanitation enzymes that break down and detoxify non-canonical nucleotides play major protective roles in nucleotide metabolism and constitute key drug targets for cancer and various pathogens. We hypothesized that owing to their protective roles in nucleotide metabolism, these house-cleaning enzymes are key drug targets in the malaria parasite.

Methods: Using the rodent malaria parasite Plasmodium berghei we evaluate here, by gene targeting, a group of conserved proteins with a putative function in the detoxification of non-canonical nucleotides as potential antimalarial drug targets: they are inosine triphosphate pyrophosphatase (ITPase), deoxyuridine triphosphate pyrophosphatase (dUTPase) and two NuDiX hydroxylases, the diadenosine tetraphosphate (Ap4A) hydrolase and the nucleoside triphosphate hydrolase (NDH).

Results: While all four proteins are expressed constitutively across the intraerythrocytic developmental cycle, neither ITPase nor NDH are required for parasite viability. dutpase and ap4ah null mutants, on the other hand, are not viable suggesting an essential function for these proteins for the malaria parasite.

Conclusions: Plasmodium dUTPase and Ap4A could be drug targets in the malaria parasite.     

Clinical profile of the functionally selective glucocorticoid receptor agonist BI 653048 in healthy male subjects

Background: An efficacious anti-inflammatory corticosteroid with reduced side effects has been long sought. We report the pooled results from three clinical proof-of-mechanism Phase I studies of BI 653048 in healthy subjects, a functionally selective, nonsteroidal glucocorticoid (GC).

Research design and methods: Three Phase I trials were conducted: a single rising-dose study and a multiple rising-dose study to evaluate the safety, tolerability, and pharmacokinetics of BI 653048, and a multiple parallel-arm-dose study with intravenous lipopolysaccharide challenge to assess in vivo pharmacodynamics. The pharmacodynamics, efficacy, and safety of BI 653048 and prednisolone were compared.

Results: Treatment with 200 mg BI 653048 was associated with a reduced expression of IL1R2, ITGB3, and SDPR versus 20 mg prednisolone; comparable levels of FKBP5, ZBTB16, and DDIT4 expression were observed. Changes in C-peptide, glucose, insulin, and cortisol were moderate compared with prednisolone. A greater reduction of osteocalcin was observed with 200 mg BI 653048 versus 20 mg prednisolone. Comparable anti-inflammatory efficacy was demonstrated for 200 mg BI 653048 and 20 mg prednisolone. BI 653048 was well tolerated in healthy subjects.

Conclusion: BI 653048 demonstrated the desired anti-inflammatory effects of the nonsteroidal GC; however, the undesirable side-effect profile associated with GC steroids could not be disassociated from BI 653048.

Trial registration: ClinicalTrials.gov identifiers NCT02217644, NCT02217631, and NCT02224105.     

Patient perception of Breezhaler® and Ellipta® device feedback mechanisms in COPD: The ADVANTAGE Study

Objectives: The primary objective of the ADVANTAGE study was to compare device-naïve chronic obstructive pulmonary disease (COPD) patients’ perception of the Breezhaler^® and Ellipta^® devices’ feedback mechanisms of dose delivery confirmation. The secondary objective was to assess comfort with the inhalers’ mouthpiece in terms of ease to form a tight seal around the mouthpiece. These objectives were achieved by using a novel, patient perception of inhaler questionnaire developed and tested during cognitive interviews of patients by Evidera, London, United Kingdom.

Methods: Ten COPD patients were interviewed to collect feedback on the interpretation, relevance and language of the questionnaire. This questionnaire was then used in ADVANTAGE to compare patients’ perception (n?=?100) of both devices. Patients completed the questionnaire after a single inhalation of placebo through each inhaler.

Results: Using the final questionnaire, patients reported being more confident of the feedback mechanism of Breezhaler than that of the Ellipta device (mean score 4.3 versus 3.6 respectively, estimated difference [95% CI]: 0.75 [0.51, 0.99], p?<?.0001). Patients also reported better comfort (ease to form a tight seal with the lips) with the Breezhaler mouthpiece than the Ellipta mouthpiece (mean score 4.3 versus 3.9 respectively, estimated difference [95% CI]: 0.41 [0.21, 0.61], p?<?.0001). There were no safety concerns associated with either device.

Conclusion: COPD patients showed greater preference for the Breezhaler over the Ellipta inhaler for confidence of dose delivery and comfort of the mouthpiece.

Trial registration: The trial is registered at ClinicalTrials.gov (ClinicalTrials.gov number NCT02551224).     

Gender,subclinical organ damage and cardiovascular risk stratification in hypertensive patients

Background: The aims of the study were to assess subclinical organ damage in men and women with hypertension and its subsequent effect on cardiovascular risk, and use of new statistical methods for more precise estimation of cardiovascular risk using vascular cardiovascular risk factors: ankle–brachial index (ABI), intima–media thickness (IMT) and pulse wave velocity (PWV).

Methods: We studied 200 patients: 100 hypertensive and 100 normotensive. The parameters we evaluated included: patient age, ABI, IMT, PWV, serum uric acid and serum C-reactive protein (CRP). In addition, the cardiovascular risk according to the SCORE and Framingham scales was assessed.

Results: In the hypertensive group, there were significant correlations between ABI and the Framingham scale in both sexes. In hypertensive women, there were also significant correlations between IMT and the SCORE scale risk, and IMT and the Framingham scale risk.

In normotensive women, there were significant correlations between ABI and the SCORE scale risk, and between ABI and the Framingham scale risk. In normotensive men, there were significant correlations between PWV and the SCORE scale risk, and between PWV and the Framingham scale risk. Lastly, in the group of normotensive men, there were significant correlations between IMT and the SCORE scale risk, and IMT and the Framingham scale risk.

The possibility of correctly classifying a patient into the high-risk category by a logistic regression model using synchronous ABI, IMT and PWV was high – 74% for the risk according to the SCORE scale (66% in men, 88% in women), and 98% for the Framingham scale.

Conclusions: The addition of recognized subclinical target organ damage tests to the estimation of cardiovascular risk can significantly strengthen the prevention of cardiovascular disease.

Cardiovascular risk estimation follow-up with ABI, PWV and IMT increased the probability of correctly classifying people, especially women, into an at least high-risk category according to the SCORE scale, which has valuable therapeutic implications.     

Assessment of drug–drug interaction potential and PBPK modeling of CC-223, a potent inhibitor of the mammalian target of rapamycin kinase

1.?CC-223 was studied in vitro for metabolism and drug–drug interactions (DDI), and in clinic for interaction with ketoconazole.

2.?In vitro, human metabolites of CC-223 included O-desmethyl CC-223 (M1), keto (M2), N-oxide (M3) and imine (M13), with M1 being the most prominent metabolite.

3.?CC-223 was metabolized by CYP2C9 and CYP3A, while metabolism of M1 was mediated by CYP2C8 and CYP3A. Ketoconazole increased CC-223 and M1 exposure by 60–70% in healthy volunteers.

4.?CC-223 (IC₅₀?≥?27?µM) and M1 (IC₅₀?≥?46?µM) were inhibitors of CYP2C9 and CYP2C19 in human liver microsomes. CC-223 and M1 were moderate inducers of CYP3A in human hepatocytes.

5.?CC-223 was a substrate of BCRP, and M1 was a substrate of P-gp and BCRP. CC-223 was an inhibitor of P-gp (IC₅₀?=?3.67?µM) and BCRP (IC₅₀?=?11.7?µM), but at a clinically relevant concentration showed no inhibition of other transporters examined. M1 is a weak inhibitor of P-gp and BCRP.

6.?PBPK model of CC-223 and M1 was developed and verified using clinical results. Model based predictions of DDI with ketoconazole were in agreement with observed results enabling prospective predictions of DDIs between CC-223 and CYP3A4 inhibitors.     

Pre-formulation investigations for establishing a protocol for treosulfan handling and activation

Introduction: Treosulfan is an alkylating agent that is used for the treatment of ovarian cancer and for conditioning prior to stem cell transplantation. It is a prodrug that is activated non-enzymatically to two active epoxides.

Objectives: To optimize a protocol for both in vivo samples handling and in vitro drug preparation. Treosulfan stability was tested in biological fluids at different conditions as well as for its cytotoxicity on cell lines.

Results: Plasma samples can be safely frozen for a short period up to 8?h, however; for longer periods, samples should be acidified. Urine samples and cell culture media can be safely frozen regardless their pH. For in vitro investigations, incubation of treosulfan at 37?°C for 24?h activated 100% of the drug. Whole blood acidification should be avoided for the risk of hemolysis. Finally; treosulfan cytotoxicity on HL-60 cells has increased following pre-incubation for 24?h at 37?°C compared to K562 cell line.

Conclusion: The stability profiling of treosulfan provided a valuable reference for handling of biological samples for both in vivo and in vitro studies. These results can be utilized for further investigations concerning the drug kinetics and dynamics in addition to the development of new pharmaceutical formulations.