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The development of the trinuclear platinum(II) complex BBR3464 (also known as triplatin) in the late 1990s was meant to be a revolution in the field of platinum chemotherapy. What made it remarkable was that it defied many of the known structure-activity rules for platinums; it is cationic, has a single labile trans leaving group on each terminal platinum, and it binds DNA in ways different to mononuclear platinum drugs, like cisplatin and oxaliplatin. The flexible, long-range adducts the drug forms with DNA means that it showed activity in cancers not typically sensitive to platinums, and more importantly, BBR3464 demonstrated an ability to overcome acquired resistance to platinum drugs. But while preclinical and phase I testing showed promise, its more severe side effects which greatly limited the deliverable dose when compared with standard platinums, combined with its lack of biostability, led to a lack of activity in phase II trials and its development was halted. But, from its ashes have risen 4 th generation complexes which target the phosphate backbone of DNA. These, and the original BBR3464 drug, could potentially be further developed and gain regulatory approval through formulation with macrocycle-based drug delivery vehicles.

Background and Objectives: Saliva is a patient-friendly matrix for therapeutic drug monitoring (TDM) but is infrequently used in routine care. This is due to the uncertainty of saliva-based TDM results to inform dosing. This study aimed to retrieve data on saliva-plasma concentration and subsequently determine the physicochemical properties that influence the excretion of drugs into saliva to increase the foundational knowledge underpinning saliva-based TDM., Methods: Medline, Web of Science and Embase (1974-2023) were searched for human clinical studies, which determined drug pharmacokinetics in both saliva and plasma. Studies with at least ten subjects and five paired saliva-plasma concentrations per subject were included. For each study, the ratio of the area under the concentration-time curve between saliva and plasma was determined to assess excretion into saliva. Physicochemical properties of each drug (e.g. pKa, lipophilicity, molecular weight, polar surface area, rotatable bonds and fraction of drug unbound to plasma proteins) were obtained from PubChem and Drugbank. Drugs were categorised by their ionisability, after which saliva-to-plasma ratios were predicted with adjustment for protein binding and physiological pH via the Henderson-Hasselbalch equation. Spearman correlation analyses were performed for each drug category to identify factors predicting saliva excretion (α = 5%). Study quality was assessed by the risk of bias in non-randomised studies of interventions tool., Results: Overall, 42 studies including 40 drugs (anti-psychotics, anti-microbials, immunosuppressants, anti-thrombotic, anti-cancer and cardiac drugs) were included. The median saliva-to-plasma ratios were similar for drugs in the amphoteric (0.59), basic (0.43) and acidic (0.41) groups and lowest for drugs in the neutral group (0.21). Higher excretion of acidic drugs (n = 5) into saliva was associated with lower ionisation and protein binding (correlation between predicted versus observed saliva-to-plasma ratios: R 2 = 0.85, p = 0.02). For basic drugs (n = 21), pKa predicted saliva excretion (Spearman correlation coefficient: R = 0.53, p = 0.02). For amphoteric drugs (n = 10), hydrogen bond donor (R = - 0.76, p = 0.01) and polar surface area (R = - 0.69, p = 0.02) were predictors. For neutral drugs (n = 10), protein binding (R = 0.84, p = 0.004), lipophilicity (R = - 0.65, p = 0.04) and hydrogen bond donor count (R = - 0.68, p = 0.03) were predictors. Drugs considered potentially suitable for saliva-based TDM are phenytoin, tacrolimus, voriconazole and lamotrigine. The studies had a low-to-moderate risk of bias., Conclusions: Many commonly used drugs are excreted into saliva, which can be partly predicted by a drug's ionisation state, protein binding, lipophilicity, hydrogen bond donor count and polar surface area. The contribution of drug transporters and physiological factors to the excretion needs to be evaluated. Continued research on drugs potentially suitable for saliva-based TDM will aid in adopting this person-centred TDM approach to improve patient outcomes., (© 2024. The Author(s).)

Purpose: Cancer treatment remains a significant and escalating healthcare expense worldwide. Although annual reports on total cancer care costs are available, the potential impact of evolving treatment guidelines and the introduction of new drugs on future budgeting remains largely uncertain. The aim of this study was to examine the trends in the use of Pharmaceutical Benefits Scheme (PBS)-subsidised cancer drugs in Australia over the past decade., Methods: PBS codes for all PBS-subsidised cancer drugs that were listed in government-endorsed treatment protocols were obtained and used to retrieve usage data. Their patterns of use, represented by the number of prescriptions (services) processed by Services Australia, were analysed for the period between 2012 and 2022., Results: The overall prescribing of cancer drugs is outpacing Australia's population growth, primarily due to an ageing population and the accelerated rise in cancer diagnoses observed over the past decade. From 846 eviQ protocols, 141 cancer drugs were available on the PBS, of which kinase inhibitor (39 drugs) and monoclonal antibody drugs (24 drugs) had the highest increase in use during the study period; 16% and 23% respectively. Of the 8 drug classes, hormonal agents (20 drugs) were the most prescribed., Conclusion: The utilisation of PBS-listed cancer drugs is increasing faster than population growth, especially for high-cost monoclonal antibody and kinase inhibitor drugs, indicating continued pressure on government spending., (© 2024. The Author(s).)

Objective: This study aimed to understand the key determinants for poor academic performance of students completing a Bachelor of Pharmacy (BPharm), Bachelor of Pharmacy and Management (BPharmMgmt), or Master of Pharmacy (MPharm) degree., Methods: Data were collected on pharmacy students who had not met academic progression requirements between 2008 and 2018 at The University of Sydney, Australia. This included: age at the start of pharmacy degree; gender; whether they transferred from another university; whether they were a domestic or international student; Australian Tertiary Admissions Rank upon entry, previous studies in biology, chemistry, or mathematics; show cause triggers (units of study failed); number of show causes; students' written show cause responses; weighted average mark at last show cause or graduation; whether they graduated and were a registered pharmacist; and, the number of years they spent studying the degree. Descriptive studies were used to analyse student characteristics using SPSS software, and student self-reported reasons for poor performance were analysed reflexively using thematic analysis procedures using NVivo., Results: This study included 164 pharmacy students enrolled in a BPharm (79.3%, n = 130), BPharmMgmt (1.2%, n = 2), or MPharm (19.5%, n = 32). Of the students, 54% (n = 88) were men, 81% (n = 133) were domestic students, 15% (n = 24) transferred from another degree program, and 38% (n = 62) graduated from the course. Show cause students were less likely to graduate if they transferred from another degree program (P = 0.0002) or failed more than three units of study (UoS; P < 0.0001). The most commonly failed UoS were related to organic or pharmaceutical chemistry, and the top student self-reported reasons for poor performance was stress/anxiety, physical health, and depression., Conclusion: Pharmacy schools should aim to address student foundational knowledge in chemistry, identify at-risk students early using pre-subject testing, and provide better services to address student mental health., (© 2024. The Author(s).)

Background: Anxiety is a condition for which current treatments are often limited by adverse events (AEs). Components of medicinal cannabis, cannabidiol (CBD) and tetrahydrocannabinol (THC), have been proposed as potential treatments for anxiety disorders, specifically posttraumatic stress disorder (PTSD). Objective: To evaluate quality-of-life outcomes after treatment with various cannabis formulations to determine the effectiveness and associated AEs. Methods: An interim analysis of data collected between September 2018 and June 2021 from the CA Clinics Observational Study. Patient-Reported Outcomes Measurement Information System-29 survey scores of 198 participants with an anxiety disorder were compared at baseline and after treatment with medicinal cannabis. The data of 568 anxiety participants were also analyzed to examine the AEs they experienced by the Medical Dictionary for Regulatory Activities organ system class. Results: The median doses taken were 50.0 mg/day for CBD and 4.4 mg/day for THC. The total participant sample reported significantly improved anxiety, depression, fatigue, and ability to take part in social roles and activities. Those who were diagnosed with PTSD (n = 57) reported significantly improved anxiety, depression, fatigue, and social abilities. The most common AEs reported across the whole participant cohort were dry mouth (32.6%), somnolence (31.3%), and fatigue (18.5%), but incidence varied with different cannabis formulations. The inclusion of THC in a formulation was significantly associated with experiencing gastrointestinal AEs; specifically dry mouth and nausea. Conclusions: Formulations of cannabis significantly improved anxiety, depression, fatigue, and the ability to participate in social activities in participants with anxiety disorders. The AEs experienced by participants are consistent with those in other studies., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: N.C.M. and S.V.A. were employed by Applied Cannabis Research. J.W.B. is a consultant to Applied Cannabis Research. E.A.S. is funded by scholarships from The University of Sydney and Canngea Pty Ltd. No commercial cannabis entities played any role in the design, conduct, or analysis of the study; writing of the manuscript; or the decision to publish., (© The Author(s) 2023.)

Microneedles (MNs) are micron-sized protrusions attached to a range of devices that are used in therapeutic delivery and diagnosis. Because MNs can be self-applied, are painless, and can carry multiple therapeutic agents, they have received extensive attention, and have been widely investigated, for local and systemic therapy. Many researchers are currently working to extend the use of MNs to clinical applications. In this review, we provide an update and analysis on MN-based clinical trials since their inception in 2007. The MNs in clinical trials are classified into five types based on their appearance and properties, including: hollow MNs, MN patches, radiofrequency MNs, MN rollers, and other MNs. The various aspects of MN trials are summarized, such as MN types, clinical trial time, and trial regions. This review aims to present an overview of MN development and provide insights for future research in this field. To our knowledge, this is the first review focused on MN clinical trials which showcases the latest applications of this advanced technology in medicine., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: To examine the tolerability and effectiveness of medicinal cannabis prescribed to patients for chronic, refractory pain, with a subset analysis on arthritis., Methods: This was an interim analysis of the CA Clinics Observational Study investigating self-reported adverse events (AEs) and changes in health-related quality of life (HRQoL) outcomes over time after commencing medicinal cannabis. Patients were prescribed medicinal cannabis by a medical practitioner, containing various ratios of Δ 9 -tetrahydrocannabinol (THC) and/or cannabidiol (CBD)., Results: The overall chronic pain cohort, and specifically the balanced CBD:THC products, were associated with significantly reduced pain intensity scores ( p = 0.003, p = 0.025), with 22% of patients reporting a clinically meaningful reduction in pain intensity. Patients in the arthritis subset ( n = 199) reported significantly reduced pain intensity scores ( p = 0.005) overall, and specifically for those taking CBD-only ( p = 0.018) and balanced products ( p = 0.005). Other HRQoL outcomes, including pain interference and pain impact scores were significantly improved depending on the CBD:THC ratio. Products that contained a balanced ratio of CBD:THC were associated with improvements in the most number of PROMIS-29 domains. Approximately half ( n = 364; 51%) of the chronic pain cohort experienced at least one AE, the most common being dry mouth (24%), somnolence (19%) or fatigue (12%). These findings were similar in the arthritis subset., Discussion: Medicinal cannabis was observed to improve pain intensity scores and HRQoL outcomes in patients with chronic, refractory pain, providing real-world insights into medicinal cannabis' therapeutic potential., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Elise A Schubert is funded by scholarships from The University of Sydney and Canngea Pty Ltd. Masego T Johnstone was a Research Lead at Applied Cannabis Research Pty Ltd. during the conduct of this analysis. Nial J Wheate is a director of the Australian Medicinal Cannabis Association and Science Director of Canngea Pty Ltd. Melissa J Benson was General Manager at Applied Cannabis Research Pty Ltd. during the conduct of this analysis. She continues to be an advisory board member at the time of publication., (© The Author(s) 2022.)

Objectives: This study aimed to explore the incidence of adverse events (AEs) reported by patients when initiating medicinal cannabis treatment for chronic pain, and the association of cannabis constituents, dose and concomitant medicines with AE incidence., Methods: Patient demographics, cannabis products and AE data were collected as part of the Cannabis Access Clinics Observational Study, and concomitant medicines were obtained from patient health summaries provided by referring doctors. Cannabis products were grouped by their constituents as either cannabidiol-only or containing both cannabidiol and Δ-9-tetrahydrocannabinol., Key Findings: From a total of 275 patients, each had a median of six concomitant medicines, with opioids (n = 179; 65%) the most common. A total of 35.6% patients took 10 or more other medicines, and they were associated with a 3.6 times higher likelihood to report the AE of fatigue (P = 0.048). Patients who received concomitant gabapentinoids were 2.4 times more likely to report dizziness (P = 0.036), patients on tricyclic antidepressants were 1.8 times more likely to report somnolence (P = 0.034) and 3.4 times more likely to report anxiety (P = 0.04), when compared with patients who were not prescribed those classes of medications. Those patients who were prescribed products containing both cannabidiol and Δ-9-tetrahydrocannabinol were 1.5 times more likely (P = 0.004) to have experienced an AE when compared with those prescribed only cannabidiol., Conclusions: These findings show that certain concomitant medications and cannabis constituents may be associated with AE incidence when initiating medicinal cannabis. These potential pharmacokinetic and pharmacodynamic interactions require further study to develop guidance for prescribers and pharmacists., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society.)

Introduction: Paediatric poisoning is a major cause of childhood injury, and most poisonings are preventable. We aimed to describe hospitalisations resulting from poisoning and envenomation in Australian children, including demographics, cause of the exposure, hospital length of stay, rates of intensive care unit admission and in-hospital deaths. We also aimed to describe risk factors for increased length of stay and intensive care unit admission., Methods: A retrospective analysis was performed of hospitalised poisoning and envenomation cases of children (<15 years) in Australia from 1 July 2009 to 30 June 2019. A nationwide hospital admissions database was used for this study., Results: During the 10-year study period 33,438 children were admitted to hospital due to a pharmaceutical or non-pharmaceutical poisoning/envenomation; an average of 74.8 cases per 100,000 population per year. Approximately 10 children were admitted to hospital each day for poisoning. Over 70% of these cases were due to pharmaceuticals ( n  = 23,628), most frequently non-opioid analgesics, anti-pyretics and anti-rheumatics ( n  = 8759, 37.1% of pharmaceutical exposures). The most common non-pharmaceutical exposure was contact with venomous animals and toxic plants ( n  = 4578, 46.7% of non-pharmaceuticals). Intentional self-harm occurred in 7833 (23.4%) of cases. Intensive care unit admission was required in 519 cases (2.5% of the 20,739 cases where this information was available), while 200 (0.96% of 20,739) needed ventilator support. Ten children (0.03%) died. Older age, female sex, poisoning with pharmaceuticals and metropolitan hospital location were associated with increased length of stay. Older age and poisoning with pharmaceuticals were also associated with intensive care unit admission., Conclusion: Approximately 10 children were admitted to hospital with poisoning every day in Australia. Most poisonings were due to pharmaceuticals, particularly simple analgesics that are found in most Australian homes. Severe outcomes (intensive care unit admissions and deaths) were rare.

Objective: This descriptive study aimed to examine whether student past coursework performance, student or research supervisor characteristics, and the type of research project are related to the overall academic performance of a pharmacy student completing an honours research program., Methods: Data on undergraduate honours students who completed a Bachelor of Pharmacy degree at The University of Sydney, Sydney, Australia, between Jan 2015 and Dec 2020 was collected. This included socio-demographic characteristics, type of project undertaken, and academic outputs. Data was also collected on each supervisor's academic role, level of experience, research area, and where they completed their PhD. Descriptive statistics were used to describe the study cohort and correlation analysis and unpaired t-tail analyses were conducted using SPSS software., Results: This five year study included 130 students of which 67% were female and 60% were domestic students. Each student was supervised by one of 48 individual academics who were a mix of early- (31%), mid-career (29%), and experienced researchers (40%) for pharmaceutical science (50%), clinical (45%), and education (5%) projects. Just less than half (49%) of students published one peer-reviewed journal article. Female students outperformed male students (p = 0.031) with female students also twice as likely (15%) to receive a university medal eligible mark compared with male students (7.0%). Similarly, domestic students were twice as likely (15%) to receive a university medal eligible mark when compared with international students (7.7%). Students who undertook a pharmaceutical science-based project outperformed education-based project students (p = 0.0235). Students who had published at least one peer-reviewed journal article outperformed those who had not published (p = 0.0014)., Conclusion: Factors that affected honours performance were student gender, residential status, type of project undertaken, and whether a student had published a peer-reviewed journal article., (© 2023. The Author(s).)

Platinum drugs have been a mainstay of cancer chemotherapy since the introduction of cisplatin in the 1970s. Since then, carboplatin and oxaliplatin have been approved world-wide and nedaplatin, lobaplatin, heptaplatin, dicycloplatin, and miriplatin have been approved in individual countries. The three main platinum drugs are not used in isolation but are combined in chemotherapy protocols from a range of 28 drugs that include: anthracyclines, alkylating agents, vinca alkaloids, antimetabolites, topoisomerase inhibitors, taxanes, and monoclonal antibodies. Interestingly, they are not yet used in combination with tyrosine kinase inhibitors or proteasome inhibitors. How platinum drugs are formulated for administration to patients is important to minimise aquation during storage and administration. Cisplatin is typically formulated in saline-based solutions while carboplatin and oxaliplatin are formulated in dextrose. Pharmacokinetics are an important factor in both the efficacy and safety of platinum drugs. This includes the quantity of protein-bound drug in blood serum, how fast the drugs are cleared by the body, and how fast the drugs are degraded and deactivated. Attempts to control platinum pharmacokinetics and side effects using rescue agents, macrocycles, and nanoparticles, and through the design of platinum(IV)-based drugs have not yet resulted in clinically successful outcomes. As cancer is predominantly a disease of old age, many cancer patients who are administered a platinum drug may have other medical conditions which means they may also be taking many non-cancer medicines. The co-administration of non-cancer medicines to patients can potentially affect the efficacy of platinum drugs and/or change the severity of their side effects through drug-drug interactions.

Objective: To describe the temporal relationships in attention-deficit hyperactivity disorder (ADHD) medication poisoning exposures in children; describe patient demographics, medications involved, poisoning exposure reasons and disposition., Design: A population-based, retrospective cohort study of calls to Australia's largest Poisons Information Centre. Poisoning exposure counts and dispensing-adjusted rates were modelled with Poisson, quasi-Poisson and negative binomial regression where appropriate., Setting: Calls to the New South Wales Poisons Information Centre and dispensings on the Pharmaceutical Benefits Scheme., Patients: Children under the age of 5 years., Results: There were 1175 poisoning exposures to ADHD psychostimulants, 2004-2019; averaging 73 per year. Accidental poisonings accounted for 94% of cases. Methylphenidate was most frequently implicated (63%). Thirty-four per cent of cases were referred to hospital and a further 21% of calls were made by hospital staff. Poisoning exposure counts for all ADHD psychostimulants increased by 2.7% (95% CI=0.42% to 4.9%) per year; however, this differed by agent. Methylphenidate poisoning exposures increased by 5.2% per year (95% CI=4.3% to 6.1%), lisdexamfetamine increased by 62% per year (95% CI=48% to 76%), while dexamphetamine poisoning exposures decreased by 5.5% per year (95% CI=-9.5% to -1.4%). These trends are reflected in the number of dispensings; however, dispensings increased at a faster rate than exposures. When poisoning exposures were expressed as dispensing-adjusted rates, there was a 16% decrease (95% CI=-20% to -13%) per year., Conclusions: ADHD medication use has increased, associated with an increased number of paediatric poisoning exposures. However, poisoning exposures per dispensed prescription has decreased. The majority of cases required hospitalisation, indicating the need for further poisoning prevention strategies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: To describe time trends in opioid exposures in children under 5 years, and to describe patient demographics, the medicines involved, the reasons for exposure and disposition., Methods: A retrospective analysis of paediatric (<5 years of age) opioid exposure calls to the New South Wales Poisons Information Centre (NSWPIC, Australia's largest poison centre), 2004-2019. Joinpoint regression analysis was used to examine temporal trends., Results: There were 4807 cases of paediatric opioid exposure during the 16 year study period, with an average of 300 exposures per year. Exposures increased, 2004-2007, with an annual percentage change (APC) of 14.6% (95% CI = 4.3 to 26.0%), then decreased, 2007-2016, APC -3.4% (95% CI = -5.3 to -1.3%). A steeper decrease was observed after 2016, APC -14.1% (95% CI = -21.8 to -5.6%). The overall APC was -2.3% (95% CI = -4.7 to 0.2%), 2004-2019. Accidental exposures accounted for 86% of calls (4137). The majority of calls were from family members regarding exposures that happened at home, highlighting the need for safety initiatives. The preparations most frequently involved were paracetamol/opioid combination products (primarily codeine), 53% (2566) and ibuprofen/opioid combinations 14% (650). Twenty-two percent of cases were referred to a hospital (1062), and a further 15% (719) of calls originated from hospital staff., Conclusion: Opioid exposures in young Australian children continue to occur; however, the rate has declined since 2007. Safe storage and parent education initiatives could further reduce the burden of paediatric opioid poisoning in Australia., (© 2021 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Six Australian and five overseas complementary medicines (CM) and meal replacement shake products were analysed for potential adulteration with two common active pharmaceutical ingredients, caffeine and sibutramine, using thin-layer chromatography and mass spectrometry. The declared amount of caffeine in each product was also reviewed. Finally, the products were examined for heavy metal contamination using inductively coupled plasma-mass spectrometry. The results showed that there was no detected adulteration of either caffeine (for those products that did not list caffeine as an ingredient) or sibutramine in the 11 products; however, based on the product labels, one Australian and one overseas (two in total) CM product contained more than the maximum daily safety limit (400 mg) of caffeine. Potentially excessive lead and/or chromium was detected in six products, including four Australian products and two products purchased online. One Australian CM product appeared to contain these heavy metals at concentrations at, or exceeding, the safety limits specified in the United States Pharmacopeia or set by the World Health Organization. The overconsumption of caffeine and heavy metals has the potential of causing significant health effects in consumers.

The macrocycle para-sulfonatocalix[8]arene, sCX[8], was examined with 2 antibiotic drugs, ciprofloxacin (CIP) and isoniazid. The drugs were shown to form complexes with sCX[8] using proton nuclear magnetic resonance, thermogravimetric analysis, fluorescence spectroscopy, and molecular modeling. Both drugs form 1:1 hydrated (H 2 O: 13%-14% w/w) host-guest complexes, with sCX[8] binding around the pyridine ring of isoniazid, and around the piperazine and cyclopropane rings of CIP. From proton nuclear magnetic resonance, the binding constant of isoniazid to sCX[8] was 6.8 (±0.3) × 10 3 M -1 . Addition of 2 equivalents of sCX[8] to CIP resulted in a 58% decrease in fluorescence, and time-resolved fluorescence anisotropy of CIP doubles with sCX[8]. Each drug binds into the cavity of the macrocycle, with binding stabilized via combinations of hydrogen bonding, electrostatic interactions, π-π stacking, and hydrophobic effects. The safety of sCX[8] was examined in vitro with human embryonic kidney 293 cells. The IC 50 of sCX[8] was 559 μM, which is a minimum of 5-fold higher than the concentration that would be used in the clinic. The in vitro effect of sCX[8] on the action of CIP was examined on a panel of bacterial lines. The results showed that sCX[8] has no inherent antibiotic activity and had no negative effect on the action of CIP., (Copyright © 2018. Published by Elsevier Inc.)

Purpose: Platinum drugs have been in use in cancer treatment for more than 40 years, but little is known about the pattern of their use. The aim of this study was to examine the patterns of platinum drug use, with a secondary aim to describe the occurrence of dose reductions., Methods: A retrospective analysis was conducted of oncology pharmacy dispensing records from a single hospital in Australia. Data related to drug choice, regimen and dose reductions were included in this study if the patient had received their last round of chemotherapy between November 2014 and July 2015., Results: Of the 156 patients included in the study, 46% were dispensed a platinum drug during their treatment. The most commonly dispensed drugs were cisplatin (40%), carboplatin (40%) and oxaliplatin (15%), while some patients (5%) received more than one platinum drug. Dose reductions were more common in patients who were treated with a platinum drug (73%) compared with patients treated with non-platinum drugs (55%). The most common reason for a dose reduction was cytopenia., Conclusions: The findings suggest that platinum drugs remain one of the most commonly dispensed drugs to treat cancer patients and most patients receive a dose reduction during treatment.

Correction for 'The side effects of platinum-based chemotherapy drugs: a review for chemists' by Rabbab Oun et al., Dalton Trans., 2018, 47, 6645-6653.

The platinum-based drugs cisplatin, carboplatin and oxaliplatin are regularly prescribed in the treatment of cancer and while they are effective, their use is limited by their severe, dose-limiting side effects (also referred to as adverse effects/events). In total, a cancer patient can experience any combination of around 40 specific side effects. The dose-limiting side effect for cisplatin is nephrotoxicity, for carboplatin it is myelosuppression, and for oxaliplatin it is neurotoxicity. Other common side effects include anaphylaxis, cytopenias (including leukopenia and neutropenia, thrombocytopenia, and anaemia), hepatotoxicity, ototoxicity, cardiotoxicity, nausea and vomiting, diarrhea, mucositis, stomatitis, pain, alopecia, anorexia, cachexia, and asthenia. The side effects may require patients to be prescribed dose reductions in their platinum drugs of between 25 and 100%. Furthermore, patients require extensive monitoring of their biochemistries, kidney and liver function, and depending on the drug, hearing tests. Finally, patients are commonly co-prescribed additional non-chemotherapy based drugs to treat the side effects which can include antiemetics, antibiotics and myeloid growth factors, mannitol, propafenone, saline hyperhydration, magnesium supplements, monoclonal antibody cytokine blockers, and antioxidants.

Novel para-sulfonatocalix[4]arene (sCX[4]) and polyamidoamine (PAMAM) dendrimer nanocomplexes were evaluated as delivery vehicles for the platinum anticancer agent [(1,10-phenanthroline)(1S,2S-diaminocyclohexane)platinum(II)] chloride (PHENSS). Different ratios of sCX[4] to PHENSS were tested for their compatibility, with a ratio of 6:1 sCX[4]:PHENSS having the best solubility. The loading of sCX[4], and sCX[4]-bound PHENSS, onto three different generations of PAMAM dendrimers (G3.0-5.0) was examined using UV-visible spectrophotometry. The quantity of sCX[4] bound was found to increase exponentially with dendrimer size: G3, 15 sCX[4] molecules per dendrimer; G4, 37; and G5, 78. Similarly, the loading of sCX[4]-bound PHENSS also increased with increasing dendrimer size: G3, 7 PHENSS molecules per dendrimer; G4, 14; and G5, 28.5. The loading of sCX[4]-bound PHENSS molecules is significantly lower when compared with that of sCX[4], which indicates that less than half of the binding sites were occupied (45, 44, and 44%, respectively). By 1 H NMR and UV-vis analysis, the nanocomplex was found to be stable in NaCl solutions at concentrations up to 150mM. While PHENSS is more active in vitro than cisplatin against the human breast cancer cell line, MCF-7, delivery of PHENSS using the sCX[4]-dendrimer nanocomplexes, regardless of dendrimer generation, had little effect on PHENSS cytotoxicity. The results of this study may have application in the delivery of a variety of small molecule metal-based drugs for which chemical conjugation to a nanoparticle is undesired or not feasible., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Herein we describe the synthesis and evaluation of antidepressant properties of seven analogues (1-7) of the low affinity/high capacity transporter blocker decynium-22 (D-22). All analogues (1-7) were synthesized via base promoted coupling reactions between N-alkylated-2-methylquinolinium iodides or N-alkylated-4-methylquinolinium iodides and electrophilic N-alkylated-2-iodoquinolinium iodides. All final compounds were purified by re-crystallization or preparative HPLC and initial evaluation studies included; 1) screening for in vitro α1-adrenoceptor activity (a property that can lead to unwanted side-effects), 2) measuring antidepressant-like activity in a mouse tail suspension test (TST), and 3) measuring effects upon mouse locomotion. The results showed some analogues have lower affinities at α1-adrenoceptors compared to D-22 and showed antidepressant-like activity without the need for co-administration of SSRIs. Additionally, many analogues did not affect mouse locomotion to the same extent as D-22. Plans for additional evaluations of these promising analogues, including measurement of antidepressant-like activity with co-administration of selective serotonin re-uptake inhibitors (SSRIs), are outlined., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Pillar[n]arenes are a new family of nanocapsules that have shown application in a number of areas, but because of their poor water solubility their biomedical applications are limited. Recently, a method of synthesizing water-soluble pillar[n]arenes was developed. In this study, carboxylated pillar[n]arenes (WP[n], n = 6 or 7) have been examined for their ability to form host-guest complexes with compounds relevant to drug delivery and biodiagnostic applications. Both pillar[n]arenes form host-guest complexes with memantine, chlorhexidine hydrochloride, and proflavine by 1 H nuclear magnetic resonance and modeling. Binding is stabilized by hydrophobic effects within the cavities, and hydrogen bonding and electrostatic interactions at the portals. Encapsulation within WP[6] results in the complete and efficient quenching of proflavine fluorescence, giving rise to "on" and "off" states that have potential in biodiagnostics. The toxicity of the pillar[n]arenes was examined using in vitro growth assays with the OVCAR-3 and HEK293 cell lines. The pillar[n]arenes are relatively nontoxic to cells except at high doses and after prolonged continuous exposure. Overall, the results show that there could be a potentially large range of medical applications for carboxylated pillar[n]arene nanocapsules., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

We examined the relationship between executive functions and both factual and conceptual learning of science, specifically chemistry, in early adolescence. Sixty-three pupils in their second year of secondary school (aged 12-13 years) participated. Pupils completed tasks of working memory (Spatial Working Memory), inhibition (Stop-Signal), attention set-shifting (ID/ED), and planning (Stockings of Cambridge), from the CANTAB. They also participated in a chemistry teaching session, practical, and assessment on the topic of acids and alkalis designed specifically for this study. Executive function data were related to (1) the chemistry assessment which included aspects of factual and conceptual learning and (2) a recent school science exam. Correlational analyses between executive functions and both the chemistry assessment and science grades revealed that science achievements were significantly correlated with working memory. Linear regression analysis revealed that visuospatial working memory ability was predictive of chemistry performance. Interestingly, this relationship was observed solely in relation to the conceptual learning condition of the assessment highlighting the role of executive functions in understanding and applying knowledge about what is learned within science teaching., (© 2016 The British Psychological Society.)

Background: Ovarian cancer is the most fatal of gynaecological malignancies, usually detected at a late stage with intraperitoneal dissemination. Appropriate preclinical models are needed that recapitulate both the histopathological and molecular features of human ovarian cancer for drug-efficacy analysis., Methods: Longitudinal studies comparing cisplatin performance either alone or in a novel cisplatin-based delivery-system, cucurbit[7]uril-encapsulated cisplatin (cisplatin@CB[7]) were performed on subcutaneous (s.c.) and intraperitoneal (i.p.) xenografts using the human ovarian cancer cell line A2780 stably expressing the small GTPase Rab25, which allows A2780 intraperitoneal growth; and luciferase, to allow tumour load measurement by non-invasive bioluminescent imaging., Results: Rab25 expression induced cisplatin resistance compared to the parental cell line as assessed by the MTT assay in vitro. These findings did not translate in vivo, where cisplatin resistance was determined by the microenvironment. Subcutaneous xenografts of either parental A2780 or cisplatin-resistant Rab25-expressing A2780 cells presented similar responses to cisplatin treatment. In contrast, increased cisplatin resistance was only detected in i.p. tumours. Treatment of the cisplatin-resistant i.p. model with the novel cisplatin@CB[7] delivery system resulted in a substantial reduction of i.p. tumour load and increased necrosis., Conclusions: Poor clinical performance of novel chemotherapeutics might reflect inappropriate preclinical models. Here we present an ovarian i.p. model that recapitulates the histopathological and chemoresistant features of the clinical disease. In addition, we demonstrate that the novel cisplatin-delivery system, cisplatin@CB[7] may have utility in the treatment of drug-resistant ovarian human cancers.

The year 2015 marks the 50th anniversary since the discovery of the anticancer potential of cisplatin and it remains just as useful now as it did back then, especially for the treatment of some endocrine-related cancers like ovarian and testicular carcinomas. Since its discovery, five other platin drugs have received approval in various countries. While several new platin drugs are in preclinical development, in the last decade only two new platin drugs have entered clinical trials, LA-12 and dicycloplatin, reflecting a shift in research focus from new drug design to improved formulations of already approved platin drugs. These formulations include their encapsulation with macrocycles to slow and prevent their degradation by proteins and peptides; their attachment to nanoparticles to passively target solid tumours through the enhanced permeability and retention effect and their coordination to important nutrients, proteins, antibodies and aptamers for active tumour targeting. These formulation methods have all shown potential but none have yet yielded a new marketable medicine containing a platin drug. The reasons for this are problems of consistent drug loading, controlling the location and timing of drug release and the inherent toxicity of some of the drug delivery vehicles. In addition to drug delivery, functional genomics is now playing an increasing role in predicting patients' responses to platin chemotherapy and their likelihood of experiencing severe side effects., (© 2015 Society for Endocrinology.)

The cucurbituril family of drug delivery vehicles have been examined for their tissue specific toxicity using ex vivo models. Cucurbit[6]uril (CB[6]), cucurbit[7]uril (CB[7]) and the linear cucurbituril-derivative Motor2 were examined for their neuro-, myo- and cardiotoxic activity and compared with β-cyclodextrin. The protective effect of drug encapsulation by CB[7] was also examined on the platinum-based anticancer drug cisplatin. The results show that none of the cucurbiturils have statistically measurable neurotoxicity as measured using mouse sciatic nerve compound action potential. Cucurbituril myotoxicity was measured by nerve-muscle force of contraction through chemical and electrical stimulation. Motor2 was found to display no myotoxicity, whereas both CB[6] and CB[7] showed myotoxic activity via a presynaptic effect. Finally, cardiotoxicity, which was measured by changes in the rate and force of right and left atria contraction, was observed for all three cucurbiturils. Free cisplatin displays neuro-, myo- and cardiotoxic activity, consistent with the side-effects seen in the clinic. Whilst CB[7] had no effect on the level of cisplatin's neurotoxic activity, drug encapsulation within the macrocycle had a marked reduction in both the drug's myo- and cardiotoxic activity. Overall the results are consistent with the relative lack of toxicity displayed by these macrocycles in whole animal acute systemic toxicity studies and indicate continued potential of cucurbiturils as drug delivery vehicles for the reduction of the side effects associated with platinum-based chemotherapy.

Amide coupling reactions can be used to synthesize bispyridine-based ligands for use as bridging linkers in multinuclear platinum anticancer drugs. Isonicotinic acid, or its derivatives, are coupled to variable length diaminoalkane chains under an inert atmosphere in anhydrous DMF or DMSO with the use of a weak base, triethylamine, and a coupling agent, 1-propylphosphonic anhydride. The products precipitate from solution upon formation or can be precipitated by the addition of water. If desired, the ligands can be further purified by recrystallization from hot water. Dinuclear platinum complex synthesis using the bispyridine ligands is done in hot water using transplatin. The most informative of the chemical characterization techniques to determine the structure and gross purity of both the bispyridine ligands and the final platinum complexes is (1)H NMR with particular analysis of the aromatic region of the spectra (7-9 ppm). The platinum complexes have potential application as anticancer agents and the synthesis method can be modified to produce trinuclear and other multinuclear complexes with different hydrogen bonding functionality in the bridging ligand.

The anticancer drug cisplatin was encapsulated within the cucurbit[7]uril macrocycle to form the host-guest complex: cisplatin@CB[7]. This was then incorporated into gelatin and 0-4% w/v polyvinyl alcohol (PVA)-based hydrogels as slow release drug delivery vehicles. The hydrogels demonstrated predicable swelling and disintegration dependent on the PVA concentration. The hydrogel with the highest PVA content was slower to swell and release drug compared with lower concentrations of PVA. The effect of the hydrogel PVA concentration on in vitro cytotoxicity was examined using A2780/CP70 ovarian cancer cells. Over the 24h drug exposure time used, hydrogels containing 4% PVA showed a 20% decrease in viable cells compared to the control, whereas hydrogels containing 0% and 2% PVA induced an 80% and 45% inhibition of cell growth, respectively. There was no measurable difference in the in vitro cytotoxicity of free cisplatin and cisplatin@CB[7] containing hydrogels. Finally, the in vivo effectiveness of a 2%-PVA hydrogel implanted under the skin of nude mice bearing A2780/CP70 xenografts showed that low dose hydrogels containing cisplatin@CB[7] (30 μg equivalent of drug) was just as effective as an intraperitoneal high dose administration of free cisplatin (150 μg) at inhibiting tumour growth., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The macrocycle family of molecules called cucurbit[n]urils are potential drug delivery vehicles as they are able to form host-guest complexes with many different classes of drugs. This study aimed to examine the utility of Cucurbit[6]uril (CB[6]) in topical cream-based formulations for either localised treatment or for transdermal delivery. Cucurbit[6]uril was formulated into both buffered cream aqueous- and oily cream-based dosage forms. The solid state interaction of CB[6] with other excipients was studied by differential scanning calorimetry and the macrocycle's transdermal permeability was determined using rat skin. Significant solid state interactions were observed between CB[6] and the other dosage form excipients. At concentrations up to 32% w/w the buffered aqueous cream maintained its normal consistency and could be effectively applied to skin, but the oily cream was too stiff and is not suitable as a dosage form. Cucurbit[6]uril does not permeate through skin; as such, the results imply that cucurbituril-based topical creams may potentially only have applications for localised skin treatment and not for transdermal drug delivery.

The sgc8c aptamer is a 41-base DNA oligonucleotide that binds to leukaemia cells with high affinity and specificity. In this work we examined the utility of this aptamer as both a delivery vehicle and an active targeting agent for an inert platinum complex [(1,10-phenathroline)(ethylenediamine)platinum(II)](2+). The aptamer forms a stem-and-loop confirmation as determined by circular dichroism. This conformation is adopted in both water and phosphate buffered saline solutions. The metal complex binds through intercalation into the aptamer's double helical stem with a binding constant of approximately 4.3 × 10(4) M(-1). Binding of the metal complex to the aptamer had a significant effect on the aptamer's global conformation, and increased its melting temperature by 28°C possibly through lengthening and stiffening of the aptamer stem. The effect of the aptamer on the metal complex's cytotoxicity and cellular uptake was determined using in vitro assays with the target leukaemia cell line CCRF-CEM and the off-target ovarian cancer cell lines A2780 and A2780cp70. The aptamer has little inherent cytotoxicity and when used to deliver the metal complex results in a significant decrease in the metal complex's cytotoxicity and uptake. The reason(s) for the poor uptake and activity may be due to the change in aptamer conformation which affects its ability to recognise leukaemia cells., (© 2013.)

Picoplatin is a sterically hindered mononuclear platinum drug undergoing clinical trials. The 2-methylpyridine ring provides steric hindrance to the drug, preventing attack from biological nucleophiles. BBR3464 is a trinuclear platinum drug which was recently in Phase II clinical trials, and is highly cytotoxic both in vitro and in vivo; it derives this activity through the flexible adducts it forms with DNA. In this work we sought to combine the properties of both drugs to synthesise a family of sterically hindered, dinuclear platinum complexes as potential anticancer agents. The bis-pyridyl-based ligands were synthesised through a peptide coupling reaction using diaminoalkanes of differing lengths (n = 2, 4 or 8) and 4-carboxypyridine or 2-methyl-4-carboxypyridine. The resultant dinuclear platinum complexes were synthesised by reacting two equivalents of transplatin or mono-aquated transplatin to each ligand, followed by purification by precipitation with acetone. The unprotected complexes react faster with 5'-guanosine monophosphate (drug to nucleotide ratio 1:2; t(1/2) = 2 h), glutathione (1:10, t(1/2) = 55 min) and human serum albumin (HSA) (1:1, t(1/2) = 24 h) compared to their hindered, protected equivalents (5'-guanosine monophosphate, t(1/2) = 3.5 h; glutathione = 1.7 h; HSA, t(1/2) = 110 h). The complexes were tested for in vitro cytotoxicity in the A2780 and A2780/cp70 ovarian cancer cell line. The unprotected platinum complexes were more cytotoxic than their protected derivatives, but none of the complexes were able to overcome resistance. The results provide important proof-of-concept for the development of a larger family of sterically hindered multinuclear-based platinum complexes.

The cucurbit[n]uril (CB[n]) family of macrocycles has been shown to have potential in drug delivery where they are able to provide physical and chemical stability to drugs, improve drug solubility, control drug release and mask the taste of drugs. Cisplatin is a small molecule platinum-based anticancer drug that has severe dose-limiting side-effects. Cisplatin forms a host-guest complex with cucurbit[7]uril (cisplatin@CB[7]) with the platinum atom and both chlorido ligands located inside the macrocycle, with binding stabilised by four hydrogen bonds (2.15-2.44 Å). Whilst CB[7] has no effect on the in vitro cytotoxicity of cisplatin in the human ovarian carcinoma cell line A2780 and its cisplatin-resistant sub-lines A2780/cp70 and MCP1, there is a significant effect on in vivo cytotoxicity using human tumour xenografts. Cisplatin@CB[7] is just as effective on A2780 tumours compared with free cisplatin, and in the cisplatin-resistant A2780/cp70 tumours cisplatin@CB[7] markedly slows tumour growth. The ability of cisplatin@CB[7] to overcome resistance in vivo appears to be a pharmacokinetic effect. Whilst the peak plasma level and tissue distribution are the same for cisplatin@CB[7] and free cisplatin, the total concentration of circulating cisplatin@CB[7] over a period of 24 hours is significantly higher than for free cisplatin when administered at the equivalent dose. The results provide the first example of overcoming drug resistance via a purely pharmacokinetic effect rather than drug design or better tumour targeting, and demonstrate that in vitro assays are no longer as important in screening advanced systems of drug delivery.

Gold nanoparticles (AuNPs) can be used as delivery vehicles for platinum anticancer drugs, improving their targeting and uptake into cells. Here, we examine the appropriateness of different-sized AuNPs as components of platinum-based drug-delivery systems, investigating their controlled synthesis, reproducibility, consistency of drug loading, and stability. The active component of cisplatin was tethered to 25, 55, and 90 nm AuNPs, with the nanoparticles being almost spherical in nature and demonstrating good batch-to-batch reproducibility (24.37 ± 0.62, 55.2 ± 1.75, and 89.1 ± 2.32 nm). The size distribution of 25 nm AuNPs has been significantly improved, compared with a previous method that produces polydispersed nanoparticles. Attachment of platinum to the AuNP surface through a poly(ethylene glycol) (PEG) linker exhibits an increase in the drug loading with increasing particle size: 25 nm (815 ± 106 drug molecules per AuNP), 55 nm (14216 ± 880), and 90 nm (54487 ± 15996). The stability of the naked, PEGylated, and platinum-conjugated nanoparticles has been examined over time under various conditions. When stored at 4 °C, there is minimal variation in the diameter for all three AuNP sizes; variation after 28 days for the 25 nm AuNPs was 2.4%; 55 nm, 3.3%; and 90 nm, 3.6%. The 25 nm AuNPs also demonstrate minimal changes in UV-visible absorbance over the same time period., (© 2012 American Chemical Society)

Aquated cisplatin was added to half-generation PAMAM dendrimers and the resultant complexes were purified by centrifuge. The drug-dendrimer complexes were then characterised by 1-D and diffusion (1)H NMR and ICP-AES. The amount of drug bound was found to increase in proportion with dendrimer size: G3.5, 22 cis-{Pt(NH(3))(2)} molecules per dendrimer; G4.5, 37; G5.5, 54; and G6.5, 94, which represent only a fraction of the available binding sites on each dendrimer (68, 58, 42 and 37%, respectively). Drug release studies showed that some drug remains bound to the dendrimer even after prolonged incubation with 5'-GMP at temperatures of 60°C for over a week (percentage of drug released 18, 30, 35 and 63%, respectively). Attachment of the drug was found to decrease the radius of the dendrimers. Finally, the effect of the dendrimer on drug cytotoxicity was determined using in vitro assays with the A2780, A2780cis and A2780cp ovarian cancer cell lines. The free dendrimers display no cytotoxicity whilst the drug-dendrimer complexes showed moderate activity. In vivo activity was examined using an A2780 tumour xenograft. Cisplatin, at its maximum tolerated dose of 6 mg/kg, reduced tumour size by 33% compared to an untreated control group. The G6.5 cisplatin-dendrimer complex was administered at two doses (6 and 8 mg/kg equivalent of cisplatin). Both were well tolerated by the mice. The lower dose displayed comparable activity to cisplatin with a tumour volume reduction of 32%, but the higher dose was significantly more active than free cisplatin with a tumour reduction of 45%., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The synthesis, processing, and solid state excipient interactions of cucurbit[6]uril (CB[6]) and its formulation into oral tablets has been examined using a range of physical chemistry techniques. Rapid precipitation from HCl by the addition of water yields microcrystalline CB[6] with smaller and more consistent particle size (30-165 μm) compared with the sieved CB[6] (50-540 μm) produced from large crystals grown by slow evaporation from HCl. The microcrystalline particles also contain fewer water molecules in the crystal compared with the sieved particles: 10 and 16% respectively. Microcrystalline CB[6] can be formulated into tablets suitable for oral delivery with a CB[6] content of 1-50% w/w, with the other excipients including lactose, talc, Avicel, magnesium stearate and Ac-Di-Sol. In the solid state microcrystalline CB[6] does not interact significantly with the talc, Ac-Di-Sol or Avicel, but significant interactions are observed when mixed or ground with either magnesium stearate or lactose, resulting in the lowering of the melting points of both excipients. This work represents the first study of the physical processing and solid state chemistry of CB[n]s for pharmaceutical formulation and represents an important development step in the use of CB[n]s as drug delivery vehicles.

Since its approval in 1979 cisplatin has become an important component in chemotherapy regimes for the treatment of ovarian, testicular, lung and bladder cancers, as well as lymphomas, myelomas and melanoma. Unfortunately its continued use is greatly limited by severe dose limiting side effects and intrinsic or acquired drug resistance. Over the last 30 years, 23 other platinum-based drugs have entered clinical trials with only two (carboplatin and oxaliplatin) of these gaining international marketing approval, and another three (nedaplatin, lobaplatin and heptaplatin) gaining approval in individual nations. During this time there have been more failures than successes with the development of 14 drugs being halted during clinical trials. Currently there are four drugs in the various phases of clinical trial (satraplatin, picoplatin, Lipoplatin and ProLindac). No new small molecule platinum drug has entered clinical trials since 1999 which is representative of a shift in focus away from drug design and towards drug delivery in the last decade. In this perspective article we update the status of platinum anticancer drugs currently approved for use, those undergoing clinical trials and those discontinued during clinical trials, and discuss the results in the context of where we believe the field will develop over the next decade.

The platinum-based anticancer drugs cisplatin, carboplatin, and oxaliplatin are an important component of chemotherapy but are limited by severe dose-limiting side effects and the ability of tumors to develop resistance rapidly. These drugs can be improved through the use of drug-delivery vehicles that are able to target cancers passively or actively. In this study, we have tethered the active component of the anticancer drug oxaliplatin to a gold nanoparticle for improved drug delivery. Naked gold nanoparticles were functionalized with a thiolated poly(ethylene glycol) (PEG) monolayer capped with a carboxylate group. [Pt(1R,2R-diaminocyclohexane)(H(2)O)(2)]2NO(3) was added to the PEG surface to yield a supramolecular complex with 280 (+/-20) drug molecules per nanoparticle. The platinum-tethered nanoparticles were examined for cytotoxicity, drug uptake, and localization in the A549 lung epithelial cancer cell line and the colon cancer cell lines HCT116, HCT15, HT29, and RKO. The platinum-tethered nanoparticles demonstrated as good as, or significantly better, cytotoxicity than oxaliplatin alone in all of the cell lines and an unusual ability to penetrate the nucleus in the lung cancer cells.

The inclusion of the cardiovascular beta-blocker drug atenolol, the antidiabetic drug glibenclamide, the Alzheimer's NMDA glutamate receptor drug memantine and the analgesic/antipyretic drug paracetamol by cucurbit[7]uril (CB[7]) has been studied by (1)H nuclear magnetic resonance spectroscopy, electrospray ionisation mass spectrometry, molecular modelling, fluorescence displacement assays and differential scanning calorimetry. All four drugs form 1 : 1 host-guest complexes with CB[7], but the exchange kinetics and location of the binding is different for each drug. Atenolol is bound over the central phenyl ring with a binding constant of 4.2 x 10(4) M(-1), whereas glibenclamide is bound over the terminal cyclohexyl group with a binding constant of 1.7 x 10(5) M(-1), and memantine is totally bound within the CB[7] cavity. Paracetamol is bound in two locations, over the central phenyl ring and over the methyl group, with the CB[7] molecule shuttling quickly between the two sites. Inclusion by CB[7] was shown by differential scanning calorimetry to physically stabilise all four drugs, which has applications preventing drug degradation and improving drug processing and formulation.

Background: Cucurbit[n]urils (CB[n]; n = 5, 6, 7, 8 or 10) are a family of macrocycles made from the acid-catalyzed condensation of glycoluril and formaldehyde., Results: The synthesis of CB[n] using microwave radiation has been examined and the effect of acid type, reaction time and temperature on the distribution of products has been determined. Synthesis in HCl yields CB[5], CB[6], CB[7] and CB[8] in 10 min and is most efficient at 160 °C. Synthesis in H(2)SO(4) yields mostly CB[6] in 3 min and is most efficient at 160 °C., Conclusion: Microwave synthesis provides an efficient and cost-effective method for the large-scale production of CB[n] for a range of applications, particularly drug delivery.

Single crystal and powder X-ray diffraction have been used to examine the host-guest complex of cucurbit[7]uril (CB[7]) and the model dinuclear platinum anticancer complex trans-[{PtCl(NH(3))(2)}(2)mu-dpzm](2+) (di-Pt, dpzm= 4,4'-dipyrazolylmethane). The single crystal structure shows that the host-guest complex forms with the di-Pt dpzm ligand within the CB[7] cavity and with the platinum groups just beyond the macrocycle portals. Binding is stabilised through hydrophobic interactions and six hydrogen bonds between the platinum ammine ligands and the dpzm pyrazole amine to the CB[7] carbonyls. Each host-guest complex crystallises with two chloride counterions and 5.5 water molecules. The unit cell comprises four asymmetric units, each of which contains three crystallographically independent CB[7]-di-Pt moieties. X-Ray powder diffraction demonstrated structural consistency of the bulk crystals with a single polycrystalline phase that is identical with the single crystal structure. Finally, the effect of CB[7] encapsulation of the thermal stability of di-Pt was examined by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). From the TGA experiments it was found that free CB[7] and the CB[7]-di-Pt complex lose 11 and 3.5% of their mass respectively, through the loss of water molecules, upon heating to 160 degrees C. The DSC results showed that the free dpzm ligand melts between 186 and 199 degrees C, with a standard enthalpy of fusion of 27.92 kJ mol(-1). As a 2+ inorganic salt the metal complex does not melt but undergoes several decomposition events between 140 and 290 degrees C. Encapsulation by CB[7] completely stabilises di-Pt with no decomposition of either the macrocycle or metal complex at temperatures up to 290 degrees C.

We have examined the biological activity of 12 platinum(II)-based DNA intercalators of the type [Pt(I(L))(A(L))](2+), where I(L) is an intercalating ligand (1,10-phenanthroline or a methylated derivative) and A(L) is an ancillary ligand (diaminocyclohexane, diphenylethylenediamine or 1,2-bis(4-fluorophenyl)-1,2-ethylenediamine). The chiral compounds (1-9) and the racemic compounds (10-12) were tested against a panel of human cancer cell lines, with a number of complexes displaying activity significantly greater than that of cisplatin (up to 100-fold increase in activity in the A-427 cell line). The activity of the complexes containing diphenylethylenediamine (8 and 9) and 1,2-bis(4-fluorophenyl)-1,2-ethylenediamine (10-12) was significantly lower compared to the complexes containing diaminocyclohexane (1-7). Further in vitro testing, such as DNA unwinding, competition assays, and DNase 1 footprinting, was conducted on the most active compound (5) and its enantiomer (6) to provide information about the mechanism of action. These complexes display activity in cisplatin resistant cell lines, have higher cellular uptake than cisplatin, and do not activate caspase-3 as cisplatin does, indicating that these complexes exhibit a different mechanism of action.

Pulsed gradient spin-echo nuclear magnetic resonance diffusion measurements have been used to show that platinum(II)-based intercalating agents self-stack in solution and form nanorods 0.45-3.9 nm in length (at 25 mM); their lengths are dependent on metal complex concentration, salt concentration and solution temperature.

The utility of p-sulphonatocalix[4]arene (s-CX[4]) as a drug delivery vehicle for multinuclear platinum anticancer agents, using trans-[{PtCl(NH(3))(2)}(2)mu-dpzm](2+) (di-Pt; where dpzm=4,4'-dipyrazolylmethane) as a model complex, has been examined using (1)H nuclear magnetic resonance, electrospray ionisation mass spectrometry, molecular modelling and in vitro growth inhibition assays. s-CX[4] binds di-Pt in a side-on fashion in a ratio of 1:1, with the dpzm ligand of the metal complex located within the s-CX[4] cavity with binding further stabilised by ion-ion interactions and hydrogen bonding between the metal complex am(m)ine groups and the s-CX[4] sulphate groups. Partial encapsulation of di-Pt within the cavity does not prevent binding of 5'-guanosine monophosphate to the metal complex. When bound to two individual guanosine molecules, di-Pt also remains partially bound by s-CX[4]. The cytotoxicity of free di-Pt and s-CX[4] and their host guest complex was examined using in vitro growth inhibition assays in the A2780 and A2780cis human ovarian cancer cell lines. Free di-Pt has an IC(50) of 100 and 60 microM, respectively, in the cell lines, which is significantly less active than cisplatin (1.9 and 8.1 microM, respectively). s-CX[4] displays no cytotoxicity at concentrations up to 1.5mM and does not affect the cytotoxicity of di-Pt, probably because its low binding constant to the metal complex (6.8 x 10(4)M(-1)) means the host-guest complex is mostly disassociated at biologically relevant concentrations.

The use of anionic half-generation poly(amidoamine) dendrimers as drug delivery vehicles for [Pt(S,S-dach)(5,6-Me(2)phen)](2+) (56MESS) (where S,S-dach=1S,2S-diaminocyclohexane; 5,6-Me(2)phen=5,6-dimethyl-1,10-phenanthroline) and [{Delta,Delta-Ru(phen)(2)}(2)(mu-bb7)](4+) (Rubb(7)) (where phen=1,10-phenanthroline; bb7=1,7-bis[4-(4'-methyl-2,2'-bipyridyl)heptane]) has been studied by nuclear magnetic resonance spectroscopy. From one- and two-dimensional (1)H NMR spectra both 56MESS and Rubb(7) were found to bind to the surface of generation 3.5, 4.5, 5.5 and 6.5 dendrimers through electrostatic interactions. The higher charge and larger size of Rubb(7) resulted in stronger binding to all dendrimer generations (K(b)> or =2 x 10(5)M(-1)) compared with 56MESS (K(b)> or =1 x 10(4)M(-1)). Interestingly, there appeared to be no observable trend between dendrimer size and binding constant strength. The size of the free and 56MESS-bound dendrimers were examined using pulsed-gradient spin-echo NMR. The dendrimers ranged in hydrodynamic diameter from 11 to 20 nm and in all cases were larger than their corresponding full-generation dendrimer. Upon the addition of 56MESS the diameter of the dendrimers increased, consistent with surface binding.