Quantifying elemental and organic carbon in diesel particulate matter by mid-infrared spectrometry.

A method for the quantification of airborne organic carbon (OC) and elemental carbon (EC) within aerosolized diesel particulate matter (DPM) is described in this article. DPM is a known carcinogen encountered in many industrial workplaces (notably mining) and in the ambient atmosphere. The method described here collects DPM particles onto a quartz fiber filter, after which reflection-mode infrared spectra are measured on a mid-infrared Fourier transform (FT-IR) spectrometer. Several infrared absorption bands are investigated for their efficacy in quantifying OC and EC. The thermo-optical (T-O) method is used to calibrate a linear regression model to predict OC and EC from the infrared spectra. The calibrated model, generated from laboratory DPM samples, is then utilized to quantify OC and EC in mine samples obtained from two metal mine locations under a variety of operating conditions. The feasibility of further improving these results by partial least squares (PLS) regression was investigated. A single calibration that is broadly applicable would be considered an improvement over currently available portable instruments, which require aerosol-specific calibration.

Ward staffing guided by a patient classification system: A multi-criteria analysis of "fit" in three acute hospitals.

AIMS: To assess how well the Safer Nursing Care Tool (SNCT) predicts staffing requirements on hospital wards, and to use professional judgement to generate hypotheses about factors associated with a "poor fit". BACKGROUND: The SNCT is widely used in the UK, but there is scant evidence about factors that influence the quality of staffing decisions based upon such patient classification systems. METHODS: Secondary analysis of data from 69 wards in three acute hospitals to assess the precision of the estimated staffing requirement, variation of estimates, correspondence with professional judgement and achieved staffing levels. Nursing workforce leads suggested factors associated with poor fit, based on the wards that rated worst. RESULTS: 39% of wards were frequently understaffed, while frequent overstaffing was less common (12%). 24% of wards needed a sample of over 182 days to estimate the establishment precisely. Potential reasons identified for poor fit included high turnover, older patients, high levels of 1-to-1 specialing, cancer care, small ward size and high within-day variation in demand. CONCLUSIONS: Using a staffing tool without applying professional judgement or triangulating against other methods can lead to inaccurate estimates of staffing requirements and unsafe staffing levels. IMPLICATIONS FOR NURSING MANAGEMENT: Despite the availability of software to calculate staffing requirements, application of professional judgement remains essential.

Auto-fluorescent PAMAM-based dendritic molecules and their potential application in pharmaceutical sciences.

The epithelial permeation of water-soluble fluorescent PAMAM dendrons based on 7H-benz[de] benzimidazo [2,1-a] isoquinoline-7-one as a fluorescent core across epithelial cell models MDCK I and MDCK II has been quantified. Hydrodynamic radii have been derived from self-diffusion coefficients obtained via pulsed-gradient spin-echo Nuclear Magnetic Resonance (PGSE-NMR). Results indicate that these dendritic molecules are molecularly disperse, non-aggregating, and only slightly larger than their parent homologues. MDCK I permeability studies across epithelial barriers show that these dendritic molecules are biocompatible with the chosen epithelial in-vitro model and can permeate across MDCK cell monolayers. Permeability is demonstrated to be a property of dendritic size and cell barrier restrictiveness indicating that paracellular mechanisms play the predominant role in the transport of these molecules.

Post-operative mortality, missed care and nurse staffing in nine countries: A cross-sectional study.

BACKGROUND: Variation in post-operative mortality rates has been associated with differences in registered nurse staffing levels. When nurse staffing levels are lower there is also a higher incidence of necessary but missed nursing care. Missed nursing care may be a significant predictor of patient mortality following surgery. AIM: Examine if missed nursing care mediates the observed association between nurse staffing levels and mortality. METHOD: Data from the RN4CAST study (2009-2011) combined routinely collected data on 422,730 surgical patients from 300 general acute hospitals in 9 countries, with survey data from 26,516 registered nurses, to examine associations between nurses' staffing, missed care and 30-day in-patient mortality. Staffing and missed care measures were derived from the nurse survey. A generalized estimation approach was used to examine the relationship between first staffing, and then missed care, on mortality. Bayesian methods were used to test for mediation. RESULTS: Nurse staffing and missed nursing care were significantly associated with 30-day case-mix adjusted mortality. An increase in a nurse's workload by one patient and a 10% increase in the percent of missed nursing care were associated with a 7% (OR 1.068, 95% CI 1.031-1.106) and 16% (OR 1.159 95% CI 1.039-1.294) increase in the odds of a patient dying within 30days of admission respectively. Mediation analysis shows an association between nurse staffing and missed care and a subsequent association between missed care and mortality. CONCLUSION: Missed nursing care, which is highly related to nurse staffing, is associated with increased odds of patients dying in hospital following common surgical procedures. The analyses support the hypothesis that missed nursing care mediates the relationship between registered nurse staffing and risk of patient mortality. Measuring missed care may provide an 'early warning' indicator of higher risk for poor patient outcomes.

Workforce characteristics and interventions associated with high-quality care and support to older people with cancer: a systematic review.

OBJECTIVES: To provide an overview of the evidence base on the effectiveness of workforce interventions for improving the outcomes for older people with cancer, as well as analysing key features of the workforce associated with those improvements. DESIGN: Systematic review. METHODS: Relevant databases were searched for primary research, published in English, reporting on older people and cancer and the outcomes of interventions to improve workforce knowledge, attitudes or skills; involving a change in workforce composition and/or skill mix; and/or requiring significant workforce reconfiguration or new roles. Studies were also sought on associations between the composition and characteristics of the cancer care workforce and older people's outcomes. A narrative synthesis was conducted and supported by tabulation of key study data. RESULTS: Studies (n=24) included 4555 patients aged 60+ from targeted cancer screening to end of life care. Interventions were diverse and two-thirds of the studies were assessed as low quality. Only two studies directly targeted workforce knowledge and skills and only two studies addressed the nature of workforce features related to improved outcomes. Interventions focused on discrete groups of older people with specific needs offering guidance or psychological support were more effective than those broadly targeting survival outcomes. Advanced Practice Nursing roles, voluntary support roles and the involvement of geriatric teams provided some evidence of effectiveness. CONCLUSIONS: An array of workforce interventions focus on improving outcomes for older people with cancer but these are diverse and thinly spread across the cancer journey. Higher quality and larger scale research that focuses on workforce features is now needed to guide developments in this field, and review findings indicate that interventions targeted at specific subgroups of older people with complex needs, and that involve input from advanced practice nurses, geriatric teams and trained volunteers appear most promising.

Prevalence of cancer chemotherapy-related problems, their relation to health-related quality of life and associated supportive care: a cross-sectional survey.

PURPOSE: The purpose of this study was to identify the treatment-associated problems that most impact on patients undergoing cancer chemotherapy, how problems relate to experiences of supportive care and variations in experience between cancer treatment centres. METHODS: A survey administered to patients at six cancer centres in England explored variations of prevalence of 17 cancer chemotherapy-associated problems and associated supportive care. Problem items were identified as the most frequently experienced and severe when experienced in a scoping and consensus exercise. A health-related quality of life (HRQoL) measure, the EQ5D, was included to measure impact of problems. RESULTS: A total of 363 completed questionnaires were returned (response rate 43 %, median 61 %). The most prevalent problem was 'tiredness/fatigued' (90 %), followed by 'changes in taste & smell' (69 %) and 'difficulty managing everyday tasks' (61 %). Significant variations in problem prevalence existed between centres, and some common problems were rarely reported in the literature. Regression analysis found that almost all problems were significantly associated with HRQoL, with social/emotional problems having as much impact on HRQoL as physical/psychological side effects of treatment. Greatest effect size was for difficulty managing everyday tasks. Respondents reported significant variations in supportive care between centres, with more supportive care received for physical/psychological problems than for social/emotional problems. Findings indicated that patients who received increased supportive care experienced less severe problems. CONCLUSION: The most common and distressing chemotherapy-associated problems were identified. These problems are mitigated by quality supportive care. Routine measurement and monitoring of problem items and supportive care are warranted to facilitate benchmarking and service improvements both within and between cancer centres.

In Vitro Evaluation of the Interaction of Dextrin-Colistin Conjugates with Bacterial Lipopolysaccharide.

Dextrin-colistin conjugates have been developed with the aim of achieving reduced clinical toxicity associated with colistin, also known as polymyxin E, and improved targeting to sites of bacterial infection. This study investigated the in vitro ability of such dextrin-colistin conjugates to bind and modulate bacterial lipopolysaccharide (LPS), and how this binding affects its biological activity. These results showed that colistin and amylase-activated dextrin-colistin conjugate to a lesser extent induced aggregation of LPS to form a stacked bilayer structure with characteristic dimensions, although this did not cause any substantial change in its secondary structure. In biological studies, both colistin and dextrin-colistin conjugate effectively inhibited LPS-induced hemolysis and tumor necrosis factor α (TNFα) secretion in a concentration-dependent manner, but only dextrin-colistin conjugate showed no additive toxicity at higher concentrations. This study provides the first direct structural experimental evidence for the binding of dextrin-colistin conjugates and LPS and gives insight into the mode of action of dextrin-colistin conjugates.

Nanoparticle diffusion within intestinal mucus: Three-dimensional response analysis dissecting the impact of particle surface charge, size and heterogeneity across polyelectrolyte, pegylated and viral particles.

Multiple particle tracking (MPT) methodology was used to dissect the impact of nanoparticle surface charge and size upon particle diffusion through freshly harvested porcine jejunum mucus. The mucus was characterised rheologically and by atomic force microscopy. To vary nanoparticle surface charge we used a series of self-assembly polyelectrolyte particles composed of varying ratios of the negatively charged polyacrylic acid polymer and the positively charged chitosan polymer. This series included a neutral or near-neutral particle to correspond to highly charged but near-neutral viral particles that appear to effectively permeate mucus. In order to negate the confounding issue of self-aggregation of such neutral synthetic particles a sonication step effectively reduced particle size (to less than 340 nm) for a sufficient period to conduct the tracking experiments. Across the polyelectrolyte particles a broad and meaningful relationship was observed between particle diffusion in mucus (×1000 difference between slowest and fastest particle types), particle size (104-373 nm) and particle surface charge (-29 mV to +19.5 mV), where the beneficial characteristic promoting diffusion was a neutral or near-neutral charge. The diffusion of the neutral polyelectrolyte particle (0.02887 cm S(-1)×10(-9)) compared favourably with that of a highly diffusive PEGylated-PLGA particle (0.03182 cm(2) S(-1)×10(-9)), despite the size of the latter (54 nm diameter) accommodating a reduced steric hindrance with the mucin network. Heterogeneity of particle diffusion within a given particle type revealed the most diffusive 10% sub-population for the neutral polyelectrolyte formulation (5.809 cm(2) S(-1)×10(-9)) to be faster than that of the most diffusive 10% sub-populations obtained either for the PEGylated-PLGA particle (4.061 cm(2) S(-1)×10(-9)) or for a capsid adenovirus particle (1.922 cm(2) S(-1)×10(-9)). While this study has used a simple self-assembly polyelectrolyte system it has substantiated the pursuance of other polymer synthesis approaches (such as living free-radical polymerisation) to deliver stable, size-controlled nanoparticles possessing a uniform high density charge distribution and yielding a net neutral surface potential. Such particles will provide an additional strategy to that of PEGylated systems where the interactions of mucosally delivered nanoparticles with the mucus barrier are to be minimised.

Nurse staffing and education and hospital mortality in nine European countries: a retrospective observational study.

BACKGROUND: Austerity measures and health-system redesign to minimise hospital expenditures risk adversely affecting patient outcomes. The RN4CAST study was designed to inform decision making about nursing, one of the largest components of hospital operating expenses. We aimed to assess whether differences in patient to nurse ratios and nurses' educational qualifications in nine of the 12 RN4CAST countries with similar patient discharge data were associated with variation in hospital mortality after common surgical procedures. METHODS: For this observational study, we obtained discharge data for 422,730 patients aged 50 years or older who underwent common surgeries in 300 hospitals in nine European countries. Administrative data were coded with a standard protocol (variants of the ninth or tenth versions of the International Classification of Diseases) to estimate 30 day in-hospital mortality by use of risk adjustment measures including age, sex, admission type, 43 dummy variables suggesting surgery type, and 17 dummy variables suggesting comorbidities present at admission. Surveys of 26,516 nurses practising in study hospitals were used to measure nurse staffing and nurse education. We used generalised estimating equations to assess the effects of nursing factors on the likelihood of surgical patients dying within 30 days of admission, before and after adjusting for other hospital and patient characteristics. FINDINGS: An increase in a nurses' workload by one patient increased the likelihood of an inpatient dying within 30 days of admission by 7% (odds ratio 1·068, 95% CI 1·031-1·106), and every 10% increase in bachelor's degree nurses was associated with a decrease in this likelihood by 7% (0·929, 0·886-0·973). These associations imply that patients in hospitals in which 60% of nurses had bachelor's degrees and nurses cared for an average of six patients would have almost 30% lower mortality than patients in hospitals in which only 30% of nurses had bachelor's degrees and nurses cared for an average of eight patients. INTERPRETATION: Nurse staffing cuts to save money might adversely affect patient outcomes. An increased emphasis on bachelor's education for nurses could reduce preventable hospital deaths. FUNDING: European Union's Seventh Framework Programme, National Institute of Nursing Research, National Institutes of Health, the Norwegian Nurses Organisation and the Norwegian Knowledge Centre for the Health Services, Swedish Association of Health Professionals, the regional agreement on medical training and clinical research between Stockholm County Council and Karolinska Institutet, Committee for Health and Caring Sciences and Strategic Research Program in Care Sciences at Karolinska Institutet, Spanish Ministry of Science and Innovation.

'Care left undone' during nursing shifts: associations with workload and perceived quality of care.

BACKGROUND: There is strong evidence to show that lower nurse staffing levels in hospitals are associated with worse patient outcomes. One hypothesised mechanism is the omission of necessary nursing care caused by time pressure-'missed care'. AIM: To examine the nature and prevalence of care left undone by nurses in English National Health Service hospitals and to assess whether the number of missed care episodes is associated with nurse staffing levels and nurse ratings of the quality of nursing care and patient safety environment. METHODS: Cross-sectional survey of 2917 registered nurses working in 401 general medical/surgical wards in 46 general acute National Health Service hospitals in England. RESULTS: Most nurses (86%) reported that one or more care activity had been left undone due to lack of time on their last shift. Most frequently left undone were: comforting or talking with patients (66%), educating patients (52%) and developing/updating nursing care plans (47%). The number of patients per registered nurse was significantly associated with the incidence of 'missed care' (p<0.001). A mean of 7.8 activities per shift were left undone on wards that are rated as 'failing' on patient safety, compared with 2.4 where patient safety was rated as 'excellent' (p < 0.001). CONCLUSIONS: Nurses working in English hospitals report that care is frequently left undone. Care not being delivered may be the reason low nurse staffing levels adversely affects quality and safety. Hospitals could use a nurse-rated assessment of 'missed care' as an early warning measure to identify wards with inadequate nurse staffing.

Development and testing of the patient-reported chemotherapy indicators of symptoms and experience: patient-reported outcome and process indicators sensitive to the quality of nursing care in ambulatory chemotherapy settings.

BACKGROUND: Outcome indicators are increasingly advocated to demonstrate the impact of high-quality care; however, generic measures do not encompass outcomes relevant to specialist areas. OBJECTIVE: The aim of this study was to develop an outcome measure (Patient-Reported Chemotherapy Indicators of Symptoms and Experience [PR-CISE]) for use in ambulatory chemotherapy settings and assess its feasibility, acceptability, and preliminary efficacy in clinical practice. METHODS: Three areas were covered by PR-CISE--symptom management, safe medication administration, and experience of supportive care. Outcome selection was guided by review of evidence and reference groups of users, clinicians, and experts. Over 12 weeks, PR-CISE was distributed to patients receiving ambulatory chemotherapy at 10 cancer centers. Data were analyzed descriptively and with case mix adjustment using regression-based models. RESULTS: There were 2466 responses. There was variability across centers in terms of symptom experience and support provided. Across the whole sample, 25% reported moderate or severe nausea; however, rates varied between centers (25%-75%). Similar results emerged for other symptoms. When asked about support for symptom management, 80% reported that chemotherapy nurses asked about and were aware of symptom severity and provided useful information/advice. Once again, there was substantial variability between centers. Unexplained variation remained after case mix adjustment, suggesting that differences may be "real" rather than caused by population differences. Stakeholders planned to make changes to care delivery based on data on their performance. CONCLUSIONS: We successfully developed and tested indicators assessing the quality of care provided in ambulatory chemotherapy services. IMPLICATIONS: Results show that monitoring outcomes demonstrate potential differences in care quality and provide a stimulus to improve the experience and health of patients.

Is a larger specialist nurse workforce in cancer care associated with better patient experience? Cross-sectional study.

OBJECTIVES: To assess whether variation in the provision of cancer specialist nurses is associated with the experiences of care for patients undergoing treatment for cancer. METHODS: This is a cross-sectional study using routinely collected national survey data in 158 acute hospital National Health Service (NHS) Trusts in England. Patients with a primary diagnosis of cancer who attended hospital as inpatients or day cases in the first three months of 2010 responded to a national survey (n = 67,713, response rate 67%). Patient perceptions of coordination of care, quality of information provision, emotional support and support for symptom management were studied. RESULTS: Patients in Trusts that had the fewest patients per specialist nurse were more likely to report that people treating and caring for them worked well together (adjusted odds ratio 1.08, 95% confidence interval 1.01-1.15; p = 0.02) and provided enough emotional support during ambulatory treatment (1.15, 1.01-1.32; p = 0.04), but were no more likely to report being given the right amount of information (0.96, 0.88-1.05; p = 0.38) when compared to patients in Trusts with the most patients per specialist nurse. Breast cancer patients undergoing chemotherapy in the Trusts with fewer patients per specialist nurse were more likely to report good support for the control of side effects from chemotherapy (1.34, 1.02-1.75; p = 0.03). CONCLUSIONS: Cancer patients' experience of care coordination and emotional support was better in Trusts with more specialist nurses. The absolute differences were small, and it was unclear whether particular roles or service configurations are associated with better experience.

Is "failure to rescue" derived from administrative data in England a nurse sensitive patient safety indicator for surgical care? Observational study.

BACKGROUND: 'Failure to rescue'--death after a treatable complication--is used as a nursing sensitive quality indicator in the USA. It is associated with the size of the nursing workforce relative to patient load, for example patient to nurse ratio, although assessments of nurse sensitivity have not previously considered other staff groups. This study aims to assess the potential to derive failure to rescue and a proxy measure, based on long length of stay, from English hospital administrative data. By exploring change in coding practice over time and measuring associations between failure to rescue and factors including staffing, we assess whether two measures of failure to rescue are useful nurse sensitive indicators. DESIGN: Cross sectional observational study of routinely collected administrative data. PARTICIPANTS: Discharge data from 66,100,672 surgical admissions to 146 general acute hospital trusts in England (1997-2009). RESULTS: Median percentage of surgical admissions with at least one secondary diagnosis recorded increased from 26% in 1997/1998 to 40% in 2008/2009. Regression analyses showed that mortality based failure to rescue rates were significantly associated (P<0.05) with several hospital characteristics previously associated with quality, including staffing levels. Lower rates of failure to rescue were associated with a greater number of nurses per bed and doctors per bed in a bivariate analysis. Higher total clinically qualified staffing (doctors+nurses) per bed and a higher number of doctors relative to the number of nurses were both associated with lower mortality based failure to rescue in the fully adjusted analysis (P<0.05); however, the extended stay based measure showed the opposite relationship. CONCLUSION: Failure to rescue can be derived from English administrative data and may be a valid quality indicator. This is the first study to assess the association between failure to rescue and medical staffing. The suggestion that it is particularly sensitive to nursing is not clearly supported, nor is the suggestion that the number of patients with an extended hospital stay is a good proxy.

Outcomes sensitive to nursing service quality in ambulatory cancer chemotherapy: Systematic scoping review.

BACKGROUND: There is long standing interest in identifying patient outcomes that are sensitive to nursing care and an increasing number of systems that include outcomes in order to demonstrate or monitor the quality of nursing care. OBJECTIVE: We undertook scoping reviews of the literature in order to identify patient outcomes sensitive to the quality of nursing services in ambulatory cancer chemotherapy settings to guide the development of an outcomes-based quality measurement system. METHODS: A 2-stage scoping review to identify potential outcome areas which were subsequently assessed for their sensitivity to nursing was carried out. Data sources included the Cochrane Library, Medline, Embase, the British Nursing Index, Google and Google scholar. RESULTS: We identified a broad range of outcomes potentially sensitive to nursing. Individual trials support many nursing interventions but we found relatively little clear evidence of effect on outcomes derived from systematic reviews and no evidence associating characteristics of nursing services with outcomes. CONCLUSION: The purpose of identifying a set of outcomes as specifically nurse-sensitive for quality measurement is to give clear responsibility and create an expectation of strong clinical leadership by nurses in terms of monitoring and acting on results. It is important to select those outcomes that nurses have most impact upon. Patient experience, nausea, vomiting, mucositis and safe medication administration were outcome areas most likely to yield sensitive measures of nursing service quality in ambulatory cancer chemotherapy.

Evaluation of the physical and biological properties of hyaluronan and hyaluronan fragments.

Hyaluronan (HA) has been extensively used for various medical applications, including osteoarthritis, tissue augmentation and ocular surgery. More recently, it has been investigated for use in polymer therapeutics as a carrier for drugs and biologically active proteins, thanks to its biodegradability, biocompatibility and inherent biological properties. Such biological functions are strongly dependent on HA's chain length, yet the molecular weight of HAs used in polymer conjugates varies widely and is inconsistent with its intended application. Therefore, this study aimed to determine the ideal chain length of HA to be used in polymer conjugates for enhanced tissue repair. HA fragments (M(w) 45,000-900,000g/mol) were prepared by acid hydrolysis of rooster comb HA and their physicochemical and biological properties were characterized. Such HA fragments had a highly extended, almost rod-like solution conformation and demonstrated chain length- and concentration-dependent viscosity, while exposure to HAase caused a rapid reduction in HA viscosity, which was most significant for the native HA. Initial HA hydrolysis rate by HAase varied strongly with HA chain length and was dependent on the formation of a stable enzyme-substrate complex. When normal human dermal fibroblasts were exposed to the different HA fragments for 72h, only native (900,000g/mol) HA reduced proliferation at 1000µg/mL. Conversely, only the smallest HA fragment (70,000g/mol) reduced the proliferation of chronic wound fibroblasts, at 1000µg/mL. The 70,000g/mol HA fragment also promoted the greatest cell attachment. These observations demonstrate that low molecular weight (70,000-120,000g/mol) HA fragments would be best suited for the delivery of proteins and peptides with applications in chronic wound healing and paves the way for the rationalized development of novel HA conjugates.

Conformational consequences of cooperative binding of a coiled-coil peptide motif to poly(N-(2-hydroxypropyl) methacrylamide) HPMA copolymers.

Small-angle neutron scattering and pulsed-gradient spin-echo NMR have been used to examine the solution conformation of a series of water soluble poly(N-(2-hydroxypropyl) methacrylamide) P(HPMA) co-polymer drug delivery vehicles incorporating a coiled-coil peptide motif as a novel pH sensitive non-covalent linker. The conformation of the HPMA homopolymer is well-described by a Gaussian coil model and changing pH from pH 7 to pH 5 has little effect on the solution conformation, as quantified via the radius of gyration. Copolymerisation with 5-10mol% of the K3 peptide bearing methacrylate monomer (K3-MA), gave a series of copolymers that exhibited an increase in radius of gyration at both pH's, despite being typically 30% lower in molecular weight, indicating that the K3-MA causes a perturbation (expansion) of the copolymer conformation. Subsequent addition of an equimolar amount of the complementary peptide E3 makes little further difference to the conformation, indicative of the intimate binding (coiled-coil motif) between the two peptides. Again, the effects of pH are small. Only the addition of a large aromatic structure such as methotrexate causes a further perturbation of the structure - the hydrophobic interaction between the MTX units causes a significant collapse of the polymer coil. These findings further elaborate the understanding of those factors that determine the solution conformation of novel polymer therapeutics.

Impact of polymer tacticity on the physico-chemical behaviour of polymers proposed as therapeutics.

Although water-soluble polymers are finding increasing use as polymer therapeutics, there has been little consideration of the effect of polymer stereochemistry on their physico-chemical and biological properties. The aim of this study was to investigate these properties using polymethacrylic acids (PMAs) of similar molecular weights with a difference in syndiotacticity of about 20% of rr triad content. Experiments to characterize the solution behaviour were conducted at pHs encountered during the transport, endocytic uptake and intracellular trafficking (7.4-3.0). These showed that with increasing rr triads, the polymer become less hydrophobic, a stronger acid, displayed a locally ordered solution conformation at pH 5.5, and interacted more strongly with dodecyl trimethylammonium bromide (DTAB) micelles. Preliminary cytotoxicity experiments using B16F10 melanoma cells showed lower toxicity in the concentration range of 1-100 µg/mL with increased rr triads. These observations indicate that the higher content of rr triads could drive a chain organization that minimize the influence of negative charges and so underline the importance of further, systematic studies to investigate the effect of tacticity on the behaviour of polymers in respect of their pharmacokinetics, toxicity and efficacy.

Poly(amidoamine) polymers: soluble linear amphiphilic drug-delivery systems for genes, proteins and oligonucleotides.

Polymer-drug and polymer-protein conjugates are emerging as a robust and well-characterized class of therapeutic entity. Although there are no low-molecular-weight soluble polymer conjugates in routine clinical use, there are many examples of routinely used high-molecular-weight drugs conjugated to soluble polymers (e.g., Oncospar). Advances in synthetic polymer chemistry have fostered the development of linear poly(amidoamine)s (PAA)s that impart both biodegradability, 'smart' (pH responsive) biological activity and biocompatibility. In their linear form, such as hyper-branched poly(amidoamine) (PAMAM) dendrimers, linear PAAs can be used to deliver large therapeutic entities such as peptides, proteins and genes to either the cytosol or nucleus. Furthermore, these polymers offer great potential in vivo due to their ability to either target the liver or be directed away from the liver and enter tumor mass via the enhanced permeability and retention (EPR) effect. PAAs also exhibit minimal toxicity (dependent upon backbone chemistry), relative to well-characterized polymers used for gene delivery. The propensity of PAAs to modulate intracellular trafficking resulting in their cytosolic translocation has also recently been quantified in vivo and is the primary focus of this article.

Enhanced pulmonary absorption of a macromolecule through coupling to a sequence-specific phage display-derived peptide.

With the aim of identifying a peptide sequence that promotes pulmonary epithelial transport of macromolecule cargo we used a stringent peptide-phage display library screening protocol against rat lung alveolar epithelial primary cell cultures. We identified a peptide-phage clone (LTP-1) displaying the disulphide-constrained 7-mer peptide sequence, C-TSGTHPR-C, that showed significant pulmonary epithelial translocation across highly restrictive polarised cell monolayers. Cell biological data supported a differential alveolar epithelial cell interaction of the LTP-1 peptide-phage clone and the corresponding free synthetic LTP-1 peptide. Delivering select phage-clones to the intact pulmonary barrier of an isolated perfused rat lung (IPRL) resulted in 8.7% of lung deposited LTP-1 peptide-phage clone transported from the IPRL airways to the vasculature compared (p<0.05) to the cumulative transport of less than 0.004% for control phage-clone groups. To characterise phage-independent activity of LTP-1 peptide, the LTP-1 peptide was conjugated to a 53kDa anionic PAMAM dendrimer. Compared to respective peptide-dendrimer control conjugates, the LTP-1-PAMAM conjugate displayed a two-fold (bioavailability up to 31%) greater extent of absorption in the IPRL. The LTP-1 peptide-mediated enhancement of transport, when LTP-1 was either attached to the phage clone or conjugated to dendrimer, was sequence-dependent and could be competitively inhibited by co-instillation of excess synthetic free LTP-1 peptide. The specific nature of the target receptor or mechanism involved in LTP-1 lung transport remains unclear although the enhanced transport is enabled through a mechanism that is non-disruptive with respect to the pulmonary transport of hydrophilic permeability probes. This study shows proof-of principle that array technologies can be effectively exploited to identify peptides mediating enhanced transmucosal delivery of macromolecule therapeutics across an intact organ.