Computational and experimental approaches for investigating nanoparticle-based drug delivery systems.

Most therapeutic agents suffer from poor solubility, rapid clearance from the blood stream, a lack of targeting, and often poor translocation ability across cell membranes. Drug/gene delivery systems (DDSs) are capable of overcoming some of these barriers to enhance delivery of drugs to their right place of action, e.g. inside cancer cells. In this review, we focus on nanoparticles as DDSs. Complementary experimental and computational studies have enhanced our understanding of the mechanism of action of nanocarriers and their underlying interactions with drugs, biomembranes and other biological molecules. We review key biophysical aspects of DDSs and discuss how computer modeling can assist in rational design of DDSs with improved and optimized properties. We summarize commonly used experimental techniques for the study of DDSs. Then we review computational studies for several major categories of nanocarriers, including dendrimers and dendrons, polymer-, peptide-, nucleic acid-, lipid-, and carbon-based DDSs, and gold nanoparticles. This article is part of a Special Issue entitled: Membrane Proteins edited by J.C. Gumbart and Sergei Noskov.

Bone mineral density and calcium metabolism of Hong Kong Chinese postpartum women--a 1-y longitudinal study.

OBJECTIVE: This paper reports longitudinal changes in bone mineral density (BMD), calcium homeostasis and dietary calcium intake in a group of Hong Kong breastfeeding women during the first year postpartum. DESIGN AND SUBJECTS: Nine mothers who breastfed exclusively or almost exclusively for at least 3 months and 14 formula feeding mothers aged 20-40 y were interviewed after delivery, 2 and 6 weeks, 3, 6 and 12 months postpartum. BMD at L2-L4 lumbar spine (LS), trochanter (Tro) and femoral neck (FN), serum intact parathyroid hormone (iPTH), serum bone-specific alkaline phosphatase (b-ALP), urinary deoxypyridinoline (Dpd), serum and urinary calcium (Ca) and phosphorus (P) and dietary intake of macronutrients were assessed. RESULTS: Compared to the formula feeding group, BMD assessed at LS, Tro and FN decreased significantly in the breastfeeding group over the first 6 months, with rebound to approximate baseline values at 12 months for the latter two sites. Serum iPTH increased in both groups, whereas serum b-ALP was consistently higher in the breastfeeders. Urinary Ca and P excretion decreased early postpartum in both groups, but the breastfeeders had higher excretion at 3 and 6 months. Breastfeeding mothers consumed significantly more Ca than the formula feeding mothers in the early postpartum. CONCLUSIONS: Increased calcium requirement during early lactation is affected through mobilisation of bone and renal calcium conservation. Bone mineral loss during lactation is temporary. Further studies are warranted to investigate the effects of diet and other hormonal factors on the calcium homeostasis during lactation.

Aquatic reclamation in the Athabasca, Canada, oil sands: naphthenate and salt effects on phytoplankton communities.

Microcosm experiments with natural indigenous phytoplankton communities were conducted to assess the effects of waters from oil sands extraction processes, emphasizing the naphthenate and salt constituents. Process waters of varying ages (zero to eight years) remediation histories, and chemical composition were obtained from outdoor mesocosms and inoculated with phytoplankton assemblages from a reference lake in the study area. Community composition measures, including percentage model affinity (PMA) and canonical correspondence analysis (CCA), revealed significant community effects of water from systems less than five years old, with naphthenate concentrations greater than 20 mg/L, compared to water from the reference lake. Canonical correspondence analysis, PMA, and regression analyses further showed that naphthenate concentration was significantly correlated with community structure. Using CCA, groups of taxa characteristic of waters with > 20 mg/L naphthenates (including Botryococcus braunii, Gloeococcus schroeteri, Cosmarium depressum, Chrysococcus rufescens, Chromulina spp., Ochromonas spp., and Keratococcus spp.) were identified. Salinity, as reflected in conductivity, was positively correlated with naphthenate concentration and itself appeared to influence the community structure. The results confirmed an important role for naphthenates in ecological effects of process waters from oil sands mining, but the influence of covarying factors such as salinity requires further investigation.

Bone mineral acquisition in low calcium intake children following the withdrawal of calcium supplement.

Our recent 18-month calcium supplementation trial demonstrated a significant increase in radial bone mineral mass in 7-year-old children with calcium intake approximately 300 mg/day (Am J Clin Nutr 1994; 60: 744-50). The persistence of higher bone mass after cessation of calcium supplementation is unknown. This is a follow-up study to investigate the lasting effect of calcium supplementation on bone acquisition. Subjects were 159 Chinese children aged 8.7 years. Distal one-third radial bone mineral content (BMC) and bone width (BW) were measured by single-photon absorptiometry. After 12 months, the significant difference in mean +/- SD percentage radial BMC disappeared between the study and control groups (7.34 +/- 6.77% vs 8.67 +/- 6.46%, p > 0.05). Dietary calcium intakes were similar between the groups. During the supplementation phase, the study group had 17.9% greater BMC gain than that of controls. In the follow-up phase, however, the study group had 16.1% less BMC gain than that of controls. It appears that an increased acquisition rate during the supplementation phase was almost balanced by a reduced acquisition rate during follow-up phase. Moreover, throughout the entire 30-month period, the overall BMC acquisition rates of the study and control groups were 25% and 23.8%, respectively. Hence, the overall acquisition rate of the study group was only 5% higher than that of controls. Therefore, the effect of calcium supplementation on bone mineral gain appears to reflect a transient reduction in bone turnover rate. Longer-term calcium trials are necessary to confirm whether a sustainable higher calcium intake throughout childhood will enhance peak bone mass.

A follow-up study on the effects of calcium-supplement withdrawal and puberty on bone acquisition of children.

Recent calcium supplementation trials in children have confirmed a positive but moderate effect of calcium intake on bone mineral accretion. However, the lasting effect of a higher bone mineral mass after calcium-supplement withdrawal is not known. This is an 18-mo follow-up study conducted after an 18-mo controlled calcium supplementation trial to study the persistent effect of higher bone mineral mass in children. Radial bone mineral mass was determined by single-photon absorptiometry; lumbar spine and femoral neck bone mineral mass were evaluated by dual-energy X-ray absorptiometry in 84 healthy Hong Kong children at age 8.5 y and these evaluations were repeated at age 10 y. Pubertal status was determined by Tanner staging. At the end of the follow-up, the differences in percentage gains in lumbar spine bone mineral content (12.1 +/- 8.2% compared with 14.9 +/- 10.05%, P = 0.24) and lumbar spine area (8.6 +/- 5.1% compared with 9.4 +/- 5.5%, P = 0.47) between the study and control groups disappeared. Dietary calcium intakes during follow-up were similar for the two groups (555 and 640 mg/d, P = 0.23). In multiple-regression analyses, pubertal status was the strongest correlate of bone acquisition and linear growth in the study period. In conclusion, higher percentage gains in bone mineral mass in childhood by calcium supplementation for 18 mo were reversible. Our study showed that the benefits of calcium supplementation disappear after treatment is withdrawn. Longer-term calcium trials are necessary to determine whether peak bone mass can be modified through sustained supplementation so that appropriate calcium intakes can be determined.

A randomized double-blind controlled calcium supplementation trial, and bone and height acquisition in children.

There is limited information relating Ca intake to bone and height acquisition among Oriental children who consume little or even no milk. The present controlled study investigated the acquisition of bone mass and height of Chinese children with an initial Ca intake of approximately 567 mg/d who were supplemented to about 800 mg/d. Eighty-four 7-year-old Hong Kong Chinese children underwent an 18-month randomized, double-blind, controlled Ca-supplementation trial. The children were randomized to receive either 300 mg elemental Ca or a placebo tablet daily. Bone mass of the distal one-third radius was measured by single-photon absorptiometry, lumbar spine and femoral neck were determined using dual-energy X-ray absorptiometry. Measurements were repeated 6-monthly. Baseline serum 25-hydroxycholecalciferol concentration and physical activity were also assessed. Baseline Ca intakes of the study group and controls were respectively 571 (SD 326) and 563 (SD 337) mg/d. There were no significant differences in baseline serum 25-hydroxycholecalciferol concentration (P = 0.71) and physical activity (P = 0.36) between the study and control groups. After 18 months the study group had significantly greater increases in lumbar-spinal bone mineral content (20.9 v. 16.34%; P = 0.035), lumbar-spinal area (11.16 v. 8.71%; P = 0.049), and a moderately greater increment in areal bone mineral density of the radius (7.74 v. 6.00%; P = 0.081) when compared with the controls. The results confirm a positive effect of Ca on bone mass of the spine and radius but no effects on femoral-neck and height increase. A longer trial is warranted to confirm a positive Ca effect during childhood that may modify future peak bone mass.

Effects of double-blind controlled calcium supplementation on calcium absorption in Chinese children measured with stable isotopes (42Ca and 44Ca).

A double-blind controlled Ca supplementation trial was conducted for 6 months in thirty-four 7-year-old Chinese children from Hongkong and Jiangmen, China. The children were randomly allocated to the study group (n 17) or control group (n 17), and a CaCO3 tablet (300 mg Ca) or a placebo tablet was taken daily. True fractional Ca absorption (TFCA) was evaluated before and after the trial using stable isotopes: 8 mg 44Ca mixed in 100 g chocolate milk was given after an intravenous injection of 0.75 mg 42Ca. There was no significant difference in baseline TFCA between the study group (60.6 (SD 11.4)%) and the controls (58.2 (SD 9.0)%; P = 0.55). Serum 25-hydroxycholecalciferol levels were comparable between the two groups (P = 0.71). After 6 months, TFCA of the study group (55.6 (SD 12.7)%) was significantly lower than that of the controls (64.3 (SD 10.7)%; P = 0.015). By comparing the individual changes in TFCA after the trial between the two groups there was a non-significant reduction in TFCA (5.03 (SD 12.4)%; P = 0.11, Wilcoxon signed-rank test) in the study group (60.6-55.6%), whereas a significant increase in TFCA (6.17 (SD 7.7)%; P = 0.004, Wilcoxon signed-rank test) was observed in the controls (58.2-64.3%). The differential in TFCA between the two groups after 6 months was significantly different (P = 0.001), and remained significant after adjustment for baseline dietary intakes, weight and height by multiple-regression analysis (P = 0.003). If the mechanism of TFCA from chocolate milk in response to the treatment effects is similar to that from the total diet, then our results suggest that children with adequate vitamin D status can adapt to a change in Ca intake by adjusting the efficiency of TFCA. In corollary, children on habitually-low Ca diets have a higher TFCA than the counterparts with higher Ca diets.

Double-blind, controlled calcium supplementation and bone mineral accretion in children accustomed to a low-calcium diet.

A randomized, double-blind, controlled calcium supplementation trial was conducted for 18 mo to determine its effects on bone acquisition and height increment in 162 7-y-old Chinese children (87 boys and 75 girls) with habitually low calcium intakes (280 mg/d). Distal one-third radial bone mineral content (BMC), area bone density (BMC/bone width), and height were evaluated every 6 mo. Baseline dietary intakes, serum 25-hydroxycholecalciferol, and physical activity were determined. The study group received 300 mg Ca/d as calcium carbonate; control subjects received placebo tablets. After 18 mo the study group had significantly greater gains in BMC (16.5% vs 13.97%; P = 0.02) and BMC/bone width (9.45% vs 6.31%; P = 0.0008) than the control subjects. The findings confirm a positive effect of calcium intake on bone acquisition but no effect on height increment. Whether a higher bone mass attained at age 8-9 y would be maintained and beneficial to future peak bone mass requires longitudinal investigation. Further study is warranted to determine calcium requirements for Chinese children.

Oral calcium treatment in vitamin D-dependent rickets type II.

Vitamin D-dependent rickets type II is a rare hereditary disease that results from target organ resistance to the action of 1,25-dihydroxyvitamin D3. There is a great heterogeneity in the clinical presentation of this condition. The affected patients usually present early in childhood with clinical and biochemical evidence of rickets. Physiological replacement dosage of 1,25-dihydroxyvitamin D3 has no therapeutic effect. Responses to pharmacological doses of vitamin D metabolites or long-term calcium infusion have been variable. A case is reported here of an 8 year old girl, of consanguineous parents with vitamin D-dependent rickets, type II, in whom treatment with high dose oral calcium resulted in marked biochemical and radiological improvement. It is concluded that high dose oral calcium treatment is an effective treatment option for patients with vitamin D-dependent rickets type II.

Vitamin D status of Hong Kong Chinese infants.

Vitamin D deficiency is a common nutritional problem of weaning infants in many parts of the world. Hong Kong infants, who are fed with traditional rice-based weaning foods and live in crowded high rise flats, might be expected to suffer from this nutritional problem. Yet a study of 150 bottle fed infants revealed that the vitamin D intake from fortified milk and cereals was more than half of the recommended amount throughout the first 18 months and that the serum 25-OH vitamin D concentration of the infants at 18 months was normal. The effect of sunlight was also evident.

Traditional Chinese infant supplementary medical foods given by mothers in Hong Kong.

Chinese mothers living in Hong Kong are used to giving their babies special medicinal food to strengthen the infant's internal defences and to restore the body's harmonious state. However since the majority of registered doctors are trained in the Western pharmacological tradition it is difficult for them to comprehend the concepts and idioms of this practice. This paper set out to investigate the frequency and varieties of medicinal foods given to 166 Chinese infants during the first 30 months after birth. One hundred and forty seven babies were given medicinal foods at some stage. The frequency of their administration varied from weekly to once or twice per month. The most popular medicinal food was "Job's tears" and the most widely administered compound herb preparations were milk preparation solution, flower teas and various cool teas. The potential pharmacological effects of these medicinal foods were searched from a Chinese medicines computerized database and found to be principally anti-inflammatory, bacteriostatic, diuretic and appetite stimulant. This study contributed a better appreciation of the popularity of infant supplementary medicinal foods in Hong Kong and the rationale for their use.