Formulation, Quality Control and Safety Issues of Nanocarriers Used for Cancer Treatment.

Cancer is becoming a leading cause of death in the last years. Although we have seen great advances, most human cancers remain incurable because many patients either do not respond or relapse to treatment. Several lines of research are disclosing new therapeutic targets which lead to new active drugs. However, there are still unsolved problems related to stabilization of the pharmaceutical ingredient in aqueous and biological media, pharmacokinetic and pharmacodynamic profiles and cellular uptake to name just a few. In this context, nanotechnology with the emerging tools of nanoengineering offers many possibilities to guide the design of new products with improved safety and efficacy. The presence of several reacting groups and the sensitivity of their properties to small changes in composition make nanocarriers tunable not only to modify their stability in a particular environment but also to respond to changes in biological situations in the right place and time frame. This review summarizes the main preparation methods and formulation strategies of nano and microcarriers designed for drug delivery applications for cancer treatment and will attempt to give a glimpse on how their structure, shape, physico-chemical properties and chemical composition may affect their overall stability and interactions with biological systems. We will also cover aspects of nanoengineering that are opening new opportunities for the development of more effective nanomedicines, emphasizing on the challenges that have to be kept in mind when dealing with biological activities of nanocarriers that depend not only on their chemical composition but also on those of the structures formed by them and by their interactions with biological systems. From this, a very important issue that emerges is that nanocarriers frequently display an intrinsic bioactivity (i.e.: immunomodulatory). Therefore, it should be stressed that nanocarriers cannot be considered as inert, biocompatible excipients. Furthermore, their biological activity will mostly depend on the physical and chemical properties of the structures of the nanoparticles that are presented to living systems. As an approach to the rational design of new pharmaceutical products, nanoengineering is providing new tools for the precise control of the properties of nanocarriers for cancer treatment.

Assessment of urine and fecal testosterone metabolite excretion in Chinchilla lanigera males.

Endemic chinchilla (Chinchilla spp.) populations are nearly extinct in the wild (South America). In captive animals (Chinchilla lanigera and C. brevicaudata), reproduction is characterized by poor fertility and limited by seasonal breeding patterns. Techniques applied for studying male reproductive physiology in these species are often invasive and stressful (i.e. repeated blood sampling for sexual steroids analysis). To evaluate endocrine testicular function, the present experiments were designed to (a) determine the main route of testosterone excretion (14C-testosterone infusion in four males); (b) validate urine and fecal testosterone metabolite measurements (HPLC was used to separate metabolites and immunoreactivity was assessed in all metabolites using a commercial testosterone radioimmunoassay, and parallelism, accuracy and precision tests were conducted to validate the immunoassay); and (c) investigate the biological relevance of the techniques applied (quantification of testosterone metabolite excretion into urine and feces from five males injected with hCG and comparison between 10 males and 10 females). Radiolabelled metabolites of 14C-testosterone were excreted, 84.7+/-4.2 % in urine and 15.2+/-3.9 % in feces. A total of 82.7+/-4.2% of urinary and 45.7+/-13.6% of fecal radioactivity was excreted over the first 24 h period post-infusion (metabolite concentration peaked at 8.2+/-2.5 h and 22.0+/-7.0 h, respectively). Several urinary and fecal androgen metabolites were separated by HPLC but only fecal metabolites were associated with native testosterone; however, there was immunoreactivity in more than one metabolite derived from 14C-testosterone. After hCG administration, an increase in androgen metabolite excretion was observed (p<0.05). Males excreted greater amounts daily of urinary androgen metabolites as compared with females (p<0.05); this difference was not evident in feces. Results of the present study indicate that the procedure used is a reliable and non-invasive method to repeatedly monitor variations in testicular endocrine activity in this species. It can be a useful tool that would help ensure the survival of the wild populations as well as to provide the basis for a more efficient use by the fur industry.

A non-invasive method for assessing adrenal activity in the chinchilla (Chinchilla lanigera).

The Chinchilla is a rodent that was once abundant in the central Andes of South America. Excessive hunting for fur greatly reduced its distribution at the beginning of the twentieth century, and today Chinchilla species are nearly extinct in the wild. Although protected, wild populations of chinchilla are still declining. In general, this species has received little research attention and its biology is poorly understood. Improvements in captive breeding, husbandry, and genetic management are needed to ensure the conservation of the species. In this study, a noninvasive corticosteroid hormone monitoring technique was validated for use in Chinchilla lanigera. Two male domestic chinchillas were administered 3H-corticosterone (i.m.) to determine the time course and relative proportion of urinary and fecal steroid metabolites. Most radioactivity was detected in urine and feces 5-10 and approximately 30 h post-isotope administration, respectively. Corticosteroid immunoreactivity was assessed by corticosterone radioimmunoassay (RIA) and cortisol enzyme immunoassay (EIA). High-pressure liquid chromatography (HPLC) separation of corticosteroid metabolites in unprocessed urine revealed the presence of highly polar corticosteroid metabolites, but after enzymatic hydrolysis and diethyl ether extraction, most immunoreactivity co-eluted with unconjugated cortisol. A 'cause-and-effect' relationship between the administration of exogenous adrenocorticotrophic hormone (ACTH), and the appearance of increased urinary corticosteroid metabolites demonstrated the physiological relevance of these measures for evaluating adrenal status in male chinchillas. From a conservation perspective, these methods can aid in situ and ex situ initiatives designed to evaluate how environmental conditions and management strategies affect overall animal health, well-being and reproduction.

Validation of a chiral HPLC assay for (R)-salbutamol sulfate.

A fast, reliable and specific method for the screening, confirmation, determination and quantitation of salbutamol enantiomers was developed and validated. The described procedure includes a single robust chiral HPLC determination employing a Teicoplanin stationary phase. The method was evaluated for specificity, robustness, linearity, precision and accuracy. Under the chromatographic conditions of the method, known impurities were separated from the active principle.