Novel cathepsin B-sensitive paclitaxel conjugate: Higher water solubility, better efficacy and lower toxicity.

In order to realize the targeted delivery of paclitaxel (PTX) to tumor through an environment-sensitive mechanism, increase its solubility in water and reformulate without toxic excipients, a novel PTX conjugate, PEG-VC-PABC-PTX was designed and synthesized in this study, using p-aminobenzylcarbonyl (PABC), a spacer, and valine-citrulline (VC), a substrate of cathepsin B (C(B)), to link polyethylene glycol (PEG) and PTX. Pegylated PTX (PEG-PTX) which was synthesized and Taxol formulation were prepared as controls. The conjugates were purified and characterized by melting points, (1)H-NMR, ESI-MS or MALDI-TOF-MS. The two conjugates were similar in particle size, water solubility and their effects on MCF-7 cell line in vitro, and both of them induced no obvious toxicity in vivo. The release of PTX from PEG-PTX was faster due to its ester bond, while PEG-VC-PABC-PTX was proved to be C(B)-sensitive in terms of PTX release and its effect on cell cycle. Additionally, PEG-VC-PABC-PTX exhibited significant effects of antitumor, anti-angiogenesis and anti-proliferation in vivo, while the control conjugate was almost inefficacious at the same in vivo test. On the other hand, PTX conjugates demonstrated a thousand-time or more improvement in water solubility compared to PTX, suggesting a very easy way in the preparation and use of its injection. Without involvement of Cremophore EL and ethanol, the PTX conjugate will guarantee less adverse effects as frequently reported for Taxol formulation. Taxol formulation had a higher cytoxicity in vitro than PEG-VC-PABC-PTX likely because of toxic additives. Importantly, the C(B)-sensitive conjugate indicated a similar in vivo efficacy with the Taxol control, but much lower in vivo toxicity at the same doses evidenced by body weight, animal status, liver toxicity and blood count. Moreover, at the tolerant dose, this novel conjugate exhibited significantly better antitumor effect than that of Taxol formulation. In general, the PEG-VC-PABC-PTX conjugate designed in this study demonstrated significant advantages in terms of high water solubility, no toxic surfactant or organic solvent, tumor environment-sensitivity and high therapeutic index.

Association between subclinical hypothyroidism and proliferative diabetic retinopathy in type 2 diabetic patients: a case-control study.

Subclinical hypothyroidism (SCH) is defined as an asymptomatic state characterized by normal serum levels of free thyroxine and elevated serum concentrations of thyrotropin (> 4.0 µU/ml). The association between SCH and type 2 diabetes has been well established. Proliferative diabetic retinopathy (PDR) that is characterized by neovascularization is a leading cause of visual loss in adults worldwide. However, whether SCH is related to PDR has not been studied. This study thus aimed to evaluate the relationship between SCH and PDR in type 2 diabetes. A total of 371 type 2 diabetic subjects were enrolled: 187 subjects with PDR and 184 subjects without diabetic retinopathy (with HbA1c above 6.5% and at least 10 years of diabetes duration). Subjects with PDR had higher blood pressure, higher serum levels of total cholesterol, low-density lipoprotein cholesterol and thyrotropin, and higher urinary albumin excretion rate. Of the 371 diabetics, 83 subjects (22.4%) were diagnosed as SCH (male 12.1% and female 29.9%). The prevalence of SCH in the PDR group (51/187, 27.3%) was higher than that in the subjects without diabetic retinopathy (32/184, 17.4%). Logistic regression analysis showed that after adjusting for compounding variables, SCH was independently related with PDR (p = 0.032, adjusted OR = 2.485). These results indicate that type 2 diabetic patients with PDR are at an increased risk of SCH. A routine screening for thyroid function may thus be considered advisable in PDR subjects. This may be helpful in investigating new strategies preventing or treating PDR in clinical practice.

Angiotensin-converting enzyme gene polymorphism is associated with type 2 diabetes: a meta-analysis.

The association of angiotensin-converting enzyme gene polymorphism with type 2 diabetes was investigated in many studies with conflicting results. To clarify this conflict, we performed a meta-analysis on recent previous reports on ACE gene polymorphism and its correlation to type 2 diabetes. A total of 15,166 subjects from 24 studies were included in this meta-analysis. Summary odds ratios (ORs) were estimated. Potential sources of heterogeneity and bias were explored. The D variant was associated with a 14% increased risk of T2D relative to the I variant (OR 1.14; 95% CI: 1.04-1.24). In subgroup analysis, Caucasian and East Asians showed significant association. No association was found in the Turkish groups. No publication bias was observed in this meta-analysis by using the Egger method (tau = 1.63, P = 0.12), as well as the Begg's test (z = 1.66, P = 0.10). Cumulative meta-analysis for the allelic contrast showed a trend of association as information accumulated. These data suggested that the variant of ACE I/D had a moderate positive association with type 2 diabetes.