Doxorubicin loaded Polymeric Nanoparticulate Delivery System to overcome drug resistance in osteosarcoma

<p>Abstract</p> <p>Background</p> <p>Drug resistance is a primary hindrance for the efficiency of chemotherapy against osteosarcoma. Although chemotherapy has improved the prognosis of osteosarcoma patients dramatically after introduction of neo-adjuvant therapy in the early 1980's, the outcome has since reached plateau at approximately 70% for 5 year survival. The remaining 30% of the patients eventually develop resistance to multiple types of chemotherapy. In order to overcome both the dose-limiting side effects of conventional chemotherapeutic agents and the therapeutic failure incurred from multidrug resistant (MDR) tumor cells, we explored the possibility of loading doxorubicin onto biocompatible, lipid-modified dextran-based polymeric nanoparticles and evaluated the efficacy.</p> <p>Methods</p> <p>Doxorubicin was loaded onto a lipid-modified dextran based polymeric nano-system. The effect of various concentrations of doxorubicin alone or nanoparticle loaded doxorubicin on KHOS, KHOS_R2, U-2OS, and U-2OS_R2cells was analyzed. Effects on drug retention, immunofluorescence, Pgp expression, and induction of apoptosis were also analyzed.</p> <p>Results</p> <p>Dextran nanoparticles loaded with doxorubicin had a curative effect on multidrug resistant osteosarcoma cell lines by increasing the amount of drug accumulation in the nucleus via Pgp independent pathway. Nanoparticles loaded with doxorubicin also showed increased apoptosis in osteosarcoma cells as compared with doxorubicin alone.</p> <p>Conclusion</p> <p>Lipid-modified dextran nanoparticles loaded with doxorubicin showed pronounced anti-proliferative effects against osteosarcoma cell lines. These findings may lead to new treatment options for MDR osteosarcoma.</p

Vitamin K deficiency bleeding in cholestatic infants with alpha-1-antitrypsin deficiency.

Item does not contain fulltextOBJECTIVE: Exclusively breastfed infants with unrecognised cholestatic jaundice are at high risk of a vitamin K deficiency (VKD) bleeding. It is presently unknown whether (the size of) this risk depends on the degree of cholestasis. Since alpha-1-antitrypsin deficiency (A1AD) induces a variable degree of cholestasis, we assessed the risk of VKD bleeding in infants with cholestatic jaundice due to A1AD. PATIENTS AND METHODS: Infants with a ZZ or SZ phenotype born in The Netherlands between January 1991 and December 2006 were identified from the databases of the five Dutch diagnostic centres for alpha-1-antitrypsin phenotyping and/or genotyping. We determined the risk of VKD bleeding upon diagnosis of A1AD in breastfed and formula fed infants and searched for correlations between serum levels of conjugated bilirubin and the risk of bleeding. RESULTS: A total of 40 infants with A1AD were studied. VKD bleeding was noted in 15/20 (75%) of breastfed infants, compared with 0/20 of formula fed infants with A1AD. The relative risk for VKD bleeding in breastfed versus formula fed infants was at least 15.8 (95% CI 2.3 to 108). Conjugated bilirubin levels at diagnosis did not correlate with the risk of VKD bleeding. CONCLUSIONS: The risk of VKD bleeding in breastfed infants with A1AD was high and did not correlate with serum level of conjugated bilirubin at diagnosis. A similar absolute risk was previously reported in breastfed infants with biliary atresia under the same prophylactic regimen. This confirms that-without adequate prophylaxis-the risk of VKD bleeding is uniformly high in exclusively breastfed infants with cholestatic jaundice, irrespective of underlying aetiology

Real life adherence of chronic hepatitis B patients to entecavir treatment

BACKGROUND: Real-life prospective data on adherence to nucleos(t)ide analogues in chronic hepatitis B patients are scarce. AIMS: We investigated adherence to entecavir in relation to virological response. METHODS: In this prospective study, we provided 100 consecutive chronic hepatitis B patients with a medication dispenser that monitored entecavir intake during 16 weeks therapy. Hepatitis B virus (HBV) DNA was measured at baseline and after 16 weeks. Beliefs about medicines were evaluated using a questionnaire. RESULTS: Adherence over 16 weeks averaged 85 ± 17%, with 70% of patients exhibiting good (i.e. ≥ 80%) adherence. Patients with poor (i.e. 20 IU/mL (n=18) and ≤ 20 IU/mL (n=81) averaged 83% and 91% respectively (p=0.19). In multivariate analysis, adherence was not a significant predictor of HBV DNA negativity (adjusted OR 1.02; p=0.34), after adjustment for duration of entecavir treatment (p<0.001) and HBe-status (p=0.001). CONCLUSIONS: 70% of chronic hepatitis B patients exhibited good adherence to entecavir, with younger age and an indifferent attitude being risk factors for poor adherence. Poor adherence was not an independent predictor of virological response

Experimentally guided computational antibody affinity maturation with de novo docking, modelling and rational design.

Antibodies are an important class of therapeutics that have significant clinical impact for the treatment of severe diseases. Computational tools to support antibody drug discovery have been developing at an increasing rate over the last decade and typically rely upon a predetermined co-crystal structure of the antibody bound to the antigen for structural predictions. Here, we show an example of successful in silico affinity maturation of a hybridoma derived antibody, AB1, using just a homology model of the antibody fragment variable region and a protein-protein docking model of the AB1 antibody bound to the antigen, murine CCL20 (muCCL20). In silico affinity maturation, together with alanine scanning, has allowed us to fine-tune the protein-protein docking model to subsequently enable the identification of two single-point mutations that increase the affinity of AB1 for muCCL20. To our knowledge, this is one of the first examples of the use of homology modelling and protein docking for affinity maturation and represents an approach that can be widely deployed