Overcoming multidrug resistance using folate receptor-targeted and pH-responsive polymeric nanogels containing covalently entrapped doxorubicin.

Multidrug resistance (MDR) contributes to failure of chemotherapy. We here show that biodegradable polymeric nanogels are able to overcome MDR via folic acid targeting. The nanogels are based on hydroxyethyl methacrylamide-oligoglycolates-derivatized poly(hydroxyethyl methacrylamide-co-N-(2-azidoethyl)methacrylamide) (p(HEMAm-co-AzEMAm)-Gly-HEMAm), covalently loaded with the chemotherapeutic drug doxorubicin (DOX) and subsequently decorated with a folic acid-PEG conjugate via copper-free click chemistry. pH-Responsive drug release is achieved via the acid-labile hydrazone bond between DOX and the methacrylamide polymeric network. Cellular uptake and cytotoxicity analyses in folate receptor-positive B16F10 melanoma versus folate receptor-negative A549 lung carcinoma cells confirmed specific uptake of the targeted nanogels. Confocal microscopy demonstrated efficient internalization, lysosomal trafficking, drug release and nuclear localization of DOX. We also show that DOX resistance in 4T1 breast cancer cells results in upregulation of the folate receptor, and that folic acid targeted nanogels can be employed to bypass drug efflux pumps, resulting in highly efficient killing of resistant cancer cells. In conclusion, folic acid functionalized nanogels with pH-controlled drug release seem to hold significant potential for treating multidrug resistant malignancies.

Serum estradiol/free testosterone ratio can be important predictor for varicose vein recurrence in men.

AIM: Recurrent varicose veins are a frustration for both the patient and the surgeon. More investigation of the exact diagnosis, proper practice, and causes for the recurrence of varicose veins is needed. METHODS: We investigated a total number of 187 patients in a five year period with an estradiol-2/free testosterone (E2/fT) ratio relationship on recurrent varicose veins in men between the ages of 20-50. Fifity years was the maximum age due to the age dependent sex steroid hormone regression that occurs after this age, which may interefere with the assessment. Fifty three men with an elevated E2/fT ratio (group A), and 143 men with no endocrinologic problems (group B) were enrolled in the study and had surgery for varicose veins. After 5 years follow up (mean 3 years), Group A (N.=29) and group B (N.=43) had recurrent varicose veins by clinical and radiologic findings. Venous blood samples were driven from all patients of both groups in the morning to detect the levels of serum E2 and fT levels. Patient history of surgery for varicose veins, physical examination, color duplex ultrasound of both limbs, and classification of CEAP were performed in both groups. RESULTS: The serum E2/fT ratio was significantly higher in Group A (5.21 ± 0.56) compared to group B (2.54±0.27) in the recurrent varicose vein groups (p ≤ 0.05). Moreover, there was a high correlation between serum E2/fT ratio and the CEAP clinical classification in group A (5) compared to group B (2) (P≤0.05). Also, recurrence rate was higher in group A (54%) compared to group B (32%)(P≤0.05). CONCLUSION: Elevated serum E2/fT ratio is a precipitating factor for recurrent varicose veins in male patients.