Film/contact loading method improves the encapsulated amount of triazene anticancer compounds in polymeric micelles.

The development of organic solvent-free methods for the encapsulation of hydrophobic molecules is necessary for advances in micelle-mediated drug delivery. In this study we investigated the film/contact approach in which the use of organic solvents is limited to the preparation of a dry film before encapsulation. Unloaded micelles of five structurally related block copolymers were placed in contact with thin homogeneous films of two hydrophobic triazene anticancer compounds (1-(4-amidophenyl)-3-(4-acetylphenyl)triazene (1) and corresponding triazenido complex with triphenylphosphanegold(I) fragment (2)). The micelle surface becomes saturated with the drug, which eventually penetrates as a front into the core. Because the drug interacts with both the shell and the core microenvironments of micelle during the process, the maximum loading capacities were very sensitive to block copolymer micelle composition, ranging from 2.2 to 20.4% (wt./wt. of polymer). We conclude that micelles with poly[2-(diisopropylamino)ethyl methacrylate] (PDPA) cores are the best option for the encapsulation of triazene compounds because i) they are prepared in absence of organic phase; ii) the drug concentration in the particles is high enough for a therapeutic effect and iii) the responsiveness properties of PDPA is appropriate for practical applications in pH-triggered drug release systems.

In vivo and in vitro effect of novel 4,16-pregnadiene-6,20-dione derivatives, as 5alpha-reductase inhibitors.

In this study, we report the synthesis and biological evaluation of several new 3-substituted pregna-4,16-diene-6,20-dione derivatives (11a-11d). These compounds were prepared from the commercially available 16-dehydropregnenolone acetate. The biological effect of these steroids was demonstrated in in vivo and in vitro experiments. In the in vivo experiments, we measured the activity of the 11a-11d on the weight of the prostate gland of gonadectomized hamsters treated with testosterone plus finasteride or with the new steroids. For the studies in vitro, we determined the IC50 values by measuring the steroid concentration that inhibits 50% of the activity of 5alpha-reductase present in human prostate. In order to study the mechanism of action of 11a-11d, we also determined the capacity of these steroids to bind to the androgen receptor (AR) present in the rat prostate cytosol using labeled mibolerone as a tracer. The results from this work indicated that compounds 11a-11d significantly decreased the weight of the prostate as compared to testosterone treated animals and this reduction of the weight of the prostate was comparable to that produced by the finasteride. On the other hand 11a-11d exhibited a high inhibitory activity for the human 5alpha-reductase enzyme with IC50 values of 1.4 x 10(-8), 1.8 x 10(-9), 1.0 x 10(-8) and 4 x 10(-5) respectively. However the IC50 value of 11a (1.8 x 10(-9)) was the only one lower than that of finasteride (8.5 x 10(-9)). Nevertheless this compound did not show a higher potency in vivo as compared to that of compounds 11b-11d. The competition analysis for the androgen receptor indicated that the IC50 value of non-labeled mibolerone used in this experiment was 1nM, whereas steroids 10, 11a-11d did not inhibit the labeled mibolerone binding to the androgen receptor. On the other hand, steroid 10 did not show any activities in vitro or in vivo, and for this reason these steroidal derivatives (11a-11d) cannot be considered as prodrugs of compound 10. In conclusion, the compounds containing chlorine 11a, bromine 11b, iodine 11c atoms, and 11d (without any substituent in the ester moiety) at C-3 produce a significant decrease of the prostate weight in castrated animals treated with T and inhibits the activity of the 5alpha-reductase. Apparently the presence of the halogen atoms in compounds 11a-11c enhances the inhibitory activity for the 5alpha-reductase enzyme.