Design, Synthesis and Studies on Novel Polymeric Prodrugs of Erlotinib for Colon Drug Delivery.

AIMS: In the present study, polymer-drug conjugates were synthesized based on azo-bond cleavage drug delivery approach for targeting erlotinib as an anticancer drug specifically to the colon for the proficient treatment of colon cancer. BACKGROUND: Colon Cancer (CC) is the third commonly detected tumor worldwide and makes up about 10% of all cases of cancers. Most of the chemotherapeutic drugs available for treating colon cancer are not only toxic to cancerous cells but also to the normal healthy cells. Among the various approaches to get rid of the adverse effects of anticancer agents, prodrugs are one of the most imperative approaches. OBJECTIVE: The objective of the study is to chemically modify the erlotinib drug through azo-bond linkage and suitable spacer which will be finally linked to the polymeric backbone to give the desired polymer linked prodrug. The azo reductase enzyme present in the colon is supposed to cleave the azo-bond specifically and augment the drug release at the colon. METHODS: The synthesized conjugates were characterized by IR and 1H-NMR spectroscopy. The cleavage of aromatic azo-bond resulted in a potential colon-specific liberation of drug from conjugate studied in rat fecal contents. In vitro release profiles of polyphosphazene-linked conjugates of erlotinib have been studied at pH 1.2, pH 6.8 and pH 7.4. The stability study was designed to exhibit that free drug was released proficiently and unmodified from polyphosphazene-erlotinib conjugates having aromatic azo-bond in artificial colon conditions. RESULTS: The synthesized conjugates were demonstrated to be stable in simulated upper gastrointestinal tract conditions. The drug release kinetics shows that all the polymer-drug conjugates of erlotinib follow zero-order release kinetics which indicates that the drug release from the polymeric backbone is independent of its concentration. Kinetic study of conjugates with slope (n) shows the anomalous type of release with an exponent (n) > 0.89 indicating a super case II type of release. CONCLUSION: These studies indicate that polyphosphazene linked drug conjugates of erlotinib could be promising candidates for the site-specific treatment of colon cancer with the least detrimental side-effects.

Synthesis and biological evaluation of 3-tetrazolo steroidal analogs: Novel class of 5α-reductase inhibitors.

In the present study, a series of steroidal tetrazole derivatives of androstane and pregnane have been prepared in which the tetrazole moiety was appended at C-3 and 17a-aza locations. 3-Tetrazolo-3,5-androstadien-17-one (6), 3-tetrazolo-19-nor-3,5-androstadien-17-one (10), 3-tetrazolo-3,5-pregnadien-20-one (14), 17a-substituted 3-tetrazolo-17a-aza-D-homo-3,5-androstadien-17-one (26-31) and 3-(2-acetyltetrazolo)-17a-aza-d-homo-3,5-androstadien-17-one (32) were synthesized from dehydroepiandrosterone acetate (1) through multiple synthetic steps. Some of the synthesized compounds were evaluated for their in vitro 5α-reductase (5AR) inhibitory activity by measuring the conversion of [(3)H] androstenedione in human embryonic kidney (HEK) cells. In vivo 5α-reductase inhibitory activity also showed a significant reduction (p <0.05) in rat prostate weight. The most potent compound 14 showed 5AR-2 inhibition with IC50 being 15.6nM as compared to clinically used drug finasteride (40nM). There was also a significant inhibition of 5AR-1 with IC50 547nM compared to finasteride (453nM).

An overview of phytotherapeutic approaches for the treatment of benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is the noncancerous growth of the prostate gland resulting due to overproliferation of the stromal and glandular elements of the prostate and is associated with lower urinary tract symptoms. Natural products, containing inherently vast structural diversity than synthetic compounds, have been the major resources of bioactive agents and will continue to play as protagonists for discovering new drugs. Phytotherapeutic products have been used traditionally in developing countries while the use of them as complementary alternative medicine is increasing rapidly in developed countries for the management of BPH. Although mono preparations (single plant only) are available, many industries manufacture combination products (plant extracts) in an attempt to provide enhanced efficacy to improve marketability, and to provide their own "unique" product that can be registered, because these products have no patent protection. The mechanism of action of the phytotherapeutic agents is not clearly understood as many in vitro experimental studies have demonstrated diverse spectrum of mechanisms. The main mechanisms of action that has received the greatest attention are anti-inflammatory, 5α-reductase inhibition, and more recently growth factor alteration. The current review covers all such studies and critiques the efficacy and value of such phytotherapeutic products and preparations available for the management of BPH.