Luteinizing hormone-releasing hormone receptor–targeted deslorelin-docetaxel conjugate enhances efficacy of docetaxel in prostate cancer therapy

Abstract

Docetaxel, a chemotherapeutic agent currently used for improving survival of prostate cancer patients, suffers from low therapeutic index. The objective of this study was to prepare a new docetaxel derivative conjugated to deslorelin, a luteinizing hormone-releasing hormone (LHRH) superagonist, and to determine whether it enhances docetaxel potency in vitro and in vivo. Because docetaxel is not amenable for conjugation with peptides, we introduced a -COOH group in docetaxel, forming docetaxel-hemiglutarate, and subsequently conjugated this to serine in deslorelin, forming deslorelin-docetaxel. Fouriertransform IR, 1 H-nuclear magnetic resonance, and liquid chromatography-mass spectrometry analyses confirmed deslorelin-docetaxel formation. Antiproliferative efficacy in LNCaP and PC-3 cell lines over 24, 48, and 72 hours exhibited the order deslorelin-docetaxel > docetaxel, whereas deslorelin alone had no effect, with deslorelindocetaxel potency being 15-fold greater than docetaxel at 72 h. Further, cells pretreated with antisense oligonucleotide against LHRH receptor exhibited decreased deslorelin-docetaxel efficacy, without any change in docetaxel efficacy. Thus, deslorelin-docetaxel efficacy is likely mediated via LHRH receptor. Cell cycle analysis showed that docetaxel treatment led to arrest in G 2 -M phase, whereas deslorelin-docetaxel treatment allowed greater progression to apoptosis in both cell lines, with deslorelin-docetaxel exerting 5-fold greater apoptosis compared with docetaxel in prostate cancer cell lines. Antitumor efficacy studies in PC-3 prostate xenograft-bearing mice indicated the efficacy order deslorelin-docetaxel > docetaxel ≫ deslorelin > PBS, with deslorelin-docetaxel exerting 5.5-fold greater tumor growth inhibition than docetaxel alone. Thus, deslorelin-docetaxel prepared in this study retains pharmacologic effects of both docetaxel and deslorelin while enhancing the antiproliferative, apoptotic, and antitumor efficacy of docetaxel by several folds in prostate cancer therapy.

Synthesis, characterization, and in vivo efficacy evaluation of PGG–docetaxel conjugate for potential cancer chemotherapy

“…18 In addition to the abovementioned approaches, DTX conjugation is another strategy to eliminate the side effects of Tween 80 and ethanol. Some examples of DTX conjugates include luteinizing hormone-releasing hormone receptor peptide, 19 linoleic, 20 methoxy polyethylene glycol, 16 albumin protein, 21 low molecular weight chitosan, 22 and N-(2-hydroxypropyl)-methacrylamide copolymers. 23 Similar to the non-conjugated formulations of DTX discussed above, the development of these DTX conjugates is also in the early stages.…”

Targeted Drug and Gene Delivery Systems for Lung Cancer Therapy

“…The LHRH-R, a member of the GPCR super family is expressed in various tissues including normal lung (10) and overexpressed on lung cancers cells (11, 12). We have established that deslorelin can be conjugated to docetaxel at the hydroxyl (-OH) group in the serine moiety (amino acid 4) via a glutarate linker (13). One objective of this study was to determine whether the in-vitro and in-vivo efficacy of docetaxel can be enhanced by its conjugation to deslorelin in a lung cancer model.…”

Prostate cancer relevant antigens and enzymes for targeted drug delivery

“…195 In addition, deslorelin-docetaxel analogues were also developed and showed 15-fold higher potency than docetaxel alone at 72 h in LNCaP and androgen-independent PC-3 cell lines. 196 …”