Cancer is the second leading cause of death affecting nearly one in two people, and the appearance of new cases is projected to rise by >70% by 2030. To effectively combat the menace of cancer, a variety of strategies have been exploited. Among them, the development of peptide–drug conjugates (PDCs) is considered as an inextricable part of this armamentarium and is continuously explored as a viable approach to target malignant tumors. The general architecture of PDCs consists of three building blocks: the tumor-homing peptide, the cytotoxic agent and the biodegradable connecting linker. The aim of the current review is to provide a spherical perspective on the basic principles governing PDCs, as also the methodology to construct them. We aim to offer basic and integral knowledge on the rational design towards the construction of PDCs through analyzing each building block, as also to highlight the overall progress of this rapidly growing field. Therefore, we focus on several intriguing examples from the recent literature, including important PDCs that have progressed to phase III clinical trials. Last, we address possible difficulties that may emerge during the synthesis of PDCs, as also report ways to overcome them.

https://www.beilstein-journals.org/bjoc/content/pdf/1860-5397-14-80.pdf

On the design principles of peptide-drug conjugates for targeted drug delivery to the malignant tumor site.

Bioconjugates with receptor-mediated tumor-targeting functions and carrying cytotoxic agents should enable the specific delivery of chemotherapeutics to malignant tissues, thus increasing their local efficacy while limiting the peripheral toxicity. In the present study, gonadotropin-releasing hormone III (GnRH-III; Glp-His-Trp-Ser-His-Asp-Trp-Lys-Pro-Gly-NH2) was employed as a targeting moiety to which daunorubicin was attached via oxime bond, either directly or by insertion of a GFLG or YRRL tetrapeptide spacer. The in vitro antitumor activity of the bioconjugates was determined on MCF-7 human breast and HT-29 human colon cancer cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Their degradation/stability (1) in human serum, (2) in the presence of cathepsin B and (3) in rat liver lysosomal homogenate was analyzed by liquid chromatography in combination with mass spectrometry. The results show that (1) all synthesized bioconjugates have in vitro antitumor effect, (2) they are stable in human serum at least for 24 h, except for the compound containing an YRRL spacer and (3) they are hydrolyzed by cathepsin B and in the lysosomal homogenate. To investigate the relationship between the in vitro antitumor activity and the structure of the bioconjugates, the smallest metabolites produced in the lysosomal homogenate were synthesized and their binding to DNA was assessed by fluorescence spectroscopy. Our data indicate that the incorporation of a peptide spacer in the structure of oxime bond-linked daunorubicin–GnRH-III bioconjugates is not required for their antitumor activity. Moreover, the antitumor activity is influenced by the structure of the metabolites (daunorubicin–amino acid derivatives) and their DNA-binding properties.

/pdf/in-vitro-degradation-and-antitumor-activity-of-oxime-bond-u001436i8b.pdf

In vitro degradation and antitumor activity of oxime bond-linked daunorubicin–GnRH-III bioconjugates and DNA-binding properties of daunorubicin–amino acid metabolites

The invention relates to an drug delivery device and a method for delivering multiple drugs over a prolonged period of time. The drug delivery device has two or more unitary segments comprising a drug-permeable polymeric substance, wherein at least one of the segments further comprises a pharmaceutically active agent. The invention also relates to a method for the treatment of a benign ovarian secretory disorder in a female mammal, a method of contraception, and a method of relieving the symptoms associated with menopausal, perimenopausal and post-menopausal periods in a woman.

Methods and devices for the sustained release of multiple drugs

Gonadotropin-releasing hormone receptors as molecular therapeutic targets in prostate cancer: Current options and emerging strategies

The invention includes a method for harvesting a polypeptide produced by a host cell, wherein the polypeptide has not undergone intra-cellular post-translational modification, such as dehydration of a serine or a threonine, and/or thioether bridge formation. The invention also includes a method for producing thioether containing peptides and dehydroalanine/dehydrobutyrine-containing peptides, wherein extracellularly thioether rings may be formed.

Export and modification of (poly)peptides in the lantibiotic way

Following the observation that the activity of gonadotropin-releasing hormone III (GnRH-III) in the suppression of growth of MDA-MB-231 and MCF-7 breast cancer cells surpasses that of GnRH and other analogs thereof, analogs of GnRH-III were synthesized to investigate the structural basis for the improved antitumor activity. Compounds synthesized include analogs with changes in the central sequence in which GnRH-III differs from GnRH and in the C- and N-terminal regions. The results indicate that a salt bridge between Asp6 and Lys8 stabilizes the active conformation of GnRH-III and show the importance of the Trp7. Replacement of the C-terminal Gly-NH2 with d-Ala-NH2 was not well tolerated, but replacement with ethylamide was. Replacement of pGlu1 with Ac-d-Trp appears to have a significantly deleterious effect on a unique conformation of GnRH-III which is responsible for its binding to the receptors on cancer cell lines and the resultant antitumor activity.

Synthesis of gonadotropin-releasing hormone III analogs. Structure-antitumor activity relationships.

The present invention provides pharmacologically active compounds of formula (I). The compounds are GnRH analogues according to the instant invention formulas. Furthermore the invention provides pharmaceutical compositions with the compounds according to the invention as their active ingredients wherein the compositions have an antitumor effect.

NOVEL GnRH ANALOGUES WITH ANTITUMOUR EFFECTS AND PHARMACEUTICAL COMPOSITIONS THEREOF

The present invention provides a novel pharmaceutical composition for the treatment of breast cancer. Also provided are various methods of treating breast cancer.

Anti-tumor effects of GnRH-III

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Synthesis of gonadotropin-releasing hormone III analogs. Structure-antitumor activity relationships.

NOVEL GnRH ANALOGUES WITH ANTITUMOUR EFFECTS AND PHARMACEUTICAL COMPOSITIONS THEREOF

Anti-tumor effects of GnRH-III