ABSTRACT
c(RGDyK)-based conjugates of gemcitabine (GEM) with the carbonate and carbamate linkages in the 6-OH group of GEM were synthesized for the targeted delivery of GEM to integrin αvß3, overexpressing cancer cells to increase the stability as well as the tumor delivery of GEM and minimize common side effects associated with GEM treatment. Competitive cell uptake experiments demonstrated that conjugate TC113 could be internalized by A549 cells through integrin αvß3. Among the synthesized conjugates, TC113 bearing the carbamate linker was stable in human plasma and was further assessed in an in vivo pharmacokinetic study. TC113 appeared to be relatively stable, releasing GEM slowly into blood, while it showed potent antiproliferative properties against WM266.4 and A549 cells. The encouraging data presented in this study with respect to TC113 provide a promising keystone for further investigation of this GEM conjugate with potential future clinical applications.
Subject(s)
Deoxycytidine/analogs & derivatives , Integrins/chemistry , Lung Neoplasms/drug therapy , Peptides, Cyclic/chemistry , A549 Cells , Animals , Antimetabolites, Antineoplastic/chemistry , Antimetabolites, Antineoplastic/pharmacology , Cell Proliferation , Deoxycytidine/chemistry , Deoxycytidine/pharmacology , Humans , Lung Neoplasms/pathology , Mice , Mice, Inbred C57BL , GemcitabineABSTRACT
Cucurbitacins (CUCUs) are triterpenoids known to display potent cytotoxic effects; however, their clinical application is limited due to poor pharmacokinetics and systemic toxicity. This work focuses on the development of c(RGDyK)-CUCU conjugates for the selective delivery of CUCUs to integrin-overexpressing cancer cells. The activity of the conjugates against various cancer cells was studied. They exhibited a mild cytostatic effect to six cancer cell lines and a cytotoxic effect against integrin-overexpressing MCF-7 and A549 cells. Their chemical and metabolic stability was extensively studied using LC-MS analysis. The conjugates maintained high affinity for αvß3 integrin receptors. c(RGDyK) conjugation via a PEG linker was beneficial for CUCU-D and the resulting conjugate was approximately three-times more active than the free CUCU-D in MCF7 cells.
Subject(s)
Antineoplastic Agents/pharmacology , Cucurbitacins/pharmacology , Oligopeptides/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Adhesion/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Cucurbitacins/chemistry , Drug Screening Assays, Antitumor , Humans , Molecular Conformation , Oligopeptides/chemistryABSTRACT
There is a growing interest for the discovery of new cancer-targeted delivery systems for drug delivery and diagnosis. A synopsis of the bibliographic data will be presented on bombesin, neurotensin, octreotide, Arg-Gly-Asp, luteinizing hormone-releasing hormone and other peptides. Many of them have reached the clinics for therapeutic or diagnostic purposes, and have been utilized as carriers of known cytotoxic agents such as doxorubicin, paclitaxel, cisplatin, methotrexate or dyes and radioisotopes. In our article, recent advances in the development of peptides as carriers of cytotoxic drugs or radiometals will be analyzed.
Subject(s)
Antineoplastic Agents/administration & dosage , Drug Carriers/metabolism , Drug Delivery Systems/methods , Neoplasms/drug therapy , Peptides/metabolism , Animals , Antineoplastic Agents/therapeutic use , Drug Carriers/chemistry , ErbB Receptors/metabolism , Erythropoietin/metabolism , Humans , Integrins/metabolism , Neoplasms/metabolism , Peptides/chemistry , Receptors, Eph Family/metabolism , Receptors, LHRH/metabolism , Receptors, Neurotensin/metabolism , Receptors, Somatostatin/metabolismABSTRACT
AIM: Alkylating agents and antimetabolites are cytotoxic drugs commonly used in cancer treatment. These medications are often associated with serious side effects on normal tissues and organs. METHODOLOGY: To improve the pharmacological profile of the alkylating agent POPAM and the antimetabolite 5-fluorouracil, novel integrin-targeted delivery systems based on c(RGDyK) were successfully synthesized. The new conjugates were tested in vitro against different cancer cells such as PC3, SKOV3, A549, MCF7 and MBA-MB-321. RESULTS & CONCLUSION: The c(RGDyK) conjugates of POPAM demonstrated better inhibitory effects and selectivity compared with c(RGDyK) and POPAM. The c(RGDyK) conjugates of 5-FUA demonstrated diverse inhibitory effects compared with c(RGDyK) and 5-FUA related to the levels of integrin expression, the conjugate stability and sensitivity of cancer cells to 5-FUA.
Subject(s)
Aniline Mustard/analogs & derivatives , Antineoplastic Agents/chemistry , Fluorouracil/chemistry , Integrins/metabolism , Peptides, Cyclic/chemistry , Propionates/chemistry , A549 Cells , Amino Acid Sequence , Aniline Mustard/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Proliferation/drug effects , Chromatography, High Pressure Liquid , Fluorouracil/analysis , Fluorouracil/pharmacology , Humans , Integrins/antagonists & inhibitors , MCF-7 Cells , Magnetic Resonance Spectroscopy , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Oligopeptides/chemistryABSTRACT
Conjugates of cytotoxic agents with RGD peptides (Arg-Gly-Asp) addressed to ανß3, α5ß1 and ανß6 integrin receptors overexpressed by cancer cells, have recently gained attention as potential selective anticancer chemotherapeutics. In this review, the design and the development of RGD conjugates coupled to different small molecules including known cytotoxic drugs and natural products will be discussed.
