Integrin-Mediated Targeted Cancer Therapy Using c(RGDyK)-Based Conjugates of Gemcitabine

Abstract

Metrics & MoreArticle Recommendations * sı Supporting Information 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 α v β 3 , 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 α v β 3 . 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.

Synthesis and Anti-Angiogenic Activity of Novel c(RGDyK) Peptide-Based JH-VII-139-1 Conjugates

“…The metastatic breast cancer cell lines MDA-MB-435 [ 44 , 45 ] and MCF-7 [ 46 , 47 ], as well as HeLa cells [ 48 ], express high levels of α V β 3 integrins. On the other hand, K562 cells express very low levels of α V β 3 integrins [ 22 ].…”

“…In previous research efforts by our group, the cyclic pentapeptide c(RGDyK), which is a potent integrin α v β 3 ligand, was employed for the targeted delivery of various anticancer drugs and bioactive molecules such as gemcitabine [ 22 ], the triterpenoids cucurbitacins [ 23 ], and platinum complexes [ 24 ]. c(RGDyK) peptide potently binds α v β 3 integrins (IC 50 = 3.8 ± 0.42 nM) and, less potently, α v β 5 (IC 50 = 503 ± 55 nM), α v β 6 (IC 50 = 86 ± 7 nM), and α 5 β 1 integrins (IC 50 = 236 ± 45 nM) [ 25 ].…”

Phase-transfer catalyzed Michael/ammonolysis cascade reactions of enaminones and olefinic azlactones: a new approach to structurally diverse quinoline-2,5-diones

“…The catalysts 5a–d were able to promote the reaction when the temperature was raised to 40 °C, but the product 3a was obtained in low yields and with poor enantioselectivities (Table 4). Since optically pure compounds are of vital importance in drug discovery, 23 the development of an elegant approach based on asymmetric phase-transfer catalysis for the formation of enantiopure quinoline-2,5-diones merits further meticulous study.…”

Nintedanib-αVβ6 Integrin Ligand Conjugates Reduce TGFβ-Induced EMT in Human Non-Small Cell Lung Cancer

“…Milano, Italy) (cytofluorimetry buffer). After blocking, cells were incubated with 1 μg/20 μL buffer of anti-αvβ6 (Bioss bs 5791R, Woburn, MA, USA, as suggested dilution 1:20) (anti-human/mouse/rat) for 1 h at 4 °C, followed by 1 h incubation with FITC-conjugated anti-rabbit (24549933) secondary antibodies at a 1 μL/50 μL dilution [ 57 ] from Immunotools (Friesoythe, Germany), or with 5 μL (1 μg) of anti-αvβ3-FITC conjugated antibody in 20 μL buffer (Thermofisher, Waltham, MA USA 11-0519-42, as suggested 5 μL/test). After extensive washes using cytofluorimetric buffer, cells were analyzed using a BD FACSCanto™ flow cytometry system (BD Bioscience, Eysins, Switzerland).…”