Development of potent CPP6–gemcitabine conjugates against human prostate cancer cell line (PC-3)

Correia, Cristiana; Xavier, Cristina P.R.; Duarte, Diana; Ferreira, Abigail; Moreira, Sara; Vasconcelos, M. Helena; Vale, Nuno

doi:10.1039/c9md00489k

Cited by 12 publications

(14 citation statements)

References 38 publications

(47 reference statements)

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“…There have been many efforts to improve gemcitabine clinical efficacy and numerous derivatives and prodrugs have been designed to alter some of the unfavorable physicochemical properties of gemcitabine and ideally improve its oral bioavailability [4]. Our research group has previously developed gemcitabine conjugates with cell-penetrating peptides (CPPs) to facilitate intracellular delivery of this drug [5][6]. In three of these new prodrugs, a cell-penetrating hexapeptide (CPP6) was covalently conjugated to the aniline moiety of gemcitabine through suitable bio-/chemoreversible bonds.…”

Section: Introductionmentioning

confidence: 99%

Permeability evaluation of gemcitabine-CPP6 conjugates in Caco-2 cells

et al. 2020

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Cancer is one of the most alarming diseases due to its high mortality and still increasing incidence rate. Currently available treatments for this condition present several shortcomings and new options are continuously being developed and evaluated, aiming at increasing the overall treatment efficiency and reducing associated adverse side effects. Gemcitabine has proven activity and is used in chemotherapy. However, its therapeutic efficiency is limited by its low bioavailability as a result of rapid enzymatic inactivation. Additionally, tumor cells often develop drug resistance after initial tumor regression related to transporter deficiency. We have previously developed three gemcitabine conjugates with cell-penetrating hexapeptides (CPP6) to facilitate intracellular delivery of this drug while also preventing enzymatic deamination. The bioactivity of these new prodrugs was evaluated in different cell lines and showed promising results. Here, we assessed the absorption and permeability across Caco-2 monolayers of these conjugates in comparison with gemcitabine and the respective isolated cell-penetrating peptides (CPPs). CPP6-2 (KLPVMW) and respective Gem-CPP6-2 conjugate showed the highest permeability in Caco-2 cells.

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Section: Introductionmentioning

confidence: 99%

Permeability evaluation of gemcitabine-CPP6 conjugates in Caco-2 cells

et al. 2020

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“…Moreover, the three new conjugates of gemcitabine with CPP6 presented more potent cell growth inhibitory activity in MCF-7 and PC-3 cells (IC 50 < 7 nM and IC 50 ≤ 15 nM, respectively) than the reference drugs, tamoxifen (IC 50 = 20 nM for MCF-7 and IC 50 > 1000 nM for PC-3 cells) or metformin (IC 50 = 9.9 nM for MCF-7 and IC 50 = 189 nM for PC-3 cells) with the exception of the dFdC-C2-CPP6-2 conjugate for the PC-3 cell line (IC 50 > 1000 nM). In addition, during this study the authors confirmed that in BxPC3 cells the dFdC-CPP6 conjugates are transported preferentially by hENT-1 transporter, and that once in the cytoplasm, dFdC-CPP6 conjugates may undergo sequential phosphorylations, disrupting DNA synthesis and causing apoptosis [ 32 ].…”

Section: Gemcitabine Conjugated With Cell-penetrating Peptides (Cpmentioning

confidence: 54%

“…Continuing the previous studies, Vale’s group synthesized new series of gemcitabine-CPPs conjugates [ 32 ] containing three novel hexapeptides—CPP6-1, CPP6-2, and CPP6-3—which are the analogues of two peptides—KLPVM and VPMLK—derived from a family of CPP5 [ 56 ]. These peptides were reported to have a high ability to cross cell membranes.…”

Section: Gemcitabine Conjugated With Cell-penetrating Peptides (Cpmentioning

confidence: 99%

“…Likewise, phosphorylated metabolites of gemcitabine are inactivated via the reduction by cellular 5′-nucleotidase (5′-NT) and then are rapidly removed from the body by the enzymatic conversion of gemcitabine [ 30 , 31 ]. Another important drawback associated with gemcitabine therapy is the drug resistance related to the nucleoside transporter deficiency, which is developed by some tumor cells after the initial tumor regression [ 32 ]. For this reason, many approaches have been made to improve the safety profile of gemcitabine and increase its chemotherapeutic index.…”

Section: Introductionmentioning

confidence: 99%

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Gemcitabine Peptide-Based Conjugates and Their Application in Targeted Tumor Therapy

Hawryłkiewicz

Ptaszyńska

2021

Molecules

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A major obstacle in tumor treatment is associated with the poor penetration of a therapeutic agent into the tumor tissue and with their adverse influence on healthy cells, which limits the dose of drug that can be safely administered to cancer patients. Gemcitabine is an anticancer drug used to treat a wide range of solid tumors and is a first-line treatment for pancreatic cancer. The effect of gemcitabine is significantly weakened by its rapid plasma degradation. In addition, the systemic toxicity and drug resistance significantly reduce its chemotherapeutic efficacy. Up to now, many approaches have been made to improve the therapeutic index of gemcitabine. One of the recently developed approaches to improve conventional chemotherapy is based on the direct targeting of chemotherapeutics to cancer cells using the drug-peptide conjugates. In this work, we summarize recently published gemcitabine peptide-based conjugates and their efficacy in anticancer therapy.

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“…Nevertheless, this is undoubtedly a much more convenient and comfortable form of administering drugs. We were encouraged by promising previous results reported for various prodrugs of gemcitabine developed to enhance oral bioavailability [8][9][10], including some studies carried out by our research group regarding gemcitabine conjugates with cell-penetrating peptides (CPPs) [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Permeability of Gemcitabine and PBPK Modeling to Assess Oral Administration

Ferreira

Lapa

Vale

2021

CIMB

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Gemcitabine is a nucleoside analog effective against several solid tumors. Standard treatment consists of an intravenous infusion over 30 min. This is an invasive, uncomfortable and often painful method, involving recurring visits to the hospital and costs associated with medical staff and equipment. Gemcitabine’s activity is significantly limited by numerous factors, including metabolic inactivation, rapid systemic clearance of gemcitabine and transporter deficiency-associated resistance. As such, there have been research efforts to improve gemcitabine-based therapy efficacy, as well as strategies to enhance its oral bioavailability. In this work, gemcitabine in vitro and clinical data were analyzed and in silico tools were used to study the pharmacokinetics of gemcitabine after oral administration following different regimens. Several physiologically based pharmacokinetic (PBPK) models were developed using simulation software GastroPlus™, predicting the PK parameters and plasma concentration–time profiles. The integrative biomedical data analyses presented here are promising, with some regimens of oral administration reaching higher AUC in comparison to the traditional IV infusion, supporting this route of administration as a viable alternative to IV infusions. This study further contributes to personalized health care based on potential new formulations for oral administration of gemcitabine, as well nanotechnology-based drug delivery systems.

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Development of potent CPP6–gemcitabine conjugates against human prostate cancer cell line (PC-3)

Abstract: Gemcitabine conjugation with CPP6 significantly enhanced cell growth inhibitory activity on PC-3 cells, with IC50 between 14 and 15 nM.

Cited by 12 publications

References 38 publications

Permeability evaluation of gemcitabine-CPP6 conjugates in Caco-2 cells

Permeability evaluation of gemcitabine-CPP6 conjugates in Caco-2 cells

Gemcitabine Peptide-Based Conjugates and Their Application in Targeted Tumor Therapy

Permeability of Gemcitabine and PBPK Modeling to Assess Oral Administration

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