Antitumoral activity of PEG–gemcitabine prodrugs targeted by folic acid

Pasut, Gianfranco; Canal, Fabiana; Via, Lisa Dalla; Berlier, Gloria; Veronese, Francesco M.; Schiavon, Oddone

doi:10.1016/j.jconrel.2008.02.002

Cited by 151 publications

(131 citation statements)

References 35 publications

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“…53 The drug linkage involved the 4-(N)-amino group of gemcitabine and the COOH of PEG, while folic acid was linked through its carboxylic function to PEG amino group. Folic acid was chosen as the targeting agent because its receptor is over-expressed in several types of cancers (lung, breast, kidney and ovarian), [54][55][56] while in normal human tissues its receptors maybe have limited distribution.…”

Section: Peg-gemcitabinementioning

confidence: 99%

“…61 In contrast, in KB-3-1 cells which over-express folate receptors, derivatives with folate are certainly less cytotoxic than native gemcitabine but are more cytotoxic than gemcitabine only coupled to PEG. 53 PEGylation is currently considered to be one of the most successful techniques to prolong the residence time of drugs in the bloodstream. In a few cases, polymer conjugation has also shown that it can confer targeting properties to the disease site, such as tumour masses, by passive diffusion (EPR effect).…”

Section: Peg-gemcitabinementioning

confidence: 99%

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Gemcitabine versus Modified Gemcitabine: A Review of Several Promising Chemical Modifications

2012

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Gemcitabine, an anticancer agent which acts against a wide range of solid tumors, is known to be rapidly deaminated in blood to the inactive metabolite 2',2'-difluorodeoxyuridine and to be rapidly excreted by the urine. Moreover, many cancers develop resistance against this drug, such as loss of transporters and kinases responsible for the first phosphorylation step. To increase its therapeutic levels, gemcitabine is administered at high dose (1000mg/m²) causing sides effects (neutropenia, nausea…).To improve its metabolic stability, its cytotoxic activity and to

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Section: Peg-gemcitabinementioning

confidence: 99%

Section: Peg-gemcitabinementioning

confidence: 99%

Gemcitabine versus Modified Gemcitabine: A Review of Several Promising Chemical Modifications

2012

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“…For example, gemcitabine amide conjugates containing folic acid 37 or a DNA binding element 38 as targeting moieties have been reported. Also, a gemcitabine 5′-OH ester conjugate with biotin as the targeting vector was recently described.…”

Section: Design Of Gnrh-gemcitabine Conjugatesmentioning

confidence: 99%

GnRH-Gemcitabine Conjugates for the Treatment of Androgen-Independent Prostate Cancer: Pharmacokinetic Enhancements Combined with Targeted Drug Delivery

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Argyros

Sayyad³

et al. 2014

Bioconjugate Chem.

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Gemcitabine, a drug with established efficacy against a number of solid tumors, has therapeutic limitations due to its rapid metabolic inactivation. The aim of this study was the development of an innovative strategy to produce a metabolically stable analogue of gemcitabine that could also be selectively delivered to prostate cancer (CaP) cells based on cell surface expression of the Gonadotropin Releasing HormoneReceptor (GnRH-R). The synthesis and evaluation of conjugated molecules, consisting of gemcitabine linked to a GnRH agonist, is presented along with results in androgen-independent prostate cancer models. NMR and ligand binding assays were employed to verify conservation of microenvironments responsible for binding of novel GnRH-gemcitabine conjugates to the GnRH-R. In vitro cytotoxicity, cellular uptake and metabolite formation of the conjugates were examined in CaP cell lines. Selected conjugates were efficacious in the in vitro assays with one of them, namely GSG, displaying high antiproliferative activity in CaP cell lines along with significant metabolic and pharmacokinetic advantages in comparison to gemcitabine. Finally, treatment of GnRH-R positive xenografted mice with GSG, showed a significant advantage in tumor growth inhibition when compared to gemcitabine. 3 IntroductionDespite advancements in methods for early cancer detection and improved insights into the molecular mechanisms and treatment options, advanced prostate cancer (CaP) remains a major health problem for the aging man. 1,2 Hormonal therapy is usually the first line of defense for CaP treatment by using drugs that lead to chemical castration, suppression of testosterone and dihydrotestosterone (DHT) biosynthesis. 3,4 The hormonal ablation approach has been achieved successfully using agonist (through desensitization) or antagonist analogue drugs, of the native Gonadotropin Releasing Hormone (GnRH). These drugs exert their effects primarily on the pituitary gland through the GnRH-R by lowering gonadotropins and downstream gonadal sex steroids. Nevertheless, in many cases after treatment, following initial tumor regression, CaP progresses to an androgen-independent state with poor prognosis, which presents a major challenge for the physician and the patient. 3,[5][6][7][8][9][10] Research on the GnRH-R has shown that its expression is not confined solely to the pituitary but that is also present in several other tissues such as prostate, breast 11-13 and the GnRH-R level of expression along with cell context is critical for cell responses to either agonist or antagonist drugs of the receptor. 14 It is also well established that GnRH-R gene expression is upregulated in patients with androgenindependent CaP, making the GnRH-R an attractive target for the design of novel and specific therapeutics. 15 A modern approach to improve conventional chemotherapy is by direct targeting of chemotherapeutic agents to cancer cells in order to enhance the tumoricidal effect and reduce peripheral toxicity of a specific drug. Linking chemo...

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“…Unfortunately, gemcitabine possesses a rapid body clearance that limits its efficacy; thus, a frequent administration schedule at high drug doses is required and this leads to significant side effects. To overcome these limitations, recently two folic acid targeted PEG-gemcitabine conjugates, differing in the drug loading, were prepared [49] and in order to evaluate their active targeting superiority three non-targeted conjugates were also synthesized. Anyway, for all types of conjugates, the drug linkage involved the N 4 -amino group of the pyrimidine ring of gemcitabine and the COOH of PEG, while folic acid was linked to the PEG amino group mainly through its γ carboxylic group.…”

Section: Peg-conjugated Systems For Targeted Delivery or Combination mentioning

confidence: 99%

Multimeric, Multifunctional Derivatives of Poly(ethylene glycol)

et al. 2011

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Abstract:This article reviews the use of multifunctional polymers founded on high-molecular weight poly(ethylene glycol) (PEG). The design of new PEG derivatives assembled in a dendrimer-like multimeric fashion or bearing different functionalities on the same molecule is described. Their use as new drug delivery systems based on the conjugation of multiple copies or diversely active drugs on the same biocompatible support is illustrated.

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Antitumoral activity of PEG–gemcitabine prodrugs targeted by folic acid

Cited by 151 publications

References 35 publications

Gemcitabine versus Modified Gemcitabine: A Review of Several Promising Chemical Modifications

Gemcitabine versus Modified Gemcitabine: A Review of Several Promising Chemical Modifications

GnRH-Gemcitabine Conjugates for the Treatment of Androgen-Independent Prostate Cancer: Pharmacokinetic Enhancements Combined with Targeted Drug Delivery

Multimeric, Multifunctional Derivatives of Poly(ethylene glycol)

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