Transmembrane diffusion of gemcitabine by a nanoparticulate squalenoyl prodrug: An original drug delivery pathway

Bildstein, Lucien; Dubernet, Catherine; Marsaud, Véronique; Chacun, Hélène; Nicolas, Valérie; Gueutin, Claire; Sarasin, Alain; Bénech, Henri; Lepêtre-Mouelhi, Sinda; Desmaële, Didier; Couvreur, Patrick

doi:10.1016/j.jconrel.2010.07.120

Cited by 87 publications

(63 citation statements)

References 30 publications

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“…According to the statistics, pancreatic cancer is the fourth, fifth, and seventh leading cause of cancer-related deaths in the USA, the European Union, and People's Republic of China, respectively. [1][2][3] Although great progress has been made for other cancers, pancreatic cancer still has a poor prognosis, with a dismal 5-year survival rate ,5%. 4 Surgery is the only effective cure, but only 20% of patients are eligible for this approach, and chemotherapy remains the standard treatment for most patients with pancreatic cancer.…”

Section: Introductionmentioning

confidence: 99%

“…Both our in vitro and in vivo studies confirmed that Gem-C14 showed equal or even superior efficacy to Gem, and several other reports also support this conclusion. 2,40,41 This enhanced antitumor activity may be attributed to the fact that, on the one hand, Gem-C14 has the ability to cross epithelial cells and localize in tumors independent of human equilibrative nucleoside transporter 1, and on the other hand, the metabolic enzyme intercellular carboxylesterase 2 is key for transforming Gem-C14 into Gem, which hydrolyzes the prodrug and confers prodrug sensitivity to cancer cells. 42 Theoretically, the albumin nanoparticles have advantages over others in being nontoxic, biocompatible, and biodegradable.…”

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confidence: 99%

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An in vitro and in vivo study of gemcitabine-loaded albumin nanoparticles in a pancreatic cancer cell line

Yang

Xie

et al. 2015

IJN

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Background and objectives Gemcitabine (Gem) is far from satisfactory as the first-line regimen for pancreatic cancer, and the emergence of albumin nanoparticles offers new hope for the delivery of Gem. In this study, Gem-loaded human serum albumin nanoparticles (Gem-HSA-NPs) were successfully synthesized, characterized, and tested on a BxPC-3 cell line both in vitro and in vivo. Materials and methods 4- N -myristoyl-gemcitabine (Gem-C14) was obtained first by coupling myristoyl with the 4-amino group of Gem. The Gem-HSA-NPs were then prepared by nanoparticle albumin-bound technology and characterized for particle size, zeta potential, morphology, encapsulation efficiency, drug-loading efficiency, and release characteristics. Using both in vitro and in vivo studies, Gem-C14 and Gem-HSA-NPs were tested on the human pancreatic cancer cell line BxPC-3. Results Gem-HSA-NPs showed an average particle size of 150±27 nm, and with an encapsulation rate of 82.99%±3.5% and a drug-loading rate of 10.42%±3.5%, they exhibited a favorable controlled- and sustained-release nature. In in vitro, Gem-C14 was equivalent in cytotoxicity to Gem. In in vivo, the Gem-HSA-NPs exhibited the strongest inhibitory effect on tumor growth but the lowest toxicity among the four groups. Conclusion The enhanced in vivo efficacy of Gem-HSA-NPs toward the pancreatic cancer cell line suggests their potential role for use in the clinical field.

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

An in vitro and in vivo study of gemcitabine-loaded albumin nanoparticles in a pancreatic cancer cell line

Yang

Xie

et al. 2015

IJN

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“…It also packed, to allow supramolecular assembly as occurs with other drug squalenoyl derivatives. Unlike Gem-SQ, which is metabolized by the endothelial reticulum and does not penetrate the cell nucleus (Bildstein et al, 2010), Ru-BPPBIhxSQ concentrates inside the cell, diffusing into the cytoplasm and intracellular organs. It is also able to diffuse throughout a more organized cell system, in the form of multicellular spheroid.…”

Section: Discussionmentioning

confidence: 99%

Ruthenium polypyridyl squalene derivative: A novel self-assembling lipophilic probe for cellular imaging

Dosio¹,

Stella²,

Ferrero³

et al. 2013

International Journal of Pharmaceutics

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Transition metal complexes provide a promising avenue for designing new therapeutic and diagnostic agents. In particular, ruthenium(II) polypyridyl complexes are useful for studying cellular uptake, due to their easy synthesis and unique photophysical properties. Dyes are frequently combined with material substrates to modulate their properties, enhance stability, reduce toxicity, and improve delivery. A novel Ru polypyridyl complex linked to a derivative of the natural lipid squalene (Ru-BIPPBI-hx-SQ) is described. Using the solvent displacement method, Ru-BIPPBI-hx-SQ easily self-assembles into nanosized aggregates in aqueous solution, as characterized by dynamic light scattering. The nanoassemblies exhibit long-lived and intense luminescence.Preliminary biological assessment showed them to be non-toxic; they are efficiently and rapidly transported across the cell membrane without requiring its permeabilization. Ru-labeled nanoassemblies are likely to be significant cellular-imaging tools, probing cellular events at very low concentrations. Moreover co-nanoassembly, with drug-derivatives based on squalenoylation technology, including gemcitabine and paclitaxel, has given interesting preliminary results.

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“…Due to its rather hydrophilic character, gemcitabine is unable to passively diffuse across the plasma membrane but it is transported into the cell by either human equilibrative (hENT) or sodiumgradient nucleoside transporters. The resistance to gemcitabine treatment often arises from the down regulation of these nucleoside transporters which impairs gemcitabine membrane transport, as shown in both the pre-clinical experimental models and the clinic [8]. Gemcitabine is also rapidly inactivated into the blood, due to the fast metabolization by blood deaminases, into the inactive difluorouracil.…”

Section: Introductionmentioning

confidence: 99%

Peptide-functionalized nanoparticles for selective targeting of pancreatic tumor

Valetti¹,

Maione

Mura

et al. 2014

Journal of Controlled Release

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Chemotherapy for pancreatic cancer is hampered by the tumor physio-pathological complexity. Here we show a targeted nanomedicine using a new ligand, the CKAAKN peptide, which had been identified by phage display, as an efficient homing device within the pancreatic pathological microenvironment. Taking advantage of the squalenoylation platform, the CKAAKN peptide was conjugated to squalene (SQCKAAKN) and then co-nanoprecitated with the squalenoyl prodrug of gemcitabine (SQdFdC) giving near monodisperse nanoparticles (NPs) for safe intravenous injection. By interacting with a novel target pathway, the Wnt-2, the CKAAKN functionalization enabled nanoparticles: (i) to specifically interact with both tumor cells and angiogenic vessels and (ii) to simultaneously promote pericyte coverage, thus leading to the normalization of the vasculature likely improving the tumor accessibility for the therapy. All together, this approach represents a unique targeted nanoparticle design with remarkable selectivity towards pancreatic cancer and multiple mechanism of action. Graphical abstract

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Transmembrane diffusion of gemcitabine by a nanoparticulate squalenoyl prodrug: An original drug delivery pathway

Cited by 87 publications

References 30 publications

An in vitro and in vivo study of gemcitabine-loaded albumin nanoparticles in a pancreatic cancer cell line

An in vitro and in vivo study of gemcitabine-loaded albumin nanoparticles in a pancreatic cancer cell line

Ruthenium polypyridyl squalene derivative: A novel self-assembling lipophilic probe for cellular imaging

Peptide-functionalized nanoparticles for selective targeting of pancreatic tumor

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Transmembrane diffusion of gemcitabine by a nanoparticulate squalenoyl prodrug: An original drug delivery pathway

Cited by 87 publications

References 30 publications

An in vitro and in vivo study of gemcitabine-loaded albumin nanoparticles in a pancreatic cancer cell&nbsp;line

An in vitro and in vivo study of gemcitabine-loaded albumin nanoparticles in a pancreatic cancer cell&nbsp;line

Ruthenium polypyridyl squalene derivative: A novel self-assembling lipophilic probe for cellular imaging

Peptide-functionalized nanoparticles for selective targeting of pancreatic tumor

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Product

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An in vitro and in vivo study of gemcitabine-loaded albumin nanoparticles in a pancreatic cancer cell line

An in vitro and in vivo study of gemcitabine-loaded albumin nanoparticles in a pancreatic cancer cell line