Plasma membrane lipid bilayer is druggable: Selective delivery of gemcitabine-squalene nano-medicine to cancer cells

Lirussi, Frédéric; Pyrshev, Kyrylo; Yesylevskyy, Semen O.; Rivel, Timothée; López, Tatiana; Coppens, Eleonore; Mura, Simona; Couvreur, Patrick; Ramseyer, Christophe

doi:10.1016/j.bbadis.2022.166614

Cited by 5 publications

(3 citation statements)

References 38 publications

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“…Non-filtered formulations either centrifuged or not were negatively stained with 2% phosphotungstic acid for 2 min and viewed on a TEM JEOL JEM1011 at 80 KV (JEOL, Peabody, MA, USA). Additionally, the morphology and structure of the formulations were analysed by FESEM (GeminiSEM, GEMINI 500, Zeiss, Oberkocken, Germany) 20 kV [ 31 , 68 ].…”

Section: Methodsmentioning

confidence: 99%

“…Conjugating GEM to lipophilic compounds may overcome the low efficiency of its encapsulation into micelles while also facilitating penetration into tumour cells [ 14 , 15 ]. To date, several lipidic blocks have been reported in the literature as being able to assemble GEM–lipid conjugates, namely N-octanoyl [ 16 ], N-dodecanoyl [ 17 ], 4-N-stearoyl (C 18 ) [ 18 ], stearic acid [ 18 , 19 , 20 , 21 , 22 , 23 , 24 ], linoleic acid [ 25 ], cholesterol [ 26 , 27 ], squalene [ 15 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ], pentadecanoic acid [ 35 ], vitamin E (VE) [ 36 ], and VE derivatives such as VE succinate [ 37 , 38 , 39 , 40 , 41 ]. Some GEM–lipid conjugates are able to release GEM in the presence of internal stimuli, such as the lysosomal proteolytic enzyme cathepsin B [ 42 , 43 ], which is frequently overexpressed in several cancer types, phospholipases [ 44 ] and carboxylesterases [ 45 ].…”

Section: Introductionmentioning

confidence: 99%

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Gemcitabine-Vitamin E Prodrug-Loaded Micelles for Pancreatic Cancer Therapy

Pereira-Silva,

Miranda-Pastoriza,

Diaz-Gomez

et al. 2024

Pharmaceutics

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Pancreatic cancer (PC) is an aggressive cancer subtype presenting unmet clinical challenges. Conventional chemotherapy, which includes antimetabolite gemcitabine (GEM), is seriously undermined by a short half-life, its lack of targeting ability, and systemic toxicity. GEM incorporation in self-assembled nanosystems is still underexplored due to GEM’s hydrophilicity which hinders efficient encapsulation. We hypothesized that vitamin E succinate–GEM prodrug (VES-GEM conjugate) combines hydrophobicity and multifunctionalities that can facilitate the development of Pluronic®F68 and Pluronic®F127 micelle-based nanocarriers, improving the therapeutic potential of GEM. Pluronic®F68/VES-GEM and Pluronic®F127/VES-GEM micelles covering a wide range of molar ratios were prepared by solvent evaporation applying different purification methods, and characterized regarding size, charge, polydispersity index, morphology, and encapsulation. Moreover, the effect of sonication and ultrasonication and the influence of a co-surfactant were explored together with drug release, stability, blood compatibility, efficacy against tumour cells, and cell uptake. The VES-GEM conjugate-loaded micelles showed acceptable size and high encapsulation efficiency (>95%) following an excipient reduction rationale. Pluronic®F127/VES-GEM micelles evidenced a superior VES-GEM release profile (cumulative release > 50%, pH = 7.4), stability, cell growth inhibition (<50% cell viability for 100 µM VES-GEM), blood compatibility, and extensive cell internalization, and therefore represent a promising approach to leveraging the efficacy and safety of GEM for PC-targeted therapies.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gemcitabine-Vitamin E Prodrug-Loaded Micelles for Pancreatic Cancer Therapy

Pereira-Silva,

Miranda-Pastoriza,

Diaz-Gomez

et al. 2024

Pharmaceutics

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“…In this context, the establishment of structure–activity relationships has an added value to the performance prediction of the different heptamethine cyanine molecules. Therefore, the systematic characterization of the NIR probes’ interaction with model membranes can provide important knowledge, since the plasma membrane is a ubiquitous barrier for cell permeation and can also be a therapeutic target [ 32 ]. Overall, it is expected that better performances correlate with the interaction of the molecules with lipid cell membranes.…”

Section: Introductionmentioning

confidence: 99%

Interaction of Near-Infrared (NIR)-Light Responsive Probes with Lipid Membranes: A Combined Simulation and Experimental Study

et al. 2023

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Cancer is considered a major societal challenge for the next decade worldwide. Developing strategies for simultaneous diagnosis and treatment has been considered a promising tool for fighting cancer. For this, the development of nanomaterials incorporating prototypic near-infrared (NIR)-light responsive probes, such as heptamethine cyanines, has been showing very promising results. The heptamethine cyanine-incorporating nanomaterials can be used for a tumor’s visualization and, upon interaction with NIR light, can also produce a photothermal/photodynamic effect with a high spatio-temporal resolution and minimal side effects, leading to an improved therapeutic outcome. In this work, we studied the interaction of 12 NIR-light responsive probes with lipid membrane models by molecular dynamics simulations. We performed a detailed characterization of the location, orientation, and local perturbation effects of these molecules on the lipid bilayer. Based on this information, the probes were divided into two groups, predicting a lower and higher perturbation of the lipid bilayer. From each group, one molecule was selected for testing in a membrane leakage assay. The experimental data validate the hypothesis that molecules with charged substituents, which function as two polar anchors for the aqueous phase while spanning the membrane thickness, are more likely to disturb the membrane by the formation of defects and pores, increasing the membrane leakage. The obtained results are expected to contribute to the selection of the most suitable molecules for the desired application or eventually guiding the design of probe modifications for achieving an optimal interaction with tumor cell membranes.

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