LogP of N-acyl-gemcitabine and lectin-corona emerge as key parameters in nanoparticulate intravesical cancer therapy.
Eur J Pharm Sci
; 180: 106330, 2023 Jan 01.
Article
en En
| MEDLINE
| ID: mdl-36379358
ABSTRACT
After surgical removal of the tumour tissue, bladder cancer is treated by intravesical instillation of cytotoxic drugs such as gemcitabine. Gemcitabine, however, is highly hydrophilic and possesses a short half-life due to fast enzymatic deamination. Additionally, continuous dilution by urine, a hardly permeable urothelial barrier and rapid excretion by urination make therapy difficult. To modify lipophilicity of the drug, N-acyl-gemcitabine derivatives with quite different solubility and logP were synthesized, purified and characterized. The loading of PLGA nanoparticles with the N-acyl-gemcitabine derivatives followed by release in artificial urine, revealed that the drug content increases but the subsequent release decreases with lipophilicity. Additionally, acylation increased cytotoxicity and opened passive diffusion as an additional pathway into cancer cells. To address physiological constraints, the surface of the monodisperse nanoparticles was grafted with bioadhesive wheat germ agglutinin. Cytoadhesion to artificial bladder cancer tissue and even uptake into the cells as indicated by microscopic imaging are expected to prolong the retention time in the bladder cavity as well as to promote uptake into the cells. By using N-caprylic-gemcitabine as most appropriate gemcitabine-derivative for drug loading and making use of the bioadhesive characteristics of wheat germ agglutinin for grafting the corona of PLGA-nanoparticles, an innovative strategy towards smart drug delivery for instillative therapy of bladder cancer is proposed.
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Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Neoplasias de la Vejiga Urinaria
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Aglutininas del Germen de Trigo
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Sistema de Administración de Fármacos con Nanopartículas
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Gemcitabina
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Antimetabolitos Antineoplásicos
Idioma:
En
Revista:
Eur J Pharm Sci
Asunto de la revista:
FARMACIA
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FARMACOLOGIA
/
QUIMICA
Año:
2023
Tipo del documento:
Article