A natural protein based platform for the delivery of Temozolomide acid to glioma cells

Proposed hypothesis in this study. Brain tumours overexpress SPARC protein which is responsible for the uptake of albumin nanoparticles (HSA NPs). Temozolomide (TMZ), a DNA alkylating agent, is the first line drug for treatment of glioma. Thus the delivery of Temozolomide acid (TMZA), a derivative o...

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Veröffentlicht in:European journal of pharmaceutics and biopharmaceutics 2021-12, Vol.169, p.297-308
Hauptverfasser: Helal, Dina O., Rouatbi, Nadia, Han, Shunping, Tzu-Wen Wang, Julie, Walters, Adam A., Abdel-Mottaleb, Mona M.A., Kamel, Amany O., Geneidi, Ahmed-Shawky, Awad, Gehanne A.S., Al-Jamal, Khuloud T.
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container_title European journal of pharmaceutics and biopharmaceutics
container_volume 169
creator Helal, Dina O.
Rouatbi, Nadia
Han, Shunping
Tzu-Wen Wang, Julie
Walters, Adam A.
Abdel-Mottaleb, Mona M.A.
Kamel, Amany O.
Geneidi, Ahmed-Shawky
Awad, Gehanne A.S.
Al-Jamal, Khuloud T.
description Proposed hypothesis in this study. Brain tumours overexpress SPARC protein which is responsible for the uptake of albumin nanoparticles (HSA NPs). Temozolomide (TMZ), a DNA alkylating agent, is the first line drug for treatment of glioma. Thus the delivery of Temozolomide acid (TMZA), a derivative of TMZ into HSA NPs (TMZA-HSA NPs) is hypothesized to ensure delivery of TMZA into glioma cells, overcoming the BBB and ensuring TMZ delivery in sufficient amounts for improved glioma therapy. [Display omitted] Glioblastoma is one of the most difficult to treat cancers with poor prognosis and survival of around one year from diagnosis. Effective treatments are desperately needed. This work aims to prepare temozolomide acid (TMZA) loaded albumin nanoparticles, for the first time, to target glioblastoma (GL261) and brain cancer stem cells (BL6). TMZA was loaded into human serum albumin nanoparticles (HSA NPs) using the desolvation method. A response surface 3-level factorial design was used to study the effect of different formulation parameters on the drug loading and particle size of NPs. The optimum conditions were found to be: 4 mg TMZA with 0.05% sodium cholate. This yielded NPs with particle size and drug loading of 111.7 nm and 5.5% respectively. The selected formula was found to have good shelf life and serum stability but with a relatively fast drug release pattern. The optimized NPs showed excellent cellular uptake with ∼ 50 and 100% of cells were positive for NP uptake after 24 h incubation with both GL261 and BL6 glioblastoma cell lines, respectively. The selected formula showed high cytotoxicity with ̴ 20% cell viability at 1 mM TMZA after 72 h incubation time. Finally, the fluorescently labelled NPs showed co-localization with the bioluminescent syngeneic BL6 intra-cranial tumour mouse model after intravenous administration.
doi_str_mv 10.1016/j.ejpb.2021.10.007
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A response surface 3-level factorial design was used to study the effect of different formulation parameters on the drug loading and particle size of NPs. The optimum conditions were found to be: 4 mg TMZA with 0.05% sodium cholate. This yielded NPs with particle size and drug loading of 111.7 nm and 5.5% respectively. The selected formula was found to have good shelf life and serum stability but with a relatively fast drug release pattern. The optimized NPs showed excellent cellular uptake with ∼ 50 and 100% of cells were positive for NP uptake after 24 h incubation with both GL261 and BL6 glioblastoma cell lines, respectively. The selected formula showed high cytotoxicity with ̴ 20% cell viability at 1 mM TMZA after 72 h incubation time. 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Brain tumours overexpress SPARC protein which is responsible for the uptake of albumin nanoparticles (HSA NPs). Temozolomide (TMZ), a DNA alkylating agent, is the first line drug for treatment of glioma. Thus the delivery of Temozolomide acid (TMZA), a derivative of TMZ into HSA NPs (TMZA-HSA NPs) is hypothesized to ensure delivery of TMZA into glioma cells, overcoming the BBB and ensuring TMZ delivery in sufficient amounts for improved glioma therapy. [Display omitted] Glioblastoma is one of the most difficult to treat cancers with poor prognosis and survival of around one year from diagnosis. Effective treatments are desperately needed. This work aims to prepare temozolomide acid (TMZA) loaded albumin nanoparticles, for the first time, to target glioblastoma (GL261) and brain cancer stem cells (BL6). TMZA was loaded into human serum albumin nanoparticles (HSA NPs) using the desolvation method. A response surface 3-level factorial design was used to study the effect of different formulation parameters on the drug loading and particle size of NPs. The optimum conditions were found to be: 4 mg TMZA with 0.05% sodium cholate. This yielded NPs with particle size and drug loading of 111.7 nm and 5.5% respectively. The selected formula was found to have good shelf life and serum stability but with a relatively fast drug release pattern. The optimized NPs showed excellent cellular uptake with ∼ 50 and 100% of cells were positive for NP uptake after 24 h incubation with both GL261 and BL6 glioblastoma cell lines, respectively. The selected formula showed high cytotoxicity with ̴ 20% cell viability at 1 mM TMZA after 72 h incubation time. 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Brain tumours overexpress SPARC protein which is responsible for the uptake of albumin nanoparticles (HSA NPs). Temozolomide (TMZ), a DNA alkylating agent, is the first line drug for treatment of glioma. Thus the delivery of Temozolomide acid (TMZA), a derivative of TMZ into HSA NPs (TMZA-HSA NPs) is hypothesized to ensure delivery of TMZA into glioma cells, overcoming the BBB and ensuring TMZ delivery in sufficient amounts for improved glioma therapy. [Display omitted] Glioblastoma is one of the most difficult to treat cancers with poor prognosis and survival of around one year from diagnosis. Effective treatments are desperately needed. This work aims to prepare temozolomide acid (TMZA) loaded albumin nanoparticles, for the first time, to target glioblastoma (GL261) and brain cancer stem cells (BL6). TMZA was loaded into human serum albumin nanoparticles (HSA NPs) using the desolvation method. A response surface 3-level factorial design was used to study the effect of different formulation parameters on the drug loading and particle size of NPs. The optimum conditions were found to be: 4 mg TMZA with 0.05% sodium cholate. This yielded NPs with particle size and drug loading of 111.7 nm and 5.5% respectively. The selected formula was found to have good shelf life and serum stability but with a relatively fast drug release pattern. The optimized NPs showed excellent cellular uptake with ∼ 50 and 100% of cells were positive for NP uptake after 24 h incubation with both GL261 and BL6 glioblastoma cell lines, respectively. The selected formula showed high cytotoxicity with ̴ 20% cell viability at 1 mM TMZA after 72 h incubation time. 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subjects Animals
Antineoplastic Agents, Alkylating - administration & dosage
Antineoplastic Agents, Alkylating - pharmacokinetics
Biological Products - pharmacology
Cell Line, Tumor
Cell Survival - drug effects
Drug Compounding - methods
Drug Delivery Systems - methods
Drug Liberation
Drug Stability
Glioma
Glioma - drug therapy
Glioma - metabolism
Glioma - pathology
Human serum albumin
Mice
Nanoparticles
Nanoparticles - therapeutic use
Osteonectin - metabolism
Particle Size
Serum Albumin, Human - pharmacology
SPARC
Temozolomide - administration & dosage
Temozolomide - pharmacokinetics
Temozolomide acid
Tissue Distribution
title A natural protein based platform for the delivery of Temozolomide acid to glioma cells
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