Staff View: Homing peptides (rgd/irgd) functionalized zeolitic imidazolate framework-8 for targeted delivery of gemcitabine to lung cancer cell

Homing peptides (rgd/irgd) functionalized zeolitic imidazolate framework-8 for targeted delivery of gemcitabine to lung cancer cell

Lung cancer is a serious threat to human health, with metastasis being the top cause of cancer-related mortality. Gemcitabine (GEM) used in treating lung cancer operates in a non-selective manner tending to accumulate in normal tissue when cancer patients face a long duration of treatment. To mit...

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Main Author:	Mohd Abdul Kamal, Nurul Akmarina
Format:	Thesis
Language:	English
Published:	2022
Subjects:	Lungs - Cancer - Research Drug delivery systems Nanomedicine
Online Access:	http://psasir.upm.edu.my/id/eprint/104076/1/FS%202022%2041%20IR.pdf http://psasir.upm.edu.my/id/eprint/104076/
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spelling	my.upm.eprints.1040762023-07-07T02:39:26Z http://psasir.upm.edu.my/id/eprint/104076/ Homing peptides (rgd/irgd) functionalized zeolitic imidazolate framework-8 for targeted delivery of gemcitabine to lung cancer cell Mohd Abdul Kamal, Nurul Akmarina Lung cancer is a serious threat to human health, with metastasis being the top cause of cancer-related mortality. Gemcitabine (GEM) used in treating lung cancer operates in a non-selective manner tending to accumulate in normal tissue when cancer patients face a long duration of treatment. To mitigate the non-selective action of the GEM on the healthy tissues, there is a vital necessity to develop targeted nano delivery systems capable of regulating optimum doses selectively to cancer cells and minimizing untoward toxicity to normal tissues. Herein, a reticular nanoparticle zeolitic imidazolate framework-8 (nZIF-8) encapsulating GEM was surface-functionalized with selective homing systems (RGD; sequence Arg-Gly-Asp and iRGD; sequence Cys-Arg-Gly-Asp-Lys-Gly- Pro-Asp-Cys, respectively) through a straightforward, one-pot solvothermal reaction. Successful surface functionalization of nZIF-8 encapsulated GEM (GEM⊂nZIF-8) with RGD and iRGD, respectively, were characterized and systematically interpreted as a function of newly-formed functional groups, particle size, surface structure, surface topography, surface area, and surface charge. These functionalized GEMRGD@nZIF-8 and GEMiRGD@nZIF-8 not only responsive to an acidic environment but also controlled the GEM dissolution released rate (57.6 and 56.2%, respectively) after 48 h compared to nonfunctionalized GEM⊂nZIF-8 (76.0%). Both functionalized nanoparticles successfully increased the cellular uptake within cancerous human adenocarcinoma alveolar epithelial cells (A549), compared with nonfunctionalized nanoparticles. The highest uptake was shown by iRGD functionalized nZIF-8. The GEM⊂RGD@nZIF-8 and GEM⊂iRGD@nZIF-8 experienced not only efficient uptake within A549, but also induced obvious cytotoxicity (75 and 73%, respectively at 10 μg mL−1) and apoptosis (62 and 74.9%) post 48 h treatment when compared to the GEM⊂nZIF-8. The apoptosis study verified the ability of functionalized GEM⊂iRGD@nZIF-8 to intensify the apoptotic population in A549 while minimizing cell death (11%) in normal human lung fibroblast cells (MRC-5). Both functionalized nanoparticles reflect a potential outstanding treatment efficacy when GEM⊂RGD@nZIF-8 and GEM⊂iRGD@nZIF-8 demonstrated selective cytotoxicity (selective index, SI > 2) towards A549 than MRC-5. The follow-up study using healthy zebrafish embryos demonstrated enhanced permeation by both functionalized nanoparticles. At the lethal endpoint (96 h), all nanoparticles at all concentrations (7.81-250 μg mL-1) did not elicit toxicity during embryonic and larvae stages. With the absence of nZIF-8, pristine GEM at a concentration of 250 μg mL-1 exhibited 33% of pericardially and yolk sac edema indicating adverse side effects of the chemotherapeutic agent alone towards healthy tissue. Taken together, it is believed that surface functionalization of zeolitic imidazolate framework-8 with RGD/iRGD holds great selective targeting and enhances the optimum chemotherapeutic dosage to human lung cancer with less unwarranted toxicity to normal human lung fibroblast. 2022-03 Thesis NonPeerReviewed text en http://psasir.upm.edu.my/id/eprint/104076/1/FS%202022%2041%20IR.pdf Mohd Abdul Kamal, Nurul Akmarina (2022) Homing peptides (rgd/irgd) functionalized zeolitic imidazolate framework-8 for targeted delivery of gemcitabine to lung cancer cell. Doctoral thesis, Universiti Putra Malaysia. Lungs - Cancer - Research Drug delivery systems Nanomedicine
institution	Universiti Putra Malaysia
building	UPM Library
collection	Institutional Repository
continent	Asia
country	Malaysia
content_provider	Universiti Putra Malaysia
content_source	UPM Institutional Repository
url_provider	http://psasir.upm.edu.my/
language	English
topic	Lungs - Cancer - Research Drug delivery systems Nanomedicine
spellingShingle	Lungs - Cancer - Research Drug delivery systems Nanomedicine Mohd Abdul Kamal, Nurul Akmarina Homing peptides (rgd/irgd) functionalized zeolitic imidazolate framework-8 for targeted delivery of gemcitabine to lung cancer cell
description	Lung cancer is a serious threat to human health, with metastasis being the top cause of cancer-related mortality. Gemcitabine (GEM) used in treating lung cancer operates in a non-selective manner tending to accumulate in normal tissue when cancer patients face a long duration of treatment. To mitigate the non-selective action of the GEM on the healthy tissues, there is a vital necessity to develop targeted nano delivery systems capable of regulating optimum doses selectively to cancer cells and minimizing untoward toxicity to normal tissues. Herein, a reticular nanoparticle zeolitic imidazolate framework-8 (nZIF-8) encapsulating GEM was surface-functionalized with selective homing systems (RGD; sequence Arg-Gly-Asp and iRGD; sequence Cys-Arg-Gly-Asp-Lys-Gly- Pro-Asp-Cys, respectively) through a straightforward, one-pot solvothermal reaction. Successful surface functionalization of nZIF-8 encapsulated GEM (GEM⊂nZIF-8) with RGD and iRGD, respectively, were characterized and systematically interpreted as a function of newly-formed functional groups, particle size, surface structure, surface topography, surface area, and surface charge. These functionalized GEMRGD@nZIF-8 and GEMiRGD@nZIF-8 not only responsive to an acidic environment but also controlled the GEM dissolution released rate (57.6 and 56.2%, respectively) after 48 h compared to nonfunctionalized GEM⊂nZIF-8 (76.0%). Both functionalized nanoparticles successfully increased the cellular uptake within cancerous human adenocarcinoma alveolar epithelial cells (A549), compared with nonfunctionalized nanoparticles. The highest uptake was shown by iRGD functionalized nZIF-8. The GEM⊂RGD@nZIF-8 and GEM⊂iRGD@nZIF-8 experienced not only efficient uptake within A549, but also induced obvious cytotoxicity (75 and 73%, respectively at 10 μg mL−1) and apoptosis (62 and 74.9%) post 48 h treatment when compared to the GEM⊂nZIF-8. The apoptosis study verified the ability of functionalized GEM⊂iRGD@nZIF-8 to intensify the apoptotic population in A549 while minimizing cell death (11%) in normal human lung fibroblast cells (MRC-5). Both functionalized nanoparticles reflect a potential outstanding treatment efficacy when GEM⊂RGD@nZIF-8 and GEM⊂iRGD@nZIF-8 demonstrated selective cytotoxicity (selective index, SI > 2) towards A549 than MRC-5. The follow-up study using healthy zebrafish embryos demonstrated enhanced permeation by both functionalized nanoparticles. At the lethal endpoint (96 h), all nanoparticles at all concentrations (7.81-250 μg mL-1) did not elicit toxicity during embryonic and larvae stages. With the absence of nZIF-8, pristine GEM at a concentration of 250 μg mL-1 exhibited 33% of pericardially and yolk sac edema indicating adverse side effects of the chemotherapeutic agent alone towards healthy tissue. Taken together, it is believed that surface functionalization of zeolitic imidazolate framework-8 with RGD/iRGD holds great selective targeting and enhances the optimum chemotherapeutic dosage to human lung cancer with less unwarranted toxicity to normal human lung fibroblast.
format	Thesis
author	Mohd Abdul Kamal, Nurul Akmarina
author_facet	Mohd Abdul Kamal, Nurul Akmarina
author_sort	Mohd Abdul Kamal, Nurul Akmarina
title	Homing peptides (rgd/irgd) functionalized zeolitic imidazolate framework-8 for targeted delivery of gemcitabine to lung cancer cell
title_short	Homing peptides (rgd/irgd) functionalized zeolitic imidazolate framework-8 for targeted delivery of gemcitabine to lung cancer cell
title_full	Homing peptides (rgd/irgd) functionalized zeolitic imidazolate framework-8 for targeted delivery of gemcitabine to lung cancer cell
title_fullStr	Homing peptides (rgd/irgd) functionalized zeolitic imidazolate framework-8 for targeted delivery of gemcitabine to lung cancer cell
title_full_unstemmed	Homing peptides (rgd/irgd) functionalized zeolitic imidazolate framework-8 for targeted delivery of gemcitabine to lung cancer cell
title_sort	homing peptides (rgd/irgd) functionalized zeolitic imidazolate framework-8 for targeted delivery of gemcitabine to lung cancer cell
publishDate	2022
url	http://psasir.upm.edu.my/id/eprint/104076/1/FS%202022%2041%20IR.pdf http://psasir.upm.edu.my/id/eprint/104076/
_version_	1772813448481079296
score	13.211869

Homing peptides (rgd/irgd) functionalized zeolitic imidazolate framework-8 for targeted delivery of gemcitabine to lung cancer cell

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