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Engineering the E2 protein scaffold ...

Ren, Dongmei.

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Engineering the E2 protein scaffold as a versatile drug delivery system.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Engineering the E2 protein scaffold as a versatile drug delivery system./
Author:	Ren, Dongmei.
Description:	253 p.
Notes:	Source: Dissertation Abstracts International, Volume: 74-07(E), Section: B.
Contained By:	Dissertation Abstracts International74-07B(E).
Subject:	Engineering, Biomedical. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3556959
ISBN:	9781267995391

Engineering the E2 protein scaffold as a versatile drug delivery system.
Ren, Dongmei.

Engineering the E2 protein scaffold as a versatile drug delivery system. - 253 p.

Source: Dissertation Abstracts International, Volume: 74-07(E), Section: B.

Thesis (Ph.D.)--University of California, Irvine, 2013.

A variety of nanoparticles have been developed to deliver traditional drugs, recombinant proteins, vaccines, and nucleotides. Nature has provided various self-assembled container-like protein architectures which are potential drug carriers. This research has focused on a dodecahedron protein cage from the E2 subunit of pyruvate dehydrogenase multienzyme complex of Bacillus stearothermophilus (B. stearothermophilus) . By modification to the interior and exterior interfaces of the caged protein particle, this scaffold is able to encapsulate various guest molecules and deliver its cargos specifically to tumor cells. We investigated the feasibility of engineering the E2 protein scaffold as a versatile drug delivery system.

ISBN: 9781267995391Subjects--Topical Terms:

1017684
Engineering, Biomedical.

Engineering the E2 protein scaffold as a versatile drug delivery system.
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020 $a 9781267995391
035 $a (UMI)AAI3556959
035 $a AAI3556959
040 $a UMI $c UMI
100 1 $a Ren, Dongmei. $3 2091999
245 1 0 $a Engineering the E2 protein scaffold as a versatile drug delivery system.
300 $a 253 p.
500 $a Source: Dissertation Abstracts International, Volume: 74-07(E), Section: B.
500 $a Adviser: Szu-Wen Wang.
502 $a Thesis (Ph.D.)--University of California, Irvine, 2013.
520 $a A variety of nanoparticles have been developed to deliver traditional drugs, recombinant proteins, vaccines, and nucleotides. Nature has provided various self-assembled container-like protein architectures which are potential drug carriers. This research has focused on a dodecahedron protein cage from the E2 subunit of pyruvate dehydrogenase multienzyme complex of Bacillus stearothermophilus (B. stearothermophilus) . By modification to the interior and exterior interfaces of the caged protein particle, this scaffold is able to encapsulate various guest molecules and deliver its cargos specifically to tumor cells. We investigated the feasibility of engineering the E2 protein scaffold as a versatile drug delivery system.
520 $a The E2 protein scaffold has been engineered to form a 25-nm caged dodecahedral protein nanoparticle. By introducing cysteines to the internal cavity (D381C), we were able to conjugate fluorescent dye Alexa Fluor 532 and the antitumor drug doxorubicin to this internal cavity through maleimides on the guest molecules. The pH-dependent hydrolysis of a hydrazone linkage to doxorubicin allowed 90% drug release from the D381C scaffold within 72 hrs at pH 5.0. Through microscopy, we observed D381C encapsulated doxorubicin mainly localized in subcellular vesicles or organelles, while free doxorubicin was more disperse in cytoplasm, suggesting different uptake mechanisms. Doxorubicin loaded in D381C retained its therapeutic activity and induced cell death with an IC 50 of 1.3 ± 0.3 µm in breast cancer cell lines MDA-MB-231.
520 $a To enhance the molecular encapsulation capacity for the model antitumor drug doxorubicin in E2 scaffold cavity, a biomimetic hydrophobic microenvironment was engineered within the E2 scaffold cavity by introducing 240 phenylalanines. The resultant scaffold exhibited over a 35-fold increase in drug encapsulation relative to native E2 scaffold, yielding encapsulation capacity several times more than the conventional chemical conjugation strategy. Confocal laser scanning microscopy indicated cellular uptake of doxorubicin-loaded E2 nanocapsule. Intracellular drug release was shown by cytotoxicity against breast cancer cells MDA-MB-231, with an IC50 of 0.33 ± 0.12 µm.
520 $a In addition, to demonstrate the versatility of the E2 protein scaffold, we combined drug encapsulation and tumor targeting capabilities in the same nanoparticle. Alexa Fluor 532 was conjugated to the internal cysteine sites of an E2 scaffold (D381C). The external surface was functionalized with approximate 30 molecules (per scaffold) of targeting ligands folic acid through polyethylene glycol (PEG) linker or PEG alone as a control. The bi-functional E2 protein scaffold with folic acid targeting ligands enhanced its cellular uptake in folate receptor positive cells up to 4 times relative to folate receptor negative cells. Further study revealed free folic acid inhibited the targeting nanoparticles uptake in folate receptor positive cells 4-fold compared to folate receptor negative cells. Our results suggest E2 nanoparticle functionalized with folic acid is taken up through a folate receptor-mediated endocytosis pathway. We also investigated the feasibility of integrating other targeting ligands to the E2 scaffold.
520 $a Together, our results demonstrated that E2 protein nanoparticle could be exploited as a versatile drug delivery system.
590 $a School code: 0030.
650 4 $a Engineering, Biomedical. $3 1017684
650 4 $a Engineering, Chemical. $3 1018531
650 4 $a Health Sciences, Pharmacy. $3 1017737
690 $a 0541
690 $a 0542
690 $a 0572
710 2 $a University of California, Irvine. $b Chemical and Biochemical Engineering - Ph.D. $3 2092000
773 0 $t Dissertation Abstracts International $g 74-07B(E).
790 1 0 $a Wang, Szu-Wen, $e advisor
790 1 0 $a Wang, Szu-Wen $e committee member
790 1 0 $a Da Silva, Nancy A. $e committee member
790 1 0 $a George, Steven C. $e committee member
790 $a 0030
791 $a Ph.D.
792 $a 2013
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3556959