fulltext.study @t Gmail

Multifunctional pH-Disintegrable micellar nanoparticles of asymmetrically functionalized β-cyclodextrin-Based star copolymer covalently conjugated with doxorubicin and DOTA-Gd moieties

Paper ID Volume ID Publish Year Pages File Format Full-Text
6994 527 2012 11 PDF Available
Title
Multifunctional pH-Disintegrable micellar nanoparticles of asymmetrically functionalized β-cyclodextrin-Based star copolymer covalently conjugated with doxorubicin and DOTA-Gd moieties
Abstract

We report on a novel type of multifunctional pH-disintegrable micellar nanoparticles fabricated from asymmetrically functionalized β-cyclodextrin (β-CD) based star copolymers covalently conjugated with doxorubicin (DOX), folic acid (FA), and DOTA-Gd moieties for integrated cancer cell-targeted drug delivery and magnetic resonance (MR) imaging contrast enhancement. Asymmetrically functionalized β-CD, (N3)7-CD-(Br)14, which possesses 7 azide functionalities and 14 α-bromopropionate moieties in the upper and lower rim of rigid toroidal β-CD core, respectively, was synthesized at first. The subsequent atom transfer radical polymerization (ATRP) of N-(2-hydroxypropyl) methacrylamide (HPMA), conjugation with DOX and FA, and click reaction with alkynyl-(DOTA-Gd) complex afforded (DOTA-Gd)7-CD-(PHPMA-FA-DOX)14 star copolymer comprising of 7 DOTA-Gd complex moieties and 14 PHPMA arms covalently anchored with DOX and FA via acid-labile carbamate linkages and ester bonds, respectively. The covalent conjugation with ∼13 DOX molecules onto PHPMA arms per star copolymer (∼14 wt% loading content) endows the initially hydrophilic one with amphiphilicity, leading to the self-assembly into micellar nanoparticles of several tens of nanometers in aqueous solution at pH 7.4. In vitro DOX release profile from micellar nanoparticles is highly pH-dependent, and over a time period of 42 h, cumulative releases of ∼10%, 53%, and 89% conjugated DOX at pH 7.4, 5.0, and 4.0, respectively, were observed. Most importantly, the pH-modulated release of conjugated DOX from micellar nanoparticles is accompanied with the micelle disintegration due to the loss of amphiphilicity of the star copolymer scaffold. In vitro cell viability assays revealed that (DOTA-Gd)7-CD-(PHPMA15)14 star copolymer is almost non-cytotoxic up to a concentration of 0.5 g/L, whereas DOX-conjugated micellar nanoparticles of (DOTA-Gd)7-CD-(PHPMA-FA-DOX)14 can effectively enter and kill HeLa cells at a concentration higher than ∼80 mg/L. In vitro MR imaging experiments indicated a considerably enhanced T1 relaxivity (r1 = 11.4 s−1 mM−1) for micellar nanoparticles compared to that for the small molecule counterpart, alkynyl-DOTA-Gd (r1 = 3.1 s−1 mM−1). In vivo MR imaging assay in rats revealed considerable accumulation of micellar nanoparticles within rat liver and kidney and prominent positive contrast enhancement. The integrated design of diagnostic and therapeutic functions of multifunctional pH-disintegrable micellar nanoparticles augurs well for their practical applications in the field of image-guided cancer chemotherapy.

Keywords
Targeted drug delivery; MR imaging; pH-labile; Intracellular; Theranostic nanocarriers
First Page Preview
Multifunctional pH-Disintegrable micellar nanoparticles of asymmetrically functionalized β-cyclodextrin-Based star copolymer covalently conjugated with doxorubicin and DOTA-Gd moieties
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us
Publisher
Database: Elsevier - ScienceDirect
Journal: Biomaterials - Volume 33, Issue 8, March 2012, Pages 2521–2531
Authors
, , , , ,
Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us