A degradable brush polymer–drug conjugate for pH-responsive release of doxorubicin

Yu, Yun; Chen, Chih Kuang; Law, Wing Cheung; Sun, Hanwen; Prasad, Paras N.; Cheng, Chong

doi:10.1039/c4py01194e

Cited by 90 publications

(65 citation statements)

References 66 publications

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“…571,572 Cheng et al recently conjugated DOX to PLA as pendant groups via an acid-sensitive Schiff base linkage (Figure 36). 573 The resulting micelles exhibit fast release kinetics under acidic conditions.…”

Section: Endogenously Triggered Drug Releasementioning

confidence: 99%

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Degradable Controlled-Release Polymers and Polymeric Nanoparticles: Mechanisms of Controlling Drug Release

et al. 2016

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Section: Endogenously Triggered Drug Releasementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Degradable Controlled-Release Polymers and Polymeric Nanoparticles: Mechanisms of Controlling Drug Release

et al. 2016

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“…branched polymers have been synthesized, including dendrimers, [ 10,13 ] hyperbranched polymers, [14][15][16][17] star polymers, [ 18 ] grafted polymers, [ 19,20 ] and cross-linked nanogels. [21][22][23][24] Since all these polymers contain at least one type of branching unit in the polymer structure, they could be categorized based on the functionality of the branching units.…”

Section: Introductionmentioning

confidence: 99%

Comparison of Loading Efficiency between Hyperbranched Polymers and Cross‐Linked Nanogels at Various Branching Densities

Graff

Shi

Wang

et al. 2015

Macromol. Rapid Commun.

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The effect of branching point structures and densities is studied between azido-containing hyperbranched polymers and cross-linked nanogels on their loading efficiency of alkynyl-containing dendron molecules. Hyperbranched polymers that contained "T"-shaped branching linkage from which three chains radiated out and cross-linked nanogels that contained "X"-shaped branching linkage with four radiating chains are synthesized in microemulsion using either atom transfer radical polymerization (ATRP) or conventional radical polymerization (RP) technique. Both polymers have similar density of azido groups in the structure and exhibit similar hydrodynamic diameter in latexes before purification. Subsequent copper-catalyzed azide-alkyne cycloaddition reactions between these polymers and alkynyl-containing dendrons in various sizes (G1-G3) demonstrate an order of dendron loading efficiencies (i.e., final conversion of alkynyl-containing dendron) as hyperbranched polymers > nanogels synthesized by ATRP > nanogels synthesized by RP. Decreasing the branching density or using smaller dendron molecules increases the click efficiency of both polymers. When G2 dendrons with a molecular weight of 627 Da are used to click with the hyperbranched polymers composed of 100% inimer, a maximum loading efficiency of G2 in the loaded hyperbranched polymer is 58% of G2 by weight. These results represent the first comparison between hyperbranched polymers and cross-linked nanogels to explore the effect of branching structures on their loading efficiencies.

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“…In this study, to achieve β-lap precisely pH responsive release and improved loading, we investigated conjugation of pH sensitive β-lap prodrugs with UPS polymer. pH sensitivity evaluation to three prodrug linkages acyl hydrazone 29–31 , ketal 32 and imine bonds 33, 34 (Scheme 1a) led to the selection of aryl imine linkage for the optimal β-Lap pH responsive prodrugs. In this study, monomer 2-(diisopropylamino) ethyl methacrylate (DPA) which has a transition pH t = 6.3 was introduced to construct hydrophobic segment of UPS polymer, and by introducing multiple of β-lap aryl imine prodrug into the UPS polymer chain via chemical conjugation, a precisely pH sensitive drug delivery system was obtained.…”

Section: Introductionmentioning

confidence: 99%

Lysosome-oriented, dual-stage pH-responsive polymeric micelles for β-lapachone delivery

et al. 2016

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β-Lapachone (β-lap), a novel anticancer agent, is bioactivated by NADP(H):quinone oxidoreductase 1 (NQO1), an enzyme over-expressed in numerous tumors, including lung, pancreas, breast, and prostate cancers. Fast renal clearance and methemaglobinemia / hemolytic side-effects from the clinical formulation (β-lap-hydroxyl propyl-β-cyclodextrin complex) hindered its clinical translation. Here, we investigated a dual model pH responsive polymers for β-lap delivery. Three pH-sensitive linkages, including acylhydrazone, ketal and imine bonds for β-lap prodrug syntheses result in an aryl imine linkage the most optimal linkage. The conversion to β-lap was 2.8%, 4.5% and 100% at pH 7.4, 6.5 and 5.0 in 8 h, respectively. β-lap aryl imine prodrug conjugated ultra pH-sensitive (UPS) polymer reached high β-lap loading density (8.3%) and exhibited dual-stages responsiveness to pH variation. In pHs under pHt, at stage I, micelle immediately dissociation and subsequently entering stage II, micelles start quickly release β-lap. In vitro release study showed that the micelles constantly release β-lap (14.9 ± 0.1%) at pHs above pHt in 72 h, whereas boosted release of β-lap (79.4 ± 1.2%) at pH 5.0. Micelle intracellular distribution predominantly in the lysosome organelle guaranteed their pH responsive dissociation and subsequently β-lap controlled release. The M-P micelles retained NQO1-dependent cytotoxicity in A549 lung cancer cells, similar to free drug in both efficacy and mechanism of cell death. The lysosome-oriented dual-stage ultra pH responsive β-lap prodrug micelles potentially offer an alternative nanotherapeutic strategy for lung, as well as other NQO1+ cancer therapies.

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A degradable brush polymer–drug conjugate for pH-responsive release of doxorubicin

Abstract: We report the synthesis, characterization andin vitroassessment of a degradable brush polymer–drug conjugate which can enable acid-triggered release of doxorubicin (DOX).

Cited by 90 publications

References 66 publications

Degradable Controlled-Release Polymers and Polymeric Nanoparticles: Mechanisms of Controlling Drug Release

Degradable Controlled-Release Polymers and Polymeric Nanoparticles: Mechanisms of Controlling Drug Release

Comparison of Loading Efficiency between Hyperbranched Polymers and Cross‐Linked Nanogels at Various Branching Densities

Lysosome-oriented, dual-stage pH-responsive polymeric micelles for β-lapachone delivery

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