Well-Defined Degradable Brush Polymer–Drug Conjugates for Sustained Delivery of Paclitaxel

Yu, Yun; Chen, Chih Kuang; Law, Wing Cheung; Mok, Jorge; Zou, Jiong; Prasad, Paras N.; Cheng, Chong

doi:10.1021/mp3004868

Cited by 120 publications

(105 citation statements)

References 45 publications

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“…37 Moreover, the 2′-CH proton peak on the 1 H NMR spectra was shifted from 4.67 ppm (free PTX) to 5.90 ppm (conjugated PTX; Figure 2). 38,39 PTX-SA was conjugated to the side chains of the amino groups in PEG-b-PLL through a typical amidation reaction to obtain an ester bond containing polymer PEG-b-(PLLg-PTX). As shown in Figure 3, PTX-SA was successfully conjugated to PEG-b-PLL, which was certified by the typical signals of the phenyl proton (δ 7.28-8.0 ppm) of PTX that appeared in the 1 H NMR spectra of PEG-b-(PLL-g-PTX).…”

Section: Resultsmentioning

confidence: 99%

pH-triggered surface charge-switchable polymer micelles for the co-delivery of paclitaxel/disulfiram and overcoming multidrug resistance in cancer

Huo¹,

Zhu²,

Niu³

et al. 2017

IJN

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Multidrug resistance (MDR) remains a major challenge for providing effective chemotherapy for many cancer patients. To address this issue, we report an intelligent polymer-based drug co-delivery system which could enhance and accelerate cellular uptake and reverse MDR. The nanodrug delivery systems were constructed by encapsulating disulfiram (DSF), a P-glyco-protein (P-gp) inhibitor, into the hydrophobic core of poly(ethylene glycol)- block -poly( l -lysine) (PEG- b -PLL) block copolymer micelles, as well as 2,3-dimethylmaleic anhydride (DMA) and paclitaxel (PTX) were grafted on the side chain of l -lysine simultaneously. The surface charge of the drug-loaded micelles represents as negative in plasma (pH 7.4), which is helpful to prolong the circulation time, and in a weak acid environment of tumor tissue (pH 6.5–6.8) it can be reversed to positive, which is in favor of their entering into the cancer cells. In addition, the carrier could release DSF and PTX successively inside cells. The results of in vitro studies show that, compared to the control group, the DSF and PTX co-loaded micelles with charge reversal exhibits more effective cellular uptake and significantly increased cytotoxicity of PTX to MCF-7/ADR cells which may be due to the inhibitory effect of DSF on the efflux function of P-gp. Accordingly, such a smart pH-sensitive nanosystem, in our opinion, possesses significant potential to achieve combinational drug delivery and overcome drug resistance in cancer therapy.

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Section: Resultsmentioning

confidence: 99%

pH-triggered surface charge-switchable polymer micelles for the co-delivery of paclitaxel/disulfiram and overcoming multidrug resistance in cancer

Huo¹,

Zhu²,

Niu³

et al. 2017

IJN

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“…A similar result has been reported in the literature. [21][22][23] The characteristics of the resulting block copolymer with different molecular weights are listed in Table I.…”

Section: Resultsmentioning

confidence: 99%

Self-Assembled Monomethoxy (Polyethylene Glycol)-b-P(D,L-Lactic-co-Glycolic Acid)-b-P(L-Glutamic Acid) Hybrid-Core Nanoparticles for Intracellular pH-Triggered Release of Doxorubicin

Xu¹,

Cai²,

Gou³

et al. 2015

j biomed nanotechnol

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Triblock copolymers, Monomethoxy (Polyethylene glycol)-b-P(D,L-lactic-co-glycolic acid)-b-P(L-glutamic acid) (mPEG-PLGA-PGlu) with different molecular weights, were synthesized and mPEG(5k)-PLGA(20.5k)-PGlu(7.9k) were self-assembled into negatively charged nanoparticles with a hybrid core of PLGA and PGlu, and a stealth PEG shell. Because of electrostatic interaction with the negative hybrid-core, the model drug, doxorubicin (DOX), could be easily loaded into the hybrid-core nanoparticles with a high drug loading of ca. 25%. The hydrophobic interaction provided by PLGA could increase the stability of drug-loaded nanoparticles with no change in particle size for at least 3 days and only minor drug leakage (< 0.5%) in pH7.4 physiological media. Due to protonation of PGlu block in pH5.0 medium, the hybrid-core of these nanoparticles was destroyed, as shown by transmission electron microscopy, and this resulted in an increase in the pH-triggered release of DOX from 38.9% in pH7.4 release medium to 71% in pH5.0 release medium at 24 h. In vitro cytotoxicity testing involving MCF-7 and NCI-H460 cells showed that DOX-loaded nanoparticles were more cytotoxic to both types of cells than free DOX. Time-dependent cellular uptake of the drug-loaded nanoparticles was observed and at least 4 hours was required for rapid internalization through caveolinmediated endocytosis and macropinocytosis by MCF-7 cells into the endosomes where pH-trigged release of DOX from the nanoparticles occurred. The hybrid-core nanoparticles represent a potentially useful therapeutic delivery system for cationic drugs due to their high drug loading, high stability in physiological media and intracellular pH-triggered release.

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“…[143] Although such polymer-drug conjugates were widely investigated, only a few polymers, such as PLA,[144, 145] PEG,[146] N-(2-hydroxypropyl)methacrylamide (HPMA) [147] and poly(L-glutamic acid) (PGA) [148] have been systemically examined or have entered clinical trials. In a very innovative approach, Cheng and co-workers used PTX as a drug initiator to formulate PTX-PLA conjugates via living polymerization.…”

Section: Prodrug Strategiesmentioning

confidence: 99%

Preclinical development of drug delivery systems for paclitaxel-based cancer chemotherapy

Wang

Porter

Konstantopoulos

et al. 2017

Journal of Controlled Release

135

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Paclitaxel (PTX) is one of the most successful drugs ever used in cancer chemotherapy, acting against a variety of cancer types. Formulating PTX with Cremophor EL and ethanol (Taxol®) realized its clinical potential, but the formulation falls short of expectations due to side effects such as peripheral neuropathy, hypotension, and hypersensitivity. Abraxane®, the albumin bound PTX, represents a superior replacement of Taxol® that mitigates the side effects associated with Cremophor EL. While Abraxane® is now considered a gold standard in chemotherapy, its 21% response rate leaves much room for further improvement. The quest for safer and more effective cancer treatments has led to the development of a plethora of innovative PTX formulations, many of which are currently undergoing clinical trials. In this context, we review recent development of PTX drug delivery systems and analyze the design principles underpinning each delivery strategy. We chose several representative examples to highlight the opportunities and challenges of polymeric systems, lipid-based formulations, as well as prodrug strategies.

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Well-Defined Degradable Brush Polymer–Drug Conjugates for Sustained Delivery of Paclitaxel

Cited by 120 publications

References 45 publications

pH-triggered surface charge-switchable polymer micelles for the co-delivery of paclitaxel/disulfiram and overcoming multidrug resistance in cancer

pH-triggered surface charge-switchable polymer micelles for the co-delivery of paclitaxel/disulfiram and overcoming multidrug resistance in cancer

Self-Assembled Monomethoxy (Polyethylene Glycol)-<I>b</I>-<I>P</I>(<I>D</I>,<I>L</I>-Lactic-<I>co</I>-Glycolic Acid)-<I>b</I>-<I>P</I>(<I>L</I>-Glutamic Acid) Hybrid-Core Nanoparticles for Intracellular pH-Triggered Release of Doxorubicin

Preclinical development of drug delivery systems for paclitaxel-based cancer chemotherapy

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