Development of Disulfide Core‐Crosslinked Pluronic Nanoparticles as an Effective Anticancer‐Drug‐Delivery System

Al-Nahain, Abdullah; Lee, Haeshin; Lee, Young Sun; Lee, Kang Dae; Park, Soo Jung

doi:10.1002/mabi.201100083

Cited by 66 publications

(16 citation statements)

References 43 publications

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“…Devices such as disulfide-linked micelles for anticancer-related drug delivery utilize the disulfides to permit triggered release in reducing environments. 51–55,58 Thus, employing maleimide–arylthiol adducts may increase blood stability and prolong the timescale of drug delivery.…”

Section: Resultsmentioning

confidence: 99%

“…0.5–10 mM), providing a level of stability for conjugates and hydrogels outside the cell and aiding in rapid degradation of disulfides intracellularly. 49,50 Accordingly, disulfides have been utilized, mainly with aims in tumor therapies, in many drug conjugates and delivery matrices, including disulfide-stabilized micelles for delivery of anticancer drugs, 51–56 disulfide-stabilized vesicles, 57 disulfide crosslinked nanoparticles, 58 carbon nanotubes with disulfide-tethered drugs 59 and targeting molecules with disulfide-linked taxoid anticancer agents. 60 …”

Section: Introductionmentioning

confidence: 99%

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Reversible maleimide–thiol adducts yield glutathione-sensitive poly(ethylene glycol)–heparin hydrogels

2013

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We have recently reported that retro Michael-type addition reactions can be employed for producing labile chemical linkages with tunable sensitivity to physiologically relevant reducing potentials. We reasoned that such strategies would also be useful in the design of glutathione-sensitive hydrogels for a variety of targeted delivery and tissue engineering applications. In this report, we describe hydrogels in which maleimide-functionalized low molecular weight heparin (LMWH) is crosslinked with various thiol-functionalized poly(ethylene glycol) (PEG) multi-arm star polymers. Judicious selection of the chemical identity of the thiol permits tuning of degradation via previously unstudied, but versatile chemical methods. Thiol pKa and hydrophobicity affected both the gelation and degradation of these hydrogels. Maleimide–thiol crosslinking reactions and retro Michael-type addition reactions were verified with 1H NMR during the crosslinking and degradation of hydrogels. PEGs esterified with phenylthiol derivatives, specifically 4-mercaptophenylpropionic acid or 2,2-dimethyl-3-(4-mercaptophenyl)propionic acid, induced sensitivity to glutathione as shown by a decrease in hydrogel degradation time of 4-fold and 5-fold respectively, measured via spectrophotometric quantification of LMWH. The degradation proceeded through the retro Michael-type addition of the succinimide thioether linkage, with apparent pseudo-first order reaction constants derived from oscillatory rheology experiments of 0.039 ± 0.006 h−1 and 0.031 ± 0.003 h−1. The pseudo-first order retro reaction constants were approximately an order of magnitude slower than the degradation rate constants for hydrogels crosslinked via disulfide linkages, indicating the potential use of these Michael-type addition products for reduction-mediated release and/or degradation, with increased blood stability and prolonged drug delivery timescales compared to disulfide moieties.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Reversible maleimide–thiol adducts yield glutathione-sensitive poly(ethylene glycol)–heparin hydrogels

2013

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“…Micelles possessing this crosslinking are more stable in circulation but upon internalized into a cell and exposure to high levels of glutathione in this environment, the stability of the system is disrupted, facilitating drug release (Heffernan and Murthy, 2009; Xu et al, 2009). Abdullah Al et al (2011) described thiolated pluronic micelles with cores formed by disulfide bonds of functionalized Pluronic F127, a PEO-PPO-PEO triblock copolymer. At increasing concentrations of the reducing agent dithiothreitol (DTT), increasing paclitaxel release was observed.…”

Section: Stimulus-triggered Release Of Therapeutic Agentsmentioning

confidence: 99%

The potential of polymeric micelles in the context of glioblastoma therapy

et al. 2013

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Glioblastoma multiforme (GBM), a type of malignant glioma, is the most common form of brain cancer found in adults. The current standard of care for GBM involves adjuvant temozolomide-based chemotherapy in conjunction with radiotherapy, yet patients still suffer from poor outcomes with a median survival of 14.6 months. Many novel therapeutic agents that are toxic to GBM cells in vitro cannot sufficiently accumulate at the site of an intracranial tumor after systemic administration. Thus, new delivery strategies must be developed to allow for adequate intratumoral accumulation of such therapeutic agents. Polymeric micelles offer the potential to improve delivery to brain tumors as they have demonstrated the capacity to be effective carriers of chemotherapy drugs, genes, and proteins in various preclinical GBM studies. In addition to this, targeting moieties and trigger-dependent release mechanisms incorporated into the design of these particles can promote more specific delivery of a therapeutic agent to a tumor site. However, despite these advantages, there are currently no micelle formulations targeting brain cancer in clinical trials. Here, we highlight key aspects of the design of polymeric micelles as therapeutic delivery systems with a review of their clinical applications in several non-brain tumor cancer types. We also discuss their potential to serve as nanocarriers targeting GBM, the major barriers preventing their clinical implementation in this disease context, as well as current approaches to overcome these limitations.

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“…[8][9][10] Environmentally, responsive technologies (eg, those based on pH sensitivity, thermal sensitivity, and redox sensitivity), combined with covalent cross-linking, have exhibited outstanding performance in the controlled release of encapsulated drugs. [11][12][13][14][15] In addition, ionic cross-linking, namely the electrostatic interaction between the positive and negative charges of the hydrophobic polymer blocks, is also a good choice in the micellar core. 16 On the other hand, weakly acidic interstitial fluid (pH 6.75-7.23) in solid tumors and acidic endosomes/ lysosomes (pH 4.0-5.5) in cells possess the characteristic acidic environment.…”

Section: Introductionmentioning

confidence: 99%

Acid-triggered core cross-linked nanomicelles for targeted drug delivery and magnetic resonance imaging in liver cancer cells

Li¹,

Li²,

Yi³

et al. 2013

IJN

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Purpose:To research the acid-triggered core cross-linked folate-poly(ethylene glycol)-b-poly [N-(N′,N′-diisopropylaminoethyl) glutamine] (folated-PEG-P[GA-DIP]) amphiphilic block copolymer for targeted drug delivery and magnetic resonance imaging (MRI) in liver cancer cells. Methods:As an appropriate receptor of protons, the N,N-diisopropyl tertiary amine group (DIP) was chosen to conjugate with the side carboxyl groups of poly(ethylene glycol)-b-poly (L-glutamic acid) to obtain PEG-P(GA-DIP) amphiphilic block copolymers. By ultrasonic emulsification, PEG-P(GA-DIP) could be self-assembled to form nanosized micelles loading doxorubicin (DOX) and superparamagnetic iron oxide nanoparticles (SPIONs) in aqueous solution. When PEG-P(GA-DIP) nanomicelles were combined with folic acid, the targeted effect of folated-PEG-P(GA-DIP) nanomicelles was evident in the fluorescence and MRI results. Results: To further increase the loading efficiency and the cell-uptake of encapsulated drugs (DOX and SPIONs), DIP (pK a ≈6.3) groups were linked with ∼50% of the side carboxyl groups of poly(L-glutamic acid) (PGA), to generate the core cross-linking under neutral or weakly acidic conditions. Under the acidic condition (eg, endosome/lysosome), the carboxyl groups were neutralized to facilitate disassembly of the P(GA-DIP) blocks' cross-linking, for duly accelerating the encapsulated drug release. Combined with the tumor-targeting effect of folic acid, specific drug delivery to the liver cancer cells and MRI diagnosis of these cells were greatly enhanced. Conclusion: Acid-triggered and folate-decorated nanomicelles encapsulating SPIONs and DOX, facilitate the targeted MRI diagnosis and therapeutic effects in tumors.

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Development of Disulfide Core‐Crosslinked Pluronic Nanoparticles as an Effective Anticancer‐Drug‐Delivery System

Cited by 66 publications

References 43 publications

Reversible maleimide–thiol adducts yield glutathione-sensitive poly(ethylene glycol)–heparin hydrogels

Reversible maleimide–thiol adducts yield glutathione-sensitive poly(ethylene glycol)–heparin hydrogels

The potential of polymeric micelles in the context of glioblastoma therapy

Acid-triggered core cross-linked nanomicelles for targeted drug delivery and magnetic resonance imaging in liver cancer cells

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