Novel reduction-sensitive micelles for triggered intracellular drug release

Peng, Sun; Zhou, Danhua; Gan, Zhihua

doi:10.1016/j.jconrel.2010.11.005

Cited by 67 publications

(39 citation statements)

References 35 publications

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“…(i) The hydroxyl group of NLG919 was activated with 4-nitrophenyl chloroformate to give NLG-NO 2 . (ii) The MBC monomer was synthesized according to the literature 23 . (iii) POEG (M n =9 kDa) was synthesized by RAFT polymerization as reported previously 24 and further served as a Macro-RAFT agent to initiate polymerization of the MBC monomer.…”

Section: Resultsmentioning

confidence: 99%

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Programmable co-delivery of the immune checkpoint inhibitor NLG919 and chemotherapeutic doxorubicin via a redox-responsive immunostimulatory polymeric prodrug carrier

et al. 2017

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To achieve synergistic therapeutic efficacy and prevent cancer relapse, chemotherapy and immunotherapy have been combined as a new modality for tumor treatment. In this work, we designed a redox-responsive immunostimulatory polymeric prodrug carrier, PSSN10, for programmable co-delivery of an immune checkpoint inhibitor NLG919 (NLG) and a chemotherapeutic doxorubicin (DOX). NLG-containing PSSN10 prodrug polymers were self-assembled into nano-sized micelles that served as a carrier to load DOX (DOX/PSSN10 micelles). DOX/PSSN10 micelles displayed spherical morphology with a size of ∼170 nm. DOX was effectively loaded into PSSN10 micelles with a loading efficiency of 84.0%. In vitro DOX release studies showed that rapid drug release could be achieved in the highly redox environment after intracellular uptake by tumor cells. In 4T1.2 tumor-bearing mice, DOX/PSSN10 micelles exhibited greater accumulation of DOX and NLG in the tumor tissues compared with other organs. The PSSN10 carrier dose-dependently enhanced T-cell immune responses in the lymphocyte-Panc02 co-culture experiments, and significantly inhibited tumor growth in vivo. DOX/PSSN10 micelles showed potent cytotoxicity in vitro against 4T1.2 mouse breast cancer cells and PC-3 human prostate cancer cells comparable to that of DOX. In 4T1.2 tumor-bearing mice, DOX/PSSN10 mixed micelles (5 mg DOX/kg, iv) was more effective than DOXIL (a clinical formulation of liposomal DOX) or free DOX in inhibiting the tumor growth and prolonging the survival of the treated mice. In addition, a more immunoactive tumor microenvironment was observed in the mice treated with PSSN10 or DOX/PSSN10 micelles compared with the other treatment groups. In conclusion, systemic delivery of DOX via PSSN10 nanocarrier results in synergistic anti-tumor activity.

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Section: Resultsmentioning

confidence: 99%

“…2-Azobis(isobutyronitrile) (AIBN, Sigma-Aldrich) was purified by recrystallization in anhydrous ethanol 22 . N , N ′-( t -butyoxycarbonyl)cystamine (MBC) 23 and POEG macroCTA 24 were prepared according to the literature. All other reagents were of analytical or chromatographic grade.…”

Section: Methodsmentioning

confidence: 99%

Programmable co-delivery of the immune checkpoint inhibitor NLG919 and chemotherapeutic doxorubicin via a redox-responsive immunostimulatory polymeric prodrug carrier

et al. 2017

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“…In the past several years, reduction-sensitive degradable nanoparticles have received particular attention for enhanced intracellular drug and protein delivery, [24][25][26][27][28] taking advantage of the fact that there is a high reducing potential inside the tumor cells, which is about 2-3 orders of magnitude higher than that in the extracellular environment including blood. 29,30 The work from different groups has demonstrated that reduction-responsive polymeric nanocarriers exhibit significantly improved in vitro and in vivo antitumor efficacy as compared to their reduction-insensitive counterparts.…”

Section: Introductionmentioning

confidence: 99%

Reductively degradable α-amino acid-based poly(ester amide)-graft-galactose copolymers: facile synthesis, self-assembly, and hepatoma-targeting doxorubicin delivery

Sun

Zou

et al. 2015

Biomater. Sci.

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Novel reductively degradable α-amino acid-based poly(ester amide)-graft-galactose (SSPEA-Gal) copolymers were designed and developed to form smart nano-vehicles for active hepatoma-targeting doxorubicin (DOX) delivery. SSPEA-Gal copolymers were readily synthesized via solution polycondensation reaction of di-p-toluenesulfonic acid salts of bis-l-phenylalanine 2,2-thiodiethanol diester and bis-vinyl sulfone functionalized cysteine hexanediol diester with dinitrophenyl ester of adipic acid, followed by conjugating with thiol-functionalized galactose (Gal-SH) via the Michael addition reaction. SSPEA-Gal formed unimodal nanoparticles (PDI = 0.10 - 0.12) in water, in which average particle sizes decreased from 138 to 91 nm with increasing Gal contents from 31.6 wt% to 42.5 wt%. Notably, in vitro drug release studies showed that over 80% DOX was released from SSPEA-Gal nanoparticles within 12 h under an intracellular mimicking reductive conditions, while low DOX release (<20%) was observed for reduction-insensitive PEA-Gal nanoparticles under otherwise the same conditions and SSPEA-Gal nanoparticles under non-reductive conditions. Notably, SSPEA-Gal nanoparticles exhibited high specificity to asialoglycoprotein receptor (ASGP-R)-overexpressing HepG2 cells. MTT assays using HepG2 cells showed that DOX-loaded SSPEA-Gal had a low half maximal inhibitory concentration (IC50) of 1.37 μg mL(-1), approaching that of free DOX. Flow cytometry and confocal laser scanning microscopy studies confirmed the efficient uptake of DOX-loaded SSPEA-Gal nanoparticles by HepG2 cells as well as fast intracellular DOX release. Importantly, SSPEA-Gal and PEA-Gal nanoparticles were non-cytotoxic to HepG2 and MCF-7 cells up to a tested concentration of 1.0 mg mL(-1). These tumor-targeting and reduction-responsive degradable nanoparticles have appeared as an interesting multi-functional platform for advanced drug delivery.

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“…Although these nanovehicles show promise in selective delivery of therapeutic agents to target sites, several intractable problems (e.g., the premature drug leakage from carriers and poor intracellular drug-release property that lead to an insufficient drug bioavailability for killing cancer cells and undesired side effects) have not been completely overcome yet [7], [8], [9]. In this regard, substantial efforts have been devoted to the development of stimuli-responsive devices as novel drug delivery systems capable of controlling payload release in response to biological stimuli such as temperature [10], [11], pH [12], [13], [14], [15], and redox potential [16], [17], [18]. The stimuli-triggered drug liberation could significantly promote therapeutic efficacy and minimize side effects.…”

Section: Introductionmentioning

confidence: 99%

Dual-Layered Nanogel-Coated Hollow Lipid/Polypeptide Conjugate Assemblies for Potential pH-Triggered Intracellular Drug Release

et al. 2014

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To achieve effective intracellular anticancer drug delivery, the polymeric vesicles supplemented with the pH-responsive outlayered gels as a delivery system of doxorubicin (DOX) were developed from self-assembly of the lipid/polypeptide adduct, distearin grafted poly(γ-glutamic acid) (poly(γ-GA)), followed by sequential deposition of chitosan and poly(γ-GA-co-γ-glutamyl oxysuccinimide)-g-monomethoxy poly(ethylene glycol) in combination with in situ covalent cross-linking on assembly surfaces. The resultant gel-caged polymeric vesicles (GCPVs) showed superior performance in regulating drug release in response to the external pH change. Under typical physiological conditions (pH 7.4 and 37°C) at which the γ-GA/DOX ionic pairings remained mostly undisturbed, the dense outlayered gels of GCPVs significantly reduced the premature leakage of the uncomplexed payload. With the environmental pH being reduced from pH 7.4 to 4.7, the drug liberation was appreciably promoted by the massive disruption of the ionic γ-GA/DOX complexes along with the significant swelling of nanogel layers upon the increased protonation of chitosan chain segments. After being internalized by HeLa cells via endocytosis, GCPVs exhibited cytotoxic effect comparable to free DOX achieved by rapidly releasing the payload in intracellular acidic endosomes and lysosomes. This strongly implies the great promise of such unique GCPVs as an intracellular drug delivery carrier for potential anticancer treatment.

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Novel reduction-sensitive micelles for triggered intracellular drug release

Cited by 67 publications

References 35 publications

Programmable co-delivery of the immune checkpoint inhibitor NLG919 and chemotherapeutic doxorubicin via a redox-responsive immunostimulatory polymeric prodrug carrier

Programmable co-delivery of the immune checkpoint inhibitor NLG919 and chemotherapeutic doxorubicin via a redox-responsive immunostimulatory polymeric prodrug carrier

Reductively degradable α-amino acid-based poly(ester amide)-graft-galactose copolymers: facile synthesis, self-assembly, and hepatoma-targeting doxorubicin delivery

Dual-Layered Nanogel-Coated Hollow Lipid/Polypeptide Conjugate Assemblies for Potential pH-Triggered Intracellular Drug Release

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