Publications by authors named "Rupei Tang"

64 Publications

A small molecule nanodrug consisting of pH-sensitive ortho ester-dasatinib conjugate for cancer therapy.

Eur J Pharm Biopharm 2021 Jun 14;163:188-197. Epub 2021 Apr 14.

Engineering Research Center for Biomedical Materials, School of Life Science, Anhui University, 111 Jiulong Road, Hefei, Anhui Province 230601, PR China. Electronic address:

The main objective of this paper is to develop a self-delivered prodrug system with nanoscale characteristics to enhance the efficacy of tumor therapy. The pH-sensitive prodrug was composed of ortho ester-linked dasatinib (DAS-OE), which was further self-assembled with or without doxorubicin (DOX) to obtain two carrier-free nanoparticles (DOX/DAS-OE NPs or DAS-OE NPs). The prodrug-based nanoparticles united the superiorities of small molecules and nano-assemblies together and displayed well-defined structure, uniform spherical shape, high drug loading ratio and on-demand drug release behavior. The drug loading content of DAS and DOX was 61.6% and 21.9%, respectively, and more than 80.2% of DAS and 60.2% DOX were released from DOX/DAS-OE NPs within 20 h at pH 5.0. Both in vitro and in vivo studies demonstrated that the pH-sensitive ortho ester bonds in the prodrug underwent hydrolysis to release DAS and DOX simultaneously after cellular internalization, resulting in remarkable antitumor effect. Tumor growth inhibition rate was 19.9% (free DAS), 35.5% (free DOX), 66.3% (DAS-OE NPs) and 82.8% (DOX/DAS-OE NPs), respectively. Thus, the ortho ester-linked prodrug system shows great potentials in cancer therapy.
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http://dx.doi.org/10.1016/j.ejpb.2021.04.008DOI Listing
June 2021

Dynamic methotrexate nano-prodrugs with detachable PEGylation for highly selective synergistic chemotherapy.

Colloids Surf B Biointerfaces 2021 May 10;201:111619. Epub 2021 Feb 10.

Engineering Research Center for Biomedical Materials, Anhui Key Laboratory of Modern Biomanufacturing, School of Life Sciences, Anhui University, 111 Jiulong Road, Hefei, Anhui Province, 230601, PR China. Electronic address:

To promote the highly selective synergistic chemotherapy, the pH-ultra-sensitive dynamic methotrexate nano-prodrugs with detachable PEGylation were successfully prepared via facile method, and the synergistic nanodrugs could be further constructed through encapsulating Doxorubicin (DOX) following the self-assembly process. The nano-prodrugs exhibited the low critical micelle concentration (CMC), negative zeta potential and stability for 5 days in PBS and FBS at physiological pH (7.4) for stable blood circulation, DePEGylation and dynamic size change at tumoral extracellular pH (6.8) for improved tumor accumulation and cellular internalization, and efficiently synergistic drug release at tumoral intracellular pH (5.0) for enhanced tumor apoptosis and cytotoxicity. Moreover, in vivo experiment suggested that the synergistic nanodrugs could significantly improve tumor accumulation and restrain tumor growth while decreasing adverse effects. Therefore, the dynamic methotrexate nano-prodrugs with detachable PEGylation are easy to clinically transform for highly selective synergistic chemotherapy.
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http://dx.doi.org/10.1016/j.colsurfb.2021.111619DOI Listing
May 2021

Self-assembled 5-fluorouracil-cinnamaldehyde nanodrugs for greatly improved chemotherapy in vivo.

J Biomater Appl 2021 Feb 16:885328221989539. Epub 2021 Feb 16.

School of Life Science, 12487Anhui University, Hefei, China.

The preferred cancer treatment is to achieve a high therapeutic effect as well as reduce side effects. In this study, we developed carrier-free nano drugs based on 5-fluorouracil (5FU) and cinnamaldehyde (CA) to meet the above goals. Two model drugs were spliced by acetal linkage and ester bond, which could self-assemble into nano drug particles (5FU-CA NPs) with a size of ∼170 nm. In vitro cell experiments showed 5FU-CA NPs were efficiently internalized by HepG2 cells. They then quickly exerted dual drug activities by the cleavage of acetal and ester bond, resulting in enhanced cell-killing efficacy and apoptosis. Synergistic mechanisms were achieved via the anti-metabolic effects mediated by 5FU-COOH and the oxidative damage induced by CA. In vivo anti-tumor evaluation further indicated that 5FU-CA NPs had higher tumor growth inhibition than 5FU-COOH/CA mixture (5FU-COOH + CA) and exhibited lower systemic toxicity under the same reducing dose of each drug. Overall, this is a successful synergistic anti-tumor attempt through rational self-assembly of drugs with different mechanisms and it can be extrapolated to other agents.
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http://dx.doi.org/10.1177/0885328221989539DOI Listing
February 2021

Dynamic micelles with detachable PEGylation at tumoral extracellular pH for enhanced chemotherapy.

Asian J Pharm Sci 2020 Nov 3;15(6):728-738. Epub 2020 Jan 3.

Engineering Research Center for Biomedical Materials, School of Life Science, Anhui University, Hefei 230601, China.

Although surface PEGylation of nanomedicines can decrease serum protein adsorption , it also blocks uptake by tumor cells. This dilemma could be overcome by employing detachably PEGylated strategy at tumoral extracellular microenvironment to achieve improved cellular uptake while prolonged circulation times. Herein, the amphiphilic graft copolymers with pH-sensitive ortho ester-linked mPEG in side chains and polyurethanes in backbone, can self-assemble into the free and doxorubicin (DOX)-loaded micelles. The pH-sensitive micelles could undergo several characteristics as follows: (i) PEGylated shells for stability in sodium dodecyl sulfonate (SDS) solution; (ii) DePEGylation via degradation of ortho ester linkages at tumoral extracellular pH (6.5) for gradually dynamic size changes and effective release of DOX; and (iii) enhanced cellular uptake and cytotoxicity via positive DOX. Moreover, the dynamic micelles with detachable PEGylation could quickly penetrate the centers of SH-SY5Y multicellular spheroids (MCs) and strongly inhibit tumor growth and , and might be considered as promising and effective drug carriers in tumor therapy.
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http://dx.doi.org/10.1016/j.ajps.2019.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750827PMC
November 2020

Chemosensitizing micelles self-assembled from amphiphilic TPGS-indomethacin twin drug for significantly synergetic multidrug resistance reversal.

J Biomater Appl 2021 Mar 6;35(8):994-1004. Epub 2020 Dec 6.

Engineering Research Center for Biomedical Materials, School of Life Science, Anhui Key Laboratory of Modern Biomanufacturing, 12487Anhui University, Hefei, China *Equal contributors.

Vitamin E d-ɑ-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS) and indomethacin (IDM) can reverse multidrug resistance (MDR) via inhibiting P-glycoprotein (P-gp) and multidrug resistance associated protein 1 (MRP1) respectively, but their drawbacks in physicochemical properties limit their clinical application. To overcome these defects and enhance MDR reversal, the amphiphilic TPGS-IDM twin drug was successfully synthesized via esterification, and could self-assemble into free and paclitaxel-loaded (PTX-loaded) micelles. The micelles exhibited lower CMC values (5.2 × 10mg/mL), long-term stability in PBS (pH 7.4) for 7 days and SDS solution (5 mg/mL) for 3 days, and effective drug release at esterase/pH 5.0. Moreover, the micelles could down-regulate ATP levels and promote ROS production in MCF-7/ADR via the mitochondrial impairment, therefore achieving MDR reversal and cell apoptosis. Additionally, the PTX-loaded micelles could significantly inhibit the cell proliferation and promote apoptosis for MCF-7/ADR via the synergistic chemosensitizing effect of TPGS and IDM, and synergistic cytotoxic effect of TPGS and PTX. Thus, the chemosensitizing micelles self-assembled from amphiphilic TPGS-indomethacin twin drug have the great potentials for reversing MDR in clinical cancer therapy.
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http://dx.doi.org/10.1177/0885328220975177DOI Listing
March 2021

Use of Microfluidics to Fabricate Bioerodable Lipid Hybrid Nanoparticles Containing Hydromorphone or Ketamine for the Relief of Intractable Pain.

Pharm Res 2020 Oct 2;37(10):211. Epub 2020 Oct 2.

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia.

Purpose: For patients with intractable cancer-related pain, administration of strong opioid analgesics and adjuvant agents by the intrathecal (i.t.) route in close proximity to the target receptors/ion channels, may restore pain relief. Hence, the aim of this study was to use bioerodable polymers to encapsulate an opioid analgesic (hydromorphone) and an adjuvant drug (ketamine) to produce prolonged-release formulations for i.t. injection.

Methods: A two-stage microfluidic method was used to fabricate nanoparticles (NPs). The physical properties were characterised using dynamic light scattering and transmission electron microscopy. A pilot in vivo study was conducted in a rat model of peripheral neuropathic pain.

Results: The in vitro release of encapsulated payload from NPs produced with a polymer mixture (CPP-SA/PLGA 50:50) was sustained for 28 days. In a pilot in vivo study, analgesia was maintained over a three day period following i.t. injection of hydromorphone-loaded NPs at 50 μg. Co-administration of ketamine-loaded NPs at 340 μg did not increase the duration of analgesia significantly.

Conclusions: The two-stage microfluidic method allowed efficient production of analgesic/adjuvant drug-loaded NPs. Our proof-of-principle in vivo study shows prolonged hydromorphone analgesic for 78 h after single i.t. injection. At the i.t. dose administered, ketamine released from NPs was insufficient to augment hydromorphone analgesia.
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http://dx.doi.org/10.1007/s11095-020-02939-0DOI Listing
October 2020

pH-sensitive deoxycholic acid dimer for improving doxorubicin delivery and antitumor activity in vivso.

Colloids Surf B Biointerfaces 2020 Dec 12;196:111319. Epub 2020 Aug 12.

Engineering Research Center for Biomedical Materials, Anhui Key Laboratory of Modern Biomanufacturing, School of Life Sciences, Anhui University, 111 Jiulong Road, Hefei, Anhui Province, 230601, PR China. Electronic address:

To develop simple and effective nano-drug delivery systems remains a major challenge in cancer treatment. Herein, we synthesized an ortho ester-linked deoxycholic acid dimer (DCA-OE), which could effectively self-assemble with doxorubicin (DOX) to form stable nanoparticles (DCA-OE/DOX NPs) by a single emulsion method. DCA-based nanoparticles had a desirable size (∼200 nm), morphology (spherical shape), and high drug encapsulation (drug loading content of ∼18.0 %, drug loading efficiency of ∼77.6 %). DCA-OE could improve the stability and solubility of DOX in physiological environment, while pH-sensitive ortho ester linkage endowed the ability to release DOX quickly in cancer cells. In vitro cytotoxicity and apoptosis verified drug-loaded dimer nanoparticles had similar toxicity with free DOX. Besides, these particles could efficiently accumulate and penetrate into human liver carcinoma cell line (HepG2) multicellular spheroids, thus resulting in enhanced antitumor effect. In vivo tests further exhibited that DCA-OE/DOX NPs had lower systemic toxicity and higher tumor inhibition effect, and its tumor inhibition rate was 84.1 %, which was far more than free DOX (49.3 %). Therefore, the strategy to link functional small molecules with ortho ester has great potentials in specific delivery of anticancer drugs.
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http://dx.doi.org/10.1016/j.colsurfb.2020.111319DOI Listing
December 2020

Effective treatment of drug-resistant lung cancer via a nanogel capable of reactivating cisplatin and enhancing early apoptosis.

Biomaterials 2020 10 22;257:120252. Epub 2020 Jul 22.

Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China; Department of Polymeric Materials, School of Materials Science and Engineering, Tongji University, 4800 Caoan Road, Shanghai, 201804, China. Electronic address:

Cisplatin resistance is a daunting obstacle in cancer therapy and one of the major causes for treatment failure due to the inadequate drug activity and apoptosis induction. To overcome cisplatin resistance, we proposed a multifunctional nanogel (designated as Valproate-D-Nanogel) capable of reactivating cisplatin and enhancing early apoptosis. This Valproate-D-Nanogel was prepared through copolymerizing carboxymethyl chitosan with diallyl disulfide and subsequent grafting with valproate to reverse the drug-resistance in cisplatin-resistant human lung adenocarcinoma cancer. It can significantly increase the proportion of G2/M phase (up to 3.2-fold enhancement) to reactivate cisplatin via high level of G2/M arrest induced by valproate. Meanwhile, the intracellular ROS-P53 crosstalk can be upregulated by diallyl disulfide (up to 8-fold increase of ROS) and valproate (up to 18-fold increase of P53) to enhance early apoptosis. The synchronization of enhanced G2/M arrest and ROS-P53 crosstalk devotes to reverse the cisplatin resistance with a high level of resistance reversion index (50.22). As a result, improved in vivo tumor inhibition (up to 15-fold higher compared to free cisplatin) and decreased systemic toxicity was observed after treatment with Valproate-D-Nanogels. Overall, this nanogel can effectively inhibit cisplatin-resistance cancer through combined pathways and provides an effective approach for overcoming cisplatin-resistance in cancer treatment.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120252DOI Listing
October 2020

Hybrid micelles based on Pt (IV) polymeric prodrug and TPGS for the enhanced cytotoxicity in drug-resistant lung cancer cells.

Colloids Surf B Biointerfaces 2020 Jul 12;195:111256. Epub 2020 Jul 12.

Engineering Research Center for Biomedical Materials, School of Life Science, Anhui Key Laboratory of Modern Biomanufacturing, Anhui University, 111 Jiulong Road, Hefei, Anhui Province, 230601, PR China. Electronic address:

Multidrug resistance (MDR) is a primary cause of failure in oncotherapy and interest is growing in the design of multi-stimuli responsive nano-carriers to synergistically deliver chemotherapeutic agents and P-gp inhibitors to reverse MDR. The hybrid micelles based on a Platinum (IV)-coordinate polymeric prodrugs and TPGS were developed to improve chemotherapy and reduce side effects. The pH/redox dual-sensitive polymers were synthesized by condensation polymerization using ortho ester monomer and diamminedichlorodisuccinatoplatinum (DSP). The hybrid micelles possessed uniform size (38 nm) and displayed good stability in various physiological conditions. In contrast, in vitro drug release profiles indicated that these micelles could be completely depolymerized under acidic and reducing environment, thereby more than 80 % cisplatin were released within 12 h at pH 5.0 plus 10 mM DTT. More importantly, a large amount of TPGS released simultaneously could effectively inhibit the function of drug efflux pumps, which significantly enhanced the cytotoxicity of cisplatin against A549/DDP cells. The growth inhibition rate of micelles on A549/DDP multicellular spheroids was 79.5 %, while that of free cisplatin was only 6.8 %. Therefore, these hybrid micelles are promising in overcoming tumor MDR and worth doing further research in vivo and extend to other therapeutic agents.
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http://dx.doi.org/10.1016/j.colsurfb.2020.111256DOI Listing
July 2020

Oxygen-producing catalase-based prodrug nanoparticles overcoming resistance in hypoxia-mediated chemo-photodynamic therapy.

Acta Biomater 2020 08 2;112:234-249. Epub 2020 Jun 2.

Engineering Research Center for Biomedical Materials, Anhui Key Laboratory of Modern Biomanufacturing, School of Life Sciences, Anhui University, 111 Jiulong Road, Hefei, Anhui Province, 230601, PR China. Electronic address:

Extreme hypoxia inside solid tumors is the primary barrier against the advance of chemotherapy and photodynamic therapy (PDT). To address this problem, a hybrid nano-enzyme prodrug system was developed to alleviate hypoxia as well as simultaneously sensitize chemo-photodynamic therapy. Lactobionic acid (LA) and doxorubicin (DOX) precursor (cis-aconitic anhydride-linked doxorubicin, CAD) were pre-conjugated onto the side chain of catalase (CAT), then co-assembled with chlorin e6 (Ce6) to form LA-CAT-CAD@Ce6 nanoparticles (LCC@Ce6-NPs). LA as the active-targeting ligand increased cellular internalization, CAD as the pH-sensitive component triggered rapid drug release, Ce6 as the photosensitizer induced reactive oxygen species (ROS) generation, and CAT decomposed intracellular HO to produce oxygen in situ. Oxygen production efficiently decreased the expression of hypoxia-inducible factor-1α (HIF-1α) and P-glycoprotein (P-gp), which enhanced chemotherapy efficiency. In addition, sufficient oxygen further amplified PDT-mediated cell-killing and apoptosis in hypoxic tumor. In vivo studies showed that combined chemo-photodynamic therapy by LCC@Ce6-NPs led to the most effective inhibition of tumor growth (TGI>90%), and even partially ablated tumor. Thus, this nano-enzyme prodrug platform can be a potentially effective treatment in clinical cancer therapy, and married to other therapeutic agents. STATEMENT OF SIGNIFICANCE: Hypoxia in solid tumors seriously impedes the efficacy of chemotherapy or photodynamic therapy. Herein, we designed hybrid nano-enzyme prodrug particles to improve hypoxia-mediated limitations on cancer therapy. Lactobionic acid (LA) as the hydrophilic outer layer of particles increased cellular uptake by receptor-mediated endocytosis, and cis-aconitic anhydride-linked doxorubicin (CAD) as the pH sensitive component inside particles efficiently triggered DOX and Ce6 release. More importantly, catalase (CAT) as the backbone of particles was capable of greatly relieving tumor hypoxia through catalyzing the decomposition of H2O2 in situ. Oxygen re-generation not only prevented hypoxia-mediated chemo-resistance, but also amplified PDT-induced ROS cell-killing ability. As a result, the multiple combination action of this nano-system could simultaneously sensitize chemo-photodynamic therapy, thus significantly enhancing tumor therapy.
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http://dx.doi.org/10.1016/j.actbio.2020.05.035DOI Listing
August 2020

pH-sensitive bromelain nanoparticles by ortho ester crosslinkage for enhanced doxorubicin penetration in solid tumor.

Mater Sci Eng C Mater Biol Appl 2020 Aug 23;113:111004. Epub 2020 Apr 23.

Engineering Research Center for Biomedical Materials, School of Life Science, Anhui Key Laboratory of Modern Biomanufacturing, Anhui University, 111 Jiulong Road, Hefei, Anhui Province 230601, PR China. Electronic address:

Dense extracellular matrix (ECM) is a primary obstacle that restrains the permeation of therapeutic drugs in tumor tissues. Degrading ECM with bromelain (Br) to increase drug penetration is an attractive strategy to enhance antitumor effects. However, the poor stability in circulation and potential immunogenicity severely limit their applications. In this work, a novel pH-sensitive nanocarrier was prepared by crosslinking Br with an ortho ester-based crosslink agent, and Br still retained a certain ability to degrade ECM after crosslinking. The nanoparticles showed higher DOX release rate than non-sensitive nanoparticles, and DOX release amount reached to 86% at pH 5.5 within 120 h. In vivo experiments revealed that the pH-sensitive nanoparticles could be degraded in mildly acidic condition, and the released Br further promoted nanoparticles penetration in tumor parenchyma via in situ hydrolysis of ECM. Furthermore, Br itself could inhibit the proliferation of tumor cells at high concentration, and produce synergistic antitumor effects with DOX. Finally, tumor growth inhibition of these nanoparticles reached to 62.5%. Overall, the bromelain-based pH-sensitive nanoparticles can be potential drug carriers for efficient drug delivery and tumor treatment.
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http://dx.doi.org/10.1016/j.msec.2020.111004DOI Listing
August 2020

pH-sensitive small molecule nanodrug self-assembled from amphiphilic vitamin B6-E analogue conjugate for targeted synergistic cancer therapy.

Colloids Surf B Biointerfaces 2020 Jul 28;191:111000. Epub 2020 Mar 28.

Engineering Research Center for Biomedical Materials, Anhui Key Laboratory of Modern Biomanufacturing, School of Life Sciences, Anhui University, 111 Jiulong Road, Hefei, Anhui Province, 230601, PR China. Electronic address:

To promote the targeted cancer therapy, the pH-sensitive small molecule nanodrug self-assembled from amphiphilic vitamin B6-E analogue conjugate was successfully constructed. Herein, water-soluble vitamin B6 with pKa (5.6) was chemically conjugated to lipid-soluble vitamin E succinate (α-TOS), which showed selective cancer cell killing ability and this amphiphilic small molecule vitamin conjugate could self-assemble to be free nanoparticles (NPs) and doxorubicin-loaded NPs (α-TOS-B6-NPs-DOX). The small molecule nanodrugs could perform the following characteristic: (i) stability in the sodium dodecyl sulfonate (SDS) solution and long-term storage stability in PBS via surface negative charge; (ii) tumor accumulation by enhanced penetration and retention (EPR) effect; (iii) improved cellular internalization by means of vitamin B6 transporting membrane carrier (VTC); and (iv) facilitating endosomal escape and rapid drug release for synergistic toxicity to tumor cells via charge reversal and ester hydrolysis at intracellular pH and/or esterase. Moreover, α-TOS-B6-NPs-DOX exhibited long blood circulation stability and significant tumor accumulation and inhibition with the decreased side effects in vivo. Thus, the pH-sensitive small molecule nanodrug self-assembled from amphiphilic vitamin B6-E analogue conjugate could be the potential drug carriers in targeted synergistic cancer therapy.
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http://dx.doi.org/10.1016/j.colsurfb.2020.111000DOI Listing
July 2020

Indomethacin-grafted and pH-sensitive dextran micelles for overcoming inflammation-mediated multidrug resistance in breast cancer.

Carbohydr Polym 2020 Jun 7;237:116139. Epub 2020 Mar 7.

Engineering Research Center for Biomedical Materials, Anhui Key Laboratory of Modern Biomanufacturing, School of Life Sciences, Anhui University, 111 Jiulong Road, Hefei, Anhui Province, 230601, PR China. Electronic address:

We first synthesized indomethacin (IND)-grafted dextran copolymer by acetal or ester linkage, which self-assembled with doxorubicin (DOX) into prodrug micelles (ID/DOX or ID/DOX) with the size of ∼200 nm. In vitro drug release test verified ID/DOX could trigger more DOX and IND release by the hydrolysis of acetal than that of ester linkage. A series cells experiments demonstrated pH-sensitive ID/DOX could greatly improve cellular uptake and intracellular drug accumulation, thus enhancing DOX toxicity in drug-resistant tumor cells. ID/DOX was capable of reversing tumor multidrug resistance (MDR) through reducing multidrug resistance-associated protein 1 (MRP1) level (0.23-fold vs control group) and regulating bcl-2/bax pathway, eventually induced more apoptosis in MCF-7/ADR cells. These nanoparticles possessed long-term blood-circulation and high tumor accumulation, thereby reducing side effect and increasing bioavailability. Anti-tumor evaluation showed that ID/DOX possessed the highest tumor growth inhibition (TGI, 92.5 %), which might provide a promising way to overcome malignant tumor resistance.
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http://dx.doi.org/10.1016/j.carbpol.2020.116139DOI Listing
June 2020

Active-targeting and acid-sensitive pluronic prodrug micelles for efficiently overcoming MDR in breast cancer.

J Mater Chem B 2020 04;8(13):2726-2737

Engineering Research Center for Biomedical Materials, School of Life Science, Anhui University, Hefei, 230601, P. R. China.

Multidrug resistance (MDR) seriously hinders therapeutic efficacy in clinical cancer treatment. Herein, we reported new polymeric prodrug micelles with tumor-targeting and acid-sensitivity properties based on two different pluronic copolymers (F127 and P123) for enhancing tumor MDR reversal and chemotherapy efficiency in breast cancer. Hybrid micelles were composed of phenylboric acid (PBA)-modified F127 (active-targeting group) and doxorubicin (DOX)-grafted P123 (prodrug groups), which were named as FBP-CAD. FBP-CAD exhibited good stability in a neutral environment and accelerated drug release under mildly acidic conditions by the cleavage of β-carboxylic amides bonds. In vitro studies demonstrated that FBP-CAD significantly increased cellular uptake and drug concentration in MCF-7/ADR cells through the homing ability of PBA and the anti-MDR effect of P123. In vivo testing further indicated that hybrid micelles facilitated drug accumulation at tumor sites as well as reduced side effects to normal organs. The synergistic effect of active-targeting and MDR-reversal leads to the highest tumor growth inhibition (TGI 78.2%). Thus, these multifunctional micelles provide a feasible approach in nanomedicine for resistant-cancer treatment.
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http://dx.doi.org/10.1039/c9tb02328cDOI Listing
April 2020

Pluronic micelles with suppressing doxorubicin efflux and detoxification for efficiently reversing breast cancer resistance.

Eur J Pharm Sci 2020 Apr 20;146:105275. Epub 2020 Feb 20.

Engineering Research Center for Biomedical Materials, School of Life Sciences, Anhui University, Anhui Key Laboratory of Modern Biomanufacturing, Hefei, Anhui Province 230601, China. Electronic address:

The antitumor activity of doxorubicin (DOX) is often limited owing to the occurrence of multidrug resistance (MDR) during treatment. Herein, we developed hybrid polymeric micelles, which consisted of pluronic F127 as long-circulating helper in blood, and phenylboronic ester-grafted pluronic P123 (PHE) as efflux and detoxification regulator to efficiently deliver DOX and reverse MDR in vivo. Hybrid F127/PHE micelles exhibited higher stability and drug encapsulation (~80%) than simple F127/P123 micelles due to its lower CMC, and displayed in vitro drug release in a hydrogen peroxide (HO)-sensitive manner. Besides, DOX-loaded hybrid micelles (F127/PHE-DOX) possessed higher cell-killing ability and induce more apoptotic in MDR-cells than other groups, which was probably because it not only could greatly increase intracellular drug concentration by inhibiting P-gp mediated drug efflux, but also promote reactive oxygen species (ROS) generation by decreasing glutathione (GSH) levels. Besides, in vivo evaluation indicated that F127/PHE-DOX could well accumulate at tumor regions and exhibit the strongest tumor growth inhibition (TGI 87.87%) accompanied with low side effects. As a result, F127/PHE micelles had great potentials as a platform for anticancer drugs delivery and tumor MDR reversal in clinical application.
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http://dx.doi.org/10.1016/j.ejps.2020.105275DOI Listing
April 2020

pH-sensitive pluronic micelles combined with oxidative stress amplification for enhancing multidrug resistance breast cancer therapy.

J Colloid Interface Sci 2020 Apr 14;565:254-269. Epub 2020 Jan 14.

Engineering Research Center for Biomedical Materials, Anhui Key Laboratory of Modern Biomanufacturing, School of Life Sciences, Anhui University, 111 Jiulong Road, Hefei, Anhui Province 230601, PR China. Electronic address:

Multidrug resistance (MDR) is one of the major obstacles to clinical cancer chemotherapy. Herein, we designed new pH-sensitive pluronic micelles with the synergistic effects of oxidative therapy and MDR reversal. Pluronic (P123) was modified with α-tocopheryl succinate (α-TOS) via an acid-labile ortho ester (OE) linkage to give a pH-sensitive copolymer (POT). Self-assembled POT micelles exhibited desirable size (~80 nm), excellent anti-dilution ability, high drug loading (~85%), acid-triggered degradation and drug release behaviours. In vitro cell experiments verified that POT micelles could significantly reverse MDR through suppressing the function of drug effluxs mediated by P123 and induce more reactive oxygen species (ROS) generation mediated by α-TOS, resulting in enhanced cytotoxicity and apoptosis in MDR cells. In vivo studies further revealed that DOX-loaded POT micelles (POT-DOX) possessed the highest drug accumulation (3.03% ID/g at 24 h) and the strongest tumour growth inhibition (TGI 83.48%). Pathological analysis also indicated that POT-DOX could induce more apoptosis or necrosis at the site of tumour without distinct damage to normal tissues. Overall, these smart POT micelles have great potential as promising nano-carriers for MDR reversal and cancer treatment.
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http://dx.doi.org/10.1016/j.jcis.2020.01.029DOI Listing
April 2020

pH-sensitive, dynamic graft polymer micelles via simple synthesis for enhanced chemotherapeutic efficacy.

J Biomater Appl 2020 03 12;34(8):1059-1070. Epub 2019 Dec 12.

Engineering Research Center for Biomedical Materials, School of Life Science, Anhui Key Laboratory of Modern Biomanufacturing, Anhui University, Hefei, China.

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http://dx.doi.org/10.1177/0885328219894695DOI Listing
March 2020

Sequentially dynamic polymeric micelles with detachable PEGylation for enhanced chemotherapeutic efficacy.

Eur J Pharm Biopharm 2019 Dec 22;145:54-64. Epub 2019 Oct 22.

Engineering Research Center for Biomedical Materials, School of Life Science, Anhui University, 111 Jiulong Road, Hefei, Anhui Province 230601, PR China. Electronic address:

To achieve enhanced cancer therapy, a sequentially dynamic polymeric drug delivery system (ortho ester-linked PEGylated poly(disulfide)s-based micelle-doxorubicin (PS-g-OEMPEG-DOX)) is successfully constructed. The PEGylated micelle can keep stable in sodium dodecyl sulfate (SDS) solution at pH 7.4, but be prone to DePEGylation and dynamic size changes via the hydrolysis of ortho ester linkages in side chains at tumoral extracellular pH value (6.5). Moreover, the micelle can rapidly release DOX via the cleavage of poly(disulfide)s in backbone at intracellular reductive milieu (10 mmol/L of dithiothreitol (DTT)). The dynamic micelle with detachable PEGylation achieves the stable blood circulation, improved cellular uptake and cytotoxicity, stronger in vitro penetration and inhibition of tumoral multicellular spheroids, and significant in vivo tumor accumulation and inhibition while decreasing side effects. Thus, the sequentially dynamic polymeric micelle with detachable PEGylation can be considered as a promising and effective drug delivery system in cancer therapy.
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http://dx.doi.org/10.1016/j.ejpb.2019.10.009DOI Listing
December 2019

pH-sensitive carboxymethyl chitosan hydrogels via acid-labile ortho ester linkage as an implantable drug delivery system.

Carbohydr Polym 2019 Dec 23;225:115237. Epub 2019 Aug 23.

Engineering Research Center for Biomedical Materials, Anhui Key Laboratory of Modern Biomanufacturing, School of Life Science, Anhui University, 111 Jiu long Road, Hefei, Anhui Province, 230601, PR China. Electronic address:

A series of pH-sensitive carboxymethyl chitosan (CMCS) hydrogels were prepared via ortho ester linkage. DOX-loaded gelatin nanoparticles with an average diameter of around 50 nm were incorporated into hydrogels to obtain hybrid hydrogels (DOX-NPs-Gel), which could be locally implanted into tumor site in any shape. The physicochemical and mechanical properties of these hydrogels could be easily controlled by adjusting the proportion of crosslinking agent. DOX-NPs-Gel showed the pH-dependent degradation and drug release, and only 29.9% of DOX was released within 144 h at pH 7.4, while the cumulative release reached 49.3% and 65% at pH 6.5 and 5.0, respectively. In vivo study demonstrated that the implanted DOX-NPs-Gel efficiently improved DOX accumulation in tumor site through continuously degradation in mildly acidic environment of tumor tissues, and the tumor volume at the end of experiment was only 81.53 mm, while tumor size reached to 229.22 mm and 174.15 mm after intravenous treatment with free DOX and DOX-NPs, respectively.
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http://dx.doi.org/10.1016/j.carbpol.2019.115237DOI Listing
December 2019

pH-sensitive and pluronic-modified pullulan nanogels for greatly improved antitumor in vivo.

Int J Biol Macromol 2019 Oct 1;139:277-289. Epub 2019 Aug 1.

Engineering Research Center for Biomedical Materials, Anhui Key Laboratory of Modern Biomanufacturing, School of Life Sciences, Anhui University, 111 Jiulong Road, Hefei, Anhui Province 230601, PR China. Electronic address:

It remains a crucial challenge to achieve efficient cellular uptake in tumor cells for nanoscale drug delivery systems. This work described that two multi-functional pullulan nanogels were prepared by co-polymerization between methacrylated pullulan (Pullulan-M) and different crosslink agents, an acid-labile ortho ester-modified pluronic (L61-MOE) or non-acid-sensitive methacrylated pluronic (L61-M). The prepared nanogels showed a regular spherical structure with the size about 200 nm measured by dynamic light scattering and transmission electron microscopy (TEM). Doxorubicin as a model drug was successfully encapsulated into nanogels. As expected, Pul-L61-MOE showed pH-dependent DOX release, and 25% of DOX was released at pH 7.4 while 84.48% of DOX was released at pH 5.0. In vitro cellular uptake and MTT results indicated that pH-sensitive nanogels (Pul-L61-MOE) displayed higher cellular internalization and cytotoxicity than acid-insensitive nanogels (Pul-L61-M) and free DOX. Flow cytometry assay suggested these nanogels remarkably increased intracellular reactive oxygen species (ROS) level and induced more cell apoptosis by the function of pluronic. Finally, in vivo antitumor results indicated that the multi-functional nanogels exhibit supreme antitumor efficiency, and the tumor growth inhibition (TGI) was 83.37%. Therefore, the pH-sensitive pullulan nanogels can be potential nano-carriers for drug delivery in tumor treatment.
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http://dx.doi.org/10.1016/j.ijbiomac.2019.07.220DOI Listing
October 2019

Biochemical characteristics and crystallographic evidence for substrate-assisted catalysis of a β-N-acetylhexosaminidase in Akkermansia muciniphila.

Biochem Biophys Res Commun 2019 09 23;517(1):29-35. Epub 2019 Jul 23.

School of Life Sciences, Anhui University, 111 Jiulong Road, Hefei, Anhui, China; Key Laboratory of Human Microenvironment and Precision Medicine of Anhui Higher Education Institute, Anhui University, 111 Jiulong Road, Hefei, Anhui, China. Electronic address:

In this paper, we characterized Am2136 as a β-N-acetylhexosaminidase from Akkermansia muciniphila to perform the biochemical characteristics and the crystal structure of selenomethionine-labeled Am2136 with GlcNAc complex. Crystallographic evidence suggests that an oxazolinium ion was formed intermediately by the 2-acetamido group during the substrate-assisted catalytic procedure. Structural and kinetic analysis of native Am2136 and D412A, E413A mutants were investigated and the results revealed substantial difference. The K/K value of D412A was decreased 4297-fold compared to native Am2136 revealed that mutation of Asp-412 results in preventing the 2-acetamido substituent from providing anchimeric assistance and thus reducing the catalytic efficiency. Moreover, Am2136 has a wide dependence on pH and temperature, while sensitive to divalent metal ions such as Ca and Mn. These biochemical and crystallographic results provide evidences that Asp-412 residue assists to orient the 2-acetamido group for catalysis. Based on crystallographic evidence and sequence alignment with other GH family 20 enzymes, Asp-412 residue is possibly fundamental for Am2136 during substrate-assisted catalysis.
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http://dx.doi.org/10.1016/j.bbrc.2019.06.150DOI Listing
September 2019

Self-Assembled Indomethacin Dimer Nanoparticles Loaded with Doxorubicin for Combination Therapy in Resistant Breast Cancer.

ACS Appl Mater Interfaces 2019 Aug 30;11(32):28597-28609. Epub 2019 Jul 30.

Engineering Research Center for Biomedical Materials, Anhui Key Laboratory of Modern Biomanufacturing, School of Life Sciences , Anhui University , 111 Jiulong Road , Hefei , Anhui Province 230601 , P. R. China.

An ortho-ester-linked indomethacin (IND) dimer-based nanodrug delivery system was prepared to improve the therapeutic effect of doxorubicin (DOX) by reversing the multidrug resistance. The synthesized dimer (IND-OE) could form stable nanoparticles (IND-OE/DOX) loaded with DOX via the single-emulsion method. Compare to insensitive nanoparticles (IND-C12/DOX), IND-OE/DOX showed a rapid degradation behavior and accelerated drug release at mildly acidic environments. In vitro cell experiments verified that IND-OE nanoparticles could increase DOX concentration due to the efficient intracellular drug release by the degradation of the ortho ester as well as reduced DOX efflux by IND-mediated P-gp downregulation. In vivo studies further demonstrated that IND-OE/DOX displayed the maximized synergetic antitumor efficacy than free DOX or IND-C12/DOX, and the tumor inhibition rates versus saline were 46.78% (free DOX), 60.23% (IND-C12/DOX), and 80.62% (IND-OE/DOX). Overall, this strategy of combination with chemosensitizers and ortho ester linkage has great potential to serve as an amplifying chemotherapy platform against various drug-resistant tumors.
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http://dx.doi.org/10.1021/acsami.9b05855DOI Listing
August 2019

TPGS-grafted and acid-responsive soy protein nanogels for efficient intracellular drug release, accumulation, penetration in 3D tumor spheroids of drug-resistant cancer cells.

Mater Sci Eng C Mater Biol Appl 2019 Sep 9;102:863-875. Epub 2019 May 9.

Engineering Research Center for Biomedical Materials, Anhui Key Laboratory of Modern Biomanufacturing, School of Life Sciences, Anhui University, 111 Jiulong Road, Hefei, Anhui Province 230601, PR China. Electronic address:

The frequent occurrence of multidrug resistance (MDR) in solid tumors is the major obstacle for nano-drug delivery systems (nDDS) to realize the successful cancer chemotherapy. Herein, we had prepared pH-responsive nanogels via cross-linking TPGS-grafted soy protein with an acid-labile ortho ester cross-linker (OEAM) to realize the efficient intracellular drugs release and accumulation, and subsequently enhance therapeutic effect in MDR tumor cells. These nanogels displayed a uniform size (~200 nm) and morphology, and the introduction of ortho ester bonds endowed nanogels stability in neutral environment and acid-degradability in acidic conditions. Cisplatin (CDDP) was successfully loaded into nanogels, which exhibited an accelerated drug release at low pH. The modification of TPGS efficiently improved cellular internalization and drug accumulation in A549/DDP cells by inhibiting the function of drug efflux pumps (MRP2 and ATP7A/7B), leading to higher cytotoxicity and apoptosis. Moreover, TPGS-grafted nanogels also showed better drug accumulation and penetration in tumor-like spheroids, and then remarkably inhibited tumor growth owing to the rapid drug release in acidic organelles. As a result, the TPGS-grafted and pH-sensitive soy protein nanogels have a great potential as a drugs carrier for the efficient cancer treatment.
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http://dx.doi.org/10.1016/j.msec.2019.05.017DOI Listing
September 2019

Co-delivery of DOX and PDTC by pH-sensitive nanoparticles to overcome multidrug resistance in breast cancer.

Colloids Surf B Biointerfaces 2019 Sep 20;181:185-197. Epub 2019 May 20.

Engineering Research Center for Biomedical Materials, Anhui Key Laboratory of Modern Biomanufacturing, School of Life Sciences, Anhui University, 111 Jiulong Road, Hefei, Anhui Province, 230601, PR China. Electronic address:

Chemotherapeutic drugs have a series of limitations in the conventional clinical treatments, mainly including serious adverse effects and multidrug resistance (MDR). Herein, we developed a pH-sensitive polymeric nanoparticle with using poly(ortho ester urethanes) copolymers for co-delivering doxorubicin (DOX) and pyrrolidinedithiocarbamate (PDTC) to settle these problems. Dual-drug-loaded nanoparticles were nano-sized (˜220 nm) with the spherical morphology and excellent physiological stability. Both drugs both could be quickly released in the mild acidic conditions due to the cleavage of ortho ester bonds. Monolayer cultured cells (2D) and multicellular spheroids (3D) experiments proved that PDTC could reverse multidrug resistance (MDR), improve intracellular drugs accumulation and enhance tumor penetration by down-regulating the expression of P-gp, then resulting in higher DOX-induced cytotoxicity and apoptosis in MCF-7 and MCF-7/ADR cells. Besides, in vivo experiments further demonstrated that co-encapsulated nanoparticles had higher DOX accumulation and superiorer tumor growth inhibition (TGI 82.9%) than free drugs or single-drug-loaded nanoparticles on MCF-7/ADR bearing-mice. Accordingly, the pH-sensitive co-delivery systems possess a promising potential to overcome MDR in cancer therapy.
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http://dx.doi.org/10.1016/j.colsurfb.2019.05.042DOI Listing
September 2019

Acid-labile hyperbranched poly(ortho ester amido amine) as efficient gene carriers: Preparation, characterization, and in vitro evaluation.

J Biomater Appl 2019 07 25;34(1):104-116. Epub 2019 Apr 25.

Engineering Research Center for Biomedical Materials, School of Life Sciences, Anhui Key Laboratory of Modern Biomanufacturing, Anhui University, Hefei, China.

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http://dx.doi.org/10.1177/0885328219845083DOI Listing
July 2019

Crystallographic evidence for substrate-assisted catalysis of β-N-acetylhexosaminidas from Akkermansia muciniphila.

Biochem Biophys Res Commun 2019 04 4;511(4):833-839. Epub 2019 Mar 4.

School of Life Sciences, Anhui University, 111 Jiulong Road, Hefei, Anhui, 230601, China; Key Laboratory of Human Microenvironment and Precision Medicine of Anhui Higher Education Institutes, Anhui University, 111 Jiulong Road, Hefei, Anhui, 230601, China. Electronic address:

β-N-acetylhexosaminidases from Akkermansia muciniphila was reported to perform the crystal structure with GlcNAc complex, which proved to be the substrate of Am2301. Domain II of Am2301 is consisted of amino acid residues 111-489 and is folded as a (β/α) barrel with the active site combined of the glycosyl hydrolases. Crystallographic evidence showed that Asp-278 and Glu-279 could be the catalytic site and Tyr-373 may plays a role on binding the substrate. Moreover, Am2301 prefers to bind Zn ion, which similar to other GH 20 family. Enzyme activity and kinetic parameters of wild-type Am2301 and mutants proved that Asp-278 and Glu-279 are the catalytic sites and they play a critical role on the catalytic process. Overall, our results demonstrate that Am2301 and its complex with GlcNAC provide obvious structural evidence for substrate-assisted catalysis. Obviously, this expands our understanding on the mode of substrate-assisted reaction for this enzyme family in Akkermansia muciniphila.
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http://dx.doi.org/10.1016/j.bbrc.2019.02.074DOI Listing
April 2019

Carboxymethyl chitosan-based nanogels via acid-labile ortho ester linkages mediated enhanced drug delivery.

Int J Biol Macromol 2019 May 13;129:477-487. Epub 2019 Feb 13.

Engineering Research Center for Biomedical Materials, Anhui Key Laboratory of Modern Biomanufacturing, School of Life Science, Anhui University, 111 Jiu long Road, Hefei, Anhui Province 230601, PR China. Electronic address:

This work described the preparation of two type nanogels based on the crosslinking between carboxymethyl chitosan (CMCS) and two different crosslink agents, an acid-labile cyclic ortho ester compound with dual epoxy end groups (OEDe) or corresponding non-sensitive ethyleneglycol diglycidyl ether (EGDE). The particle size, zeta potential, and micromorphology were characterized by dynamic light scattering and electron microscopy, respectively. Nanogels' stability was also investigated at physiological environments. Doxorubicin hydrochloride as a therapeutic drug model was efficiently embedded into nanogels. The pH-triggered size changing, degradation and drug release were then investigated at three different pH values. Cellular uptake and cytotoxicity evaluation demonstrated that NG1/DOX could be successfully degraded and efficiently release DOX in acid cell organelles, leading to higher cytotoxicity than NG2/DOX. The accumulation and penetration of these DOX-loaded nanogel were then investigated by tumor-like multicellular spheroids (MCTS). The results indicated that the acid-degradable nanogels can deliver more DOX into the inner of MCTS by the hydrolysis of ortho ester bonds, thus efficiently inhibit the growth of MCTS. All results suggested that the acid-degradable nanogels could be degraded in mildly acidic conditions and remain stable at physiological environment, which indicated that the acid-degradable nanogels would be potentially useful as drug carriers.
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http://dx.doi.org/10.1016/j.ijbiomac.2019.02.072DOI Listing
May 2019

pH/redox dual-sensitive platinum (IV)-based micelles with greatly enhanced antitumor effect for combination chemotherapy.

J Colloid Interface Sci 2019 Apr 17;541:30-41. Epub 2019 Jan 17.

Engineering Research Center for Biomedical Materials, School of Life Science, Anhui Key Laboratory of Modern Biomanufacturing, Anhui University, 111 Jiu long Road, Hefei, Anhui Province 230601, PR China. Electronic address:

To achieve precise control of nano-carrier structure and drug release behavior, we designed a pH/redox dual-responsive polymeric prodrug by condensation polymerization using octahedrally coordinated cisplatin (Pt IV) and ortho ester monomer. The prodrug was then self-assembled with doxorubicin (DOX) in aqueous solution to give a synergetic drug delivery system. The polymer backbone can completely degrade and release cisplatin (Pt II) and DOX under the acidic and reductive environment of tumor cells, owing to the breakage of ortho ester bonds and the reduction of Pt (IV). The size and micromorphology of micelles were observed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). In vitro study of drug release, cellular uptake and cytotoxicity revealed that the micelles could be triggered intracellularly to release two drugs. In vivo drug distribution and antitumor activity also provide the evidence for the excellent antitumor effect of micelles.
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http://dx.doi.org/10.1016/j.jcis.2019.01.076DOI Listing
April 2019

Surface-fluorinated and pH-sensitive carboxymethyl chitosan nanoparticles to overcome biological barriers for improved drug delivery in vivo.

Carbohydr Polym 2019 Mar 21;208:59-69. Epub 2018 Dec 21.

Engineering Research Center for Biomedical Materials, Anhui Key Laboratory of Modern Biomanufacturing, School of Life Sciences, Anhui University, 111 Jiulong Road, Hefei, Anhui Province, 230601, PR China. Electronic address:

Herein, pH-sensitive carboxymethyl chitosan (CMCS) nanoparticles with fluorinated surface modification were prepared for efficient drug delivery. N-(3-Aminopropyl)-imidazole was pre-grafted onto carboxymethyl chitosan to fabricate the pH-sensitive nanoparticles (AM NPs), then was surface-modified with perfluorobutyric anhydride to give the fluorinated nanoparticles (FM NPs). AM and FM NPs had a regular spherical structure with the size about 150-160 nm, which was kinetically stabled in the physical environment and showed pH-triggered drug release at mildly acidic conditions. A series of cell experiments verified that surface fluorination of nanoparticles could enhance cellular uptake and improve cytotoxicity in different tumor cells without the targeting recognition between host and ligands. Besides, fluorine-modified nanoparticles had longer-term blood circulation and more accumulation in tumor site, resulting in higher bioavailability and superior antitumor efficiency for anticancer drugs in vivo. These results suggested that the pH-sensitive and fluorinated nanoparticles had great potential as be efficient drug currieries for cancer chemotherapy.
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http://dx.doi.org/10.1016/j.carbpol.2018.12.063DOI Listing
March 2019

Acid-breakable TPGS-functionalized and diallyl disulfide-crosslinked nanogels for enhanced inhibition of MCF-7/ADR solid tumours.

J Mater Chem B 2019 01 12;7(2):240-250. Epub 2018 Dec 12.

Engineering Research Center for Biomedical Materials, Anhui Key Laboratory of Modern Biomanufacturing, School of Life Sciences, Anhui University, 111 Jiulong Road, Hefei, Anhui Province 230601, P. R. China.

Herein, a diallyl disulfide (DADS)-crosslinked nanogel (NG) and an ortho ester-conjugated TPGS (T-OE) were synthesized using free radical copolymerization and transesterification, respectively. Then, T-OE was grafted onto the NG to fabricate a dual-functionalized nanogel (TNG), and both the NG and TNG possessed a uniform diameter (∼160 nm) and excellent stability. The DOX-loaded nanogel (NG/D and TNG/D) displayed appropriate release properties under reducing conditions. MCF-7/ADR cell experiments showed that although both the NG/D and TNG/D could increase the production of reactive oxygen species (ROS), only the TNG could effectively overcome the drug efflux by inducing mitochondrial depolarization and by interfering with the metabolism of ATP. Both the cell cytotoxicity and the MCF-7/ADR solid cancer assay indicated that TNG/D possessed a long-acting drug enrichment and enhanced the inhibition, resulting from the combined action of the high ROS level and the suppressed drug efflux. These results demonstrated that the T-OE-functionalized and the DADS-crosslinked NG had a great potential for use in the treatment of MCF-7/ADR tumours.
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http://dx.doi.org/10.1039/c8tb02742kDOI Listing
January 2019