Publications by authors named "Danfei Chen"

4 Publications

  • Page 1 of 1

Targeted GSH-exhausting and hydroxyl radical self-producing manganese-silica nanomissiles for MRI guided ferroptotic cancer therapy.

Nanoscale 2020 Aug;12(32):16738-16754

Department of Pharmacy, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.

Ferroptosis, a cell death path induced by the generation of reactive oxygen species (ROS), will cause the accumulation of lipid peroxides (PL-PUFA-OOH) and achieve potent tumor-regression. However, glutathione (GSH)-dependent glutathione peroxidase 4 (GPx4) can reduce PL-PUFA-OOH and antagonize the ferroptosis inducing effect of ROS. Herein, folate-PEG modified dihydroartemisinin (DHA) loaded manganese doped mesoporous silica nanoparticles (described as nanomissiles) were constructed for integrating the effect of GSH exhaustion and ROS generation. After endocytosis by tumor cells, intracellular GSH triggered the degradation of nanomissiles, which allowed the simultaneous release of DHA and Fenton catalytic Mn2+ due to the redox reaction between the manganese-oxygen bonds and GSH. The degradation would lead to GSH exhaustion, activation of Mn2+-based magnetic resonance imaging (MRI), and DHA-driven ˙OH generation. The GSH-free environment inhibited the activity of GPx4 and enhanced the accumulation of PL-PUFA-OOH oxidized by ˙OH. Furthermore, the cooperative effects suppressed tumor metastasis by destroying the structure of polyunsaturated fatty acids in the cell membranes and showed potent antitumor activity. This innovative ferroptotic therapy integrating the GSH exhaustion and ROS generation will be a promising strategy for cancer therapy.
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http://dx.doi.org/10.1039/d0nr02396eDOI Listing
August 2020

Dual GSH-exhausting sorafenib loaded manganese-silica nanodrugs for inducing the ferroptosis of hepatocellular carcinoma cells.

Int J Pharm 2019 Dec 31;572:118782. Epub 2019 Oct 31.

Department of Pharmacy, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China. Electronic address:

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths. Unfortunately, there is still no completely effective treatment. Ferroptosis could affect the development of HCC by regulating the level of glutathione (GSH), intracellular lipid peroxidation, and other related substances. This paper introduced a new one-pot reaction for the synthesis of manganese doped mesoporous silica nanoparticles (manganese-silica nanoparticles, MMSNs) which could induce ferroptosis of the tumor cells through the consumption of intracellular GSH caused by the degradation of MMSNs. The more amount of MnCl added during the preparation, the larger doping amount of manganese presented in MMSNs. When the molar ratio of TEOS to MnCl was 5:1, the prepared MMSNs had a small size (102.6 ± 3.06 nm), uniform structure (pore sizes of 3.67 nm) and large pore volume. Manganese-oxidation bonds of MMSNs could break in high GSH concentration, which in turn consume GSH in the environment rapidly. Sorafenib (SO), an inhibitor of X transport system was loaded in the MMSNs ([email protected]) with a drug loading rate of 2.68 ± 0.32%. [email protected] achieved on-demand drug release in the tumor microenvironment due to the degradation of MMSNs. Subsequently, a significant tumor cell (HepG2) suppression effect of [email protected] was achieved through the consumption of GSH and synthesis inhibition of intracellular GSH. The depletion of GSH led to the inactivity of glutathione peroxidase 4 and increase of intracellular lipid peroxide, which could induce the ferroptosis of HCC cells. In summary, such dual GSH-exhausting nanodrugs have a great potential to induce ferroptosis of HCC cells.
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http://dx.doi.org/10.1016/j.ijpharm.2019.118782DOI Listing
December 2019

Kidney-targeted rhein-loaded liponanoparticles for diabetic nephropathy therapy via size control and enhancement of renal cellular uptake.

Theranostics 2019 14;9(21):6191-6208. Epub 2019 Aug 14.

Department of Ultrasound in Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China.

The optimization of nanoparticle size for passing through glomerular filtration membrane, inefficient renal cellular uptake and rapid urinary excretion of nanoparticles are the major obstacles for renal disease treatment via a nanoparticle delivery system. Herein, we propose a concept of a two-step nanoparticular cascade of size control and enhancement of renal cellular uptake to overcome the renal delivery obstacles. : We prepared kidney-targeted rhein (RH)-loaded liponanoparticles (KLPPR) with a yolk-shell structure composed by polycaprolactone-polyethyleneimine (PCL-PEI)-based cores and kidney targeting peptide (KTP)-modified lipid layers. The KLPPR size within the range of 30 ~ 80 nm allowed KLPPR distribute into kidney by passing through the glomerular filtration membrane and the KTP (sequence: CSAVPLC) decoration promoted the renal cellular uptake and endocytosis via a non-lysosomal pathway. : The KLPPR had an average size of 59.5±6.2 nm and exhibited high RH loading, sustained release, good stability and biocompatibility, rapid cellular uptake in HK-2 cells. In addition, intravenous administration of KLPPR resulted in excellent kidney-targeted distribution and low urinary excretion in mice with streptozocin-induced diabetic nephropathy (DN), lowered the parameters of urea nitrogen, serum creatinine and kidney index, as well as facilitated the recovery of renal physiological function in improving the levels of urinary creatinine and the creatinine clearance rate by suppressing secretion and accumulation of fibronectin and TGF-β1. : Definitely, KLPPR were able to target the diseased kidney and improve the therapeutic effect of RH on DN by exploiting the two-step nanoparticular cascade of size control and enhancement of cellular uptake. This study offers a promising strategy for renal diseases treatment using liponanoparticle delivery system.
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http://dx.doi.org/10.7150/thno.37538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735513PMC
September 2020

Kidney-targeted drug delivery via rhein-loaded polyethyleneglycol--polycaprolactone--polyethylenimine nanoparticles for diabetic nephropathy therapy.

Int J Nanomedicine 2018 19;13:3507-3527. Epub 2018 Jun 19.

College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, 310053 China.

Introduction: Diabetic nephropathy (DN) is the primary root of morbidity and mortality in diabetic patients. Unfortunately, currently, no effective therapeutic strategies are available to ameliorate and reverse the progression of DN. Rhein (RH) is an anthraquinone derivative extracted from herbal medicines with various pharmacological effects on DN. However, its clinical administration is limited by its poor solubility, low bioavailability, reduced distribution into the kidney and adverse effects.

Methods And Results: To improve the delivery of RH into kidney and the therapeutic effect on DN, we synthesized and utilized polyethyleneglycol--polycaprolactone--polyethylenimine triblock amphiphilic polymers to prepare RH-loaded polyethyleneglycol--polycaprolactone--polyethylenimine nanoparticles (PPP-RH-NPs). PPP-RH-NP size was optimized to 75 ± 25 nm for kidney-targeted drug delivery; the positive zeta potential allowed an effective cellular uptake and the polyethylenimine amine groups facilitate the endosomal escape quickly. The distribution and pharmacodynamics of PPP-RH-NPs were studied in a streptozocin-induced DN model, which explicitly demonstrated kidney-targeted distribution and improved the therapeutic effects of RH on DN by ameliorating several pathological indicators.

Conclusion: Therefore, this study not only stimulates further clinical research on RH but also, more importantly, proposes a promising DN therapy consisting of an effective kidney-targeted drug delivery.
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http://dx.doi.org/10.2147/IJN.S166445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6016261PMC
July 2018
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