Bufalin-loaded mPEG-PLGA-PLL-cRGD nanoparticles: Preparation, cellular uptake, tissue distribution, and anticancer activity

Yin, Peihao; Qiu, Yanyan

doi:10.1016/j.toxicon.2018.10.193

Cited by 19 publications

(21 citation statements)

References 26 publications

(27 reference statements)

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“…However, very little is known concerning the role of CBF in circumvention MDR in colon cancer. Our group previously investigated ChanSu and its active ingredients (17)(18)(19) indicating that CBF can reverse chemoresistance of cancer cells, but its mechanism was not clear. In this study, we investigated the role and mechanism of CBF on reversing P-gp mediated MDR both in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

Reversal of P-gp-mediated multidrug resistance in colon cancer by cinobufagin

et al. 2017

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Cinobufagin (CBF) is isolated from the skin and posterior auricular glands of the Asiatic toad (Bufo gargarizans). This study investigated the reversal effect of CBF on P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in colon cancer. The effect of CBF on the cytotoxicity of anticancer drugs in P-gp overexpressing LoVo/ADR, HCT116/L, Cao-2/ADR cells and their parental cells was determined using CCK-8 assay. Apoptosis of anti-cancer drugs and accumulation of doxorubicin (DOX) and Rhodamine 123 (Rho123) in P-gp overexpressing cells were evaluated by flow cytometry. Results indicated that CBF significantly enhanced the sensitivity of P-gp substrate drugs on P-gp overexpressing cells, but had no effect on their parental cells. CBF enhanced the effect of DOX against P-gp-overexpressing LoVo/ADR cell xenografts in nude mice. Moreover, CBF also increased cell apoptosis of chemotherapy agents and intracellular accumulation of DOX and Rho123 in the MDR cells. Further research on the mechanisms revealed non-competitive inhibition of P-gp ATPase activity, but without altering the expression of P-gp. These findings demonstrated that CBF could be further developed into a safe and potent P-gp modulator for combination use with anticancer drugs in cancer chemotherapy.

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Section: Introductionmentioning

confidence: 99%

Reversal of P-gp-mediated multidrug resistance in colon cancer by cinobufagin

et al. 2017

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“…The mechanisms of bufalin-induced cell death comprise its (i) influence on the expression of apoptosis-related genes, (ii) inhibition of tumor cell proliferation, (iii) generation of reactive oxygen species, (iv) endoplasmic reticulum stress, (v) JNK (c-Jun N-terminal kinase) activation, (vi) protein kinase modulating effect, (vii) caspase-and mitochondria-dependent signaling pathways, and (viii) cell cycle arrest via the c-Myc/NF-kappa B pathway [26][27][28][29][30][31][32][33][34][35][36][37]. Despite that BUF is considered as a promising antitumor agent, its poor water solubility, high cardiac toxicity, short circulation half-life and narrow therapeutic window have limited the clinical application of the drug [26].…”

Section: Introductionmentioning

confidence: 99%

“…Despite that BUF is considered as a promising antitumor agent, its poor water solubility, high cardiac toxicity, short circulation half-life and narrow therapeutic window have limited the clinical application of the drug [26]. Various types of drug delivery systems have been investigated with the purpose to improve the absorption and bioavailability of bufalin in anticancer therapies [33][34][35][36][37][38].…”

Section: Introductionmentioning

confidence: 99%

“…This carrier system has been more stable in comparison to traditional liposomes, but the drug entrapment efficiency was about 49%. Polymer nanoparticle made of mPEG-PLGA-PLL-cRGD (methoxy polyethylene glycol (mPEG), polylactic-co-glycolic acid (PLGA), poly-L-lysine (PLL), and cyclic arginine-glycine-aspartic acid (cRGD)) have been investigated as a potential delivery system of BUF in antitumor therapy [34]. Bufalin-loaded mPEG-PLGA-PLL-cRGD nanoparticles have been characterized by drug entrapment efficiency (EE) of (81.7±0.9)% and drug loading (DL) of (3.92±0.2)%.…”

Section: Introductionmentioning

confidence: 99%

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In situ phase transition of microemulsions for parenteral injection yielding lyotropic liquid crystalline carriers of the antitumor drug bufalin

Angelova

Liu

et al. 2019

Colloids and Surfaces B: Biointerfaces

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In this work, we use the small angle X-ray scattering (SAXS) method for controlled preparation of in situ forming sustained-release carriers of the antitumor drug bufalin (BUF), which has very poor solubility and a considerable cardiotoxicity in a non-encapsulated state. To that aim, we exploit the pseudo-ternary phase diagram of an oil(O)/surfactant(S)/water(W) system containing medium chain capric/caprylic triglycerides (MCT) and a co-surfactant blend of Macrogol (15)-hydroxystearate (Solutol HS 15) and sorbitan monooleate (Span 80). Two compositions with different oil contents (B-LC-ME and C-LC-ME) are selected from the microemulsion region of the diagram in order to study the effect of the aqueous environment on their structural behaviour. A phase transition from a microemulsion to a lamellar liquid crystalline phase and multilamellar vesicles is established by SAXS upon progressive dilution. The drug bufalin (BUF) is encapsulated in the microemulsions, which have low viscosity, whereas the release of the drug occurred from the in situ generated lamellar liquid crystalline structures. The formulations are characterized by SAXS, dynamic light scattering (DLS), cryogenic transmission electron microscopy (Cryo-TEM), rheology, drug loading and entrapment efficiency, and in vitro release profiles. A correlation is suggested between the structures of the in situ phase-transition formed LC-ME formulations and the differences in their viscosities and drug release profiles. The performed cytotoxicity, cell apoptosis and pharmacokinetic experiments show an enhanced bioavailability of BUF after encapsulation. These results suggest potential clinical applications for the obtained safe in situ phase-transition sustained-release formulations of BUF.

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“…19 It has been reported that nanocarriers could effectively load BU, prolong its retention time in vivo, improve its antitumor effect, and reduce its toxicity. [20][21][22][23][24][25][26] However, there is no study on BU-loaded nano-delivery systems to overcome MDR. Polymer micelles are ideal carriers for both active and passive targeted drug delivery.…”

Section: Introductionmentioning

confidence: 99%

Bufalin-loaded vitamin E succinate-grafted-chitosan oligosaccharide/RGD conjugated TPGS mixed micelles demonstrated improved antitumor activity against drug-resistant colon cancer

Yuan¹,

Yuan²,

Han³

et al. 2018

IJN

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BackgroundMultidrug resistance (MDR) is the major reason for the failure of chemotherapy in colon cancer. Bufalin (BU) is one of the most effective antitumor active constituents in Chansu. Our previous study found that BU can effectively reverse P-glycoprotein (P-gp)-mediated MDR in colon cancer. However, the clinical application of BU is limited due to its low solubility in water and high toxicity. In the present study, a multifunctional delivery system based on vitamin-E- succinate grafted chitosan oligosaccharide (VES-CSO) and cyclic (arginine-glycine-aspartic acid peptide) (RGD)-modified d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) was prepared by emulsion solvent evaporation method for targeted delivery of BU to improve the efficacy of drug-resistant colon cancer therapy.MethodsThe cytotoxicity of BU-loaded micelles against drug-resistant colon cancer LoVo/ADR and HCT116/LOHP cells was measured by CCK-8 assay. The cellular uptake, Rho123 accumulation, and cell apoptosis were determined by flow cytometry. The expression of apoptosis-related protein and P-gp was measured by Western blot assay. The antitumor activity of BU-loaded micelles was evaluated in LoVo/ADR-bearing nude mice.ResultsBU-loaded VES-CSO/TPGS-RGD mixed micelles (BU@VeC/T-RGD MM) were 140.3 nm in diameter with zeta potential of 8.66 mV. The BU@VeC/T-RGD MM exhibited good stability, sustained-release pattern, higher intracellular uptake, and greater cytotoxicity in LoVo/ADR cells. Furthermore, the mechanisms of the BU@VeC/T-RGD MM to overcome MDR might be due to enhanced apoptosis rate and P-gp efflux inhibition. Subsequently, in vivo studies confirmed an enhanced therapeutic efficiency and reduced side effects associated with BU@VeC/T-RGD MM compared with free BU, owing to the enhanced permeation and retention effect, improved pharmacokinetic behavior, and tumor targeting, which lead to MDR-inhibiting effect in LoVo/ADR-bearing nude mice.ConclusionOur results demonstrated that VeC/T-RGD MM could be developed as a potential delivery system for BU to improve its antitumor activity against drug-resistant colon cancer.

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Bufalin-loaded mPEG-PLGA-PLL-cRGD nanoparticles: Preparation, cellular uptake, tissue distribution, and anticancer activity

Cited by 19 publications

References 26 publications

Reversal of P-gp-mediated multidrug resistance in colon cancer by cinobufagin

Reversal of P-gp-mediated multidrug resistance in colon cancer by cinobufagin

In situ phase transition of microemulsions for parenteral injection yielding lyotropic liquid crystalline carriers of the antitumor drug bufalin

Bufalin-loaded vitamin E succinate-grafted-chitosan oligosaccharide/RGD conjugated TPGS mixed micelles demonstrated improved antitumor activity against drug-resistant colon cancer

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