Transporter-targeted cholic acid-cytarabine conjugates for improved oral absorption

Zhang, Dong; Li, Dongpo; Shang, Lei; Zhang, He; Sun, Jin

doi:10.1016/j.ijpharm.2016.06.139

Cited by 31 publications

(21 citation statements)

References 39 publications

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“…Liver is the primary acting site of insulin (Arbit, 2004 ). HepG-2 cells express bile acid transporters, such as NTCP and OATPs (Swaan et al., 1996 ; Zhang et al., 2016a ). Therefore, in this study, HepG-2 cells were used as an in vitro hepatocyte model to investigate hepatocyte uptake of the nanoparticles.…”

Section: In Vitro Insulin Releasementioning

confidence: 99%

“…It was reported that the oral delivery systems conjugated with bile acid can deliver the drugs to the liver directly by use of enterohepatic circulation mechanism (HO, 1987 ; Swaan et al., 1996 ; Zhang et al., 2016a ). Enterocytes in ileum express apical Na + -dependent bile acid transporter (ASBT) and cytosolic ileal bile acid-binding protein (IBABP) (Gong et al., 1994 ; Kolhatkar & Polli, 2012 ; Fan et al., 2018 ).…”

Section: Introductionmentioning

confidence: 99%

“…These bile acid transporters are involved in the enterohepatic circulation of bile acids. The high capacity of the bile acid transporters and high efficacy of both intestinal and liver absorptions make the enterohepatic circulation of bile acids be utilized in oral delivery systems to increase the therapeutic concentration in the liver and reduce the general toxicity of the drugs (Swaan et al., 1996 ; Zhang et al., 2016a ). For insulin delivery, it was evidenced that the bile acid conjugated insulin was taken up by the ileal bile acid transporters after infusion into the small intestine (McGinn & Morrison, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

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Liver-targeted delivery of insulin-loaded nanoparticles via enterohepatic circulation of bile acids

Zhang

Yao

2018

Drug Delivery

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Liver is the primary acting site of insulin. In this study, we developed innovative nanoparticles for oral and liver-targeted delivery of insulin by using enterohepatic circulation of bile acids. The nanoparticles were produced from cholic acid and quaternary ammonium modified chitosan derivative and hydroxypropyl methylcellulose phthalate (HPMCP). The nanoparticles had a diameter of 239 nm, an insulin loading efficiency of 90.9%, and a loading capacity of 18.2%. Cell culture studies revealed that the cholic acid groups effectively enhanced the transport of the nanoparticles through Caco-2 cell monolayer and greatly increased the absorption of the nanoparticles in HepG-2 cells via bile acid transporter mechanism. Ex vivo fluorescence images of ileum section, gastrointestinal tract, and liver demonstrated that the HPMCP increased the mucoadhesion of the nanoparticles in ileum, and the cholic acid groups facilitated the absorptions of the nanoparticles in both ileum and liver by use of bile acid transporters via enterohepatic circulation of bile acids. The therapy for diabetic mice displayed that the oral nanoparticle group could maintain hypoglycemic effect for more than 24 h and its pharmacological availability was about 30% compared with the insulin injection group. For the first time, this study demonstrates that using enterohepatic circulation of bile acids is an effective strategy for oral delivery of insulin.

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Section: In Vitro Insulin Releasementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Liver-targeted delivery of insulin-loaded nanoparticles via enterohepatic circulation of bile acids

Zhang

Yao

2018

Drug Delivery

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“…20) Furthermore, they are part of the enterohepatic circulation, which circulates 6-15 times a day. 21) Thus, bile acids have powerful transport capacity. Zhang et al 22) demonstrated that coupling with bile acids could increase the oral bioavailability of cytarabine.…”

Section: Introductionmentioning

confidence: 99%

Transporter-Targeted Bile Acid-Camptothecin Conjugate for Improved Oral Absorption

et al. 2019

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Camptothecin (CPT), a natural alkaloid, possesses potent anticancer activity. However, its application was terminated due to its low bioavailability and high toxicity. This work evaluated the potential of deoxycholic acid-CPT conjugate (G2) to improve the oral absorption of CPT. Deoxycholic acid significantly reduced cytotoxicity and inhibited the uptake of G2, in vitro. And G2 showed sodium-dependent uptake. In addition, in vivo study in rats indicated that the oral bioavailability of G2 was 2.06-fold higher than that of CPT. The present study suggested that using bile acid as the conjugated moiety is a hopeful strategy to improve the oral bioavailability of CPT.

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“…Cholic acid receptor-mediated nanoparticle drug delivery systems have frequently been reported as oral hepatic drug delivery systems because of oral hepatic targeting properties of cholic acid [15][16][17][18][19] and because of their ability to maintain the structural integrity in the process of physiological disposition. Therefore, it is vital to understand the related mechanisms.…”

Section: And Zhumentioning

confidence: 99%

Mechanism of hepatic targeting via oral administration of DSPE–PEG–cholic acid-modified nanoliposomes

Liu

Zhu

2017

IJN

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In oral administration, gastrointestinal physiological environment, gastrointestinal epithelial cell membranes, and blood circulation are typical biological barriers to hepatic delivery of ligand-modified nanoparticle drug delivery systems. To elucidate the mechanism of oral hepatic targeting of cholic acid receptor-mediated nanoliposomes (LPs) (distearoyl phosphatidylethanolamine–polyethylene glycol–cholic acid-modified LPs, CA-LPs), evaluations were performed on colon cancer Caco-2 cell monolayers, liver cancer HepG2 cells, and a rat intestinal perfusion model. CA-LPs, ~100 nm in diameter, exhibited sustained-release behavior and had the greatest stability in rat gastrointestinal fluid and serum for both size and entrapment efficiency. CA-LPs demonstrated highest transport across Caco-2 cells and highest cellular uptake by HepG2 cells. The enhanced endocytosis of CA-LPs was found to be mediated by Na + /taurocholate cotransporting polypeptide and involved the caveolin-mediated endocytosis pathway. Further, we used fluorescence resonance energy transfer (FRET) technology to show that the CA-LPs maintained their structural integrity in part during the transport across the Caco-2 cell monolayer and uptake by HepG2 cells.

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Transporter-targeted cholic acid-cytarabine conjugates for improved oral absorption

Cited by 31 publications

References 39 publications

Liver-targeted delivery of insulin-loaded nanoparticles via enterohepatic circulation of bile acids

Liver-targeted delivery of insulin-loaded nanoparticles via enterohepatic circulation of bile acids

Transporter-Targeted Bile Acid-Camptothecin Conjugate for Improved Oral Absorption

Mechanism of hepatic targeting via oral administration of DSPE–PEG–cholic acid-modified nanoliposomes

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Transporter-targeted cholic acid-cytarabine conjugates for improved oral absorption

Cited by 31 publications

References 39 publications

Liver-targeted delivery of insulin-loaded nanoparticles via enterohepatic circulation of bile acids

Liver-targeted delivery of insulin-loaded nanoparticles via enterohepatic circulation of bile acids

Transporter-Targeted Bile Acid-Camptothecin Conjugate for Improved Oral Absorption

Mechanism of hepatic targeting via oral administration of DSPE&ndash;PEG&ndash;cholic acid-modified nanoliposomes

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Mechanism of hepatic targeting via oral administration of DSPE–PEG–cholic acid-modified nanoliposomes