Oral delivery of a potent anti-angiogenic heparin conjugate by chemical conjugation and physical complexation using deoxycholic acid

Alam, Fakhrul; Al-Hilal, Taslim A.; Chung, Soo Kyo; Seo, Dong-Hoan; Mahmud, Foyez; Kim, Han Sung; Kim, Sang Yoon; Byun, Youngro

doi:10.1016/j.biomaterials.2014.04.050

Cited by 47 publications

(35 citation statements)

References 32 publications

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“…LHTD4 was then synthesized by end-site conjugation of LHT7 with tetraDOCA following the previous procedure [10]. At first, LHT7 was oxidized by using potassium metaperiodate (57.5 mg) in acetate buffer at pH 4.5.…”

Section: Synthesis and Characterization Of Lht7 Lhtd4 And Dckmentioning

confidence: 99%

“…These properties of LHT7 contribute to the selective blocking of interactions with ATIII while enhancing its binding with VEGF and bFGF. Furthermore, in order to administer LHT7 via oral route, we synthesized LHTD4 by conjugating LHT7 with a newly developed bile acid-derived moiety that consists of 4 molecules of deoxycholic acid (tetraDOCA) [10]. We saw that this conjugation imposed high binding affinity to membrane transporters on LHTD4, enabling it to be orally absorbed through the apical sodium-dependent bile acid transporter (ASBT)-mediated pathway [11,12].…”

Section: Introductionmentioning

confidence: 98%

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Antiangiogenic and anticancer effect of an orally active low molecular weight heparin conjugates and its application to lung cancer chemoprevention

Kim

Al-Hilal

Chung

et al. 2015

Journal of Controlled Release

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Section: Synthesis and Characterization Of Lht7 Lhtd4 And Dckmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Antiangiogenic and anticancer effect of an orally active low molecular weight heparin conjugates and its application to lung cancer chemoprevention

Kim

Al-Hilal

Chung

et al. 2015

Journal of Controlled Release

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“…[12][13][14][15] In the case of CS, the preparation of self-assembling micelles as the drug carrier system was developed based on the conjugation with α-linoleic acid. 16) In addition, novel nanomaterials are being developed to improve the oral bioavailability of low molecular mass compounds, proteins, and recombinant DNAs.…”

Section: 3)mentioning

confidence: 99%

“…[12][13][14][15] However, there are two issues for evaluation of PIC generated in this study. One is the toxicity of extracellular SPM because amine oxidase in fetal calf serum produces aminodialdehyde-generating acrolein.…”

Section: Effect Of the Molecular Size Of Cs On Pic Formation Efficiencymentioning

confidence: 99%

Poly-ion Complex of Chondroitin Sulfate and Spermine and Its Effect on Oral Chondroitin Sulfate Bioavailability

Higashi

Ito

Kenichi

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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Chondroitin sulfate (CS) has been accepted as an ingredient in health foods for the treatment of symptoms related to arthritis and cartilage repair. However, CS is poorly absorbed through the gastrointestinal tract because of its high negative electric charges and molecular weight (MW). In this study, poly-ion complex (PIC) formation was found in aqueous solutions through electrostatic interaction between CS and polyamines-organic molecules having two or more primary amino groups ubiquitously distributed in natural products at high concentrations. Characteristic properties of various PICs generated by mixing CS and natural polyamines, including unusual polyamines, were studied based on the turbidity for PIC formation, the dynamic light scattering for the size of PIC particles, and ζ-potential measurements for the surface charges of PIC particles. The efficiency of PIC formation between CS and spermine increased in a CS MW-dependent manner, with 15 kDa CS being critical for the formation of PIC (particle size: 3.41 µm) having nearly neutral surface charge (ζ-potential: 0.80 mV). Comparatively, mixing tetrakis(3-aminopropyl)ammonium and 15 kDa of CS afforded significant levels of PIC (particle size: 0.42 0.16 µm) despite a strongly negative surface charge ( 34.67 1.15 mV). Interestingly, the oral absorption efficiency of CS was greatly improved only when PIC possessing neutral surface charges was administered to mice. High formation efficiency and electrically neutral surface charge of PIC particles are important factors for oral CS bioavailability.

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“…Oral BA: hardly absorbed (Chen et al, 2009) Positively charged nanoparticles (chitosan with a low MW of 30 kDa): increased oral BA, 20.5% (rats) (Chen et al, 2009) Low-MW heparin A highly sulfated glycosaminoglycans; MW, less than 8 kDa Injection: t 1/2 , 0.57-4 h (Samama & Gerotziafas, 2000;Hwang et al, 2012). Oral BA: hardly absorbed (Dong et al, 2007;Hwang et al, 2012;Alam et al, 2014); 1.6% (monkeys) and 7.4% (rats) (Alhilal et al, 2014) Positively charged nanoparticles (poly(e-caprolactone)/Eudragit V R RS,1:1): increased oral BA, 51-59% (rabbits); prolonged anticoagulant effect, 8-11.5 h (Hoffart et al, 2006) Conjugation (DA): increased oral BA, $16% (mice) (Dong et al, 2007) Conjugation (dimeric DA): increased oral BA, 19.3% (rats) (Hwang et al, 2012) Conjugation (T-DA): increased oral BA, 19.9% (monkeys) and 33.5% (rats) (Alhilal et al, 2014) Conjugation (T-DA)þcomplexation (DCEA): increased oral BA, 34.3% (rats); prolonged MRT, 7.5 h; improved antiangiogenic efficacy Chinese yam PS A neutral PS composed of glucose and galactose (1.52:1, molar ratio); MW, 16.6 kDa (Yang et al, 2015) PLGA nanoparticles: slowed release and improved immunomodulatory activity in vitro (Luo et al, 2016 et al, 2016a). Overall, ROPS-loaded liposomes (ROPS-Ls) showed significantly better efficacy than free ROPS.…”

Section: Synergistic Immunomodulatory Effectsmentioning

confidence: 99%

Drug delivery for bioactive polysaccharides to improve their drug-like properties and curative efficacy

Wang

Lin

et al. 2017

Drug Delivery

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Over several decades, natural polysaccharides (PSs) have been actively exploited for their wide bioactivities. So far, many PS-related reviews have been published; however, none focused on the delivery of bioactive PSs as therapeutic molecules. Herein, we summarized and discussed general pharmacokinetic properties of PSs and drug delivery systems (DDSs) developed for them, together with the challenges and prospects. Overall, most bioactive PSs suffer from undesirable pharmacokinetic attributes, which negatively affect their efficacy and clinical use. Various DDSs therefore have been being utilized to improve the drug-like properties and curative efficacy of bioactive PSs by means of improving oral absorption, controlling the release, enhancing the in vivo retention ability, targeting the delivery, exerting synergistic effects, and so on. Specifically, nano-sized insoluble DDSs were mainly applied to improve the oral absorption and target delivery of PSs, among which liposome was especially suitable for immunoregulatory and/or anti-ischemic PSs due to its synergistic effects in immunoregulation and biomembrane repair. Chemical conjugation of PSs was mainly utilized to improve their oral absorption and/or prolong their blood residence. With formulation flexibility, in situ forming systems alone or in combination with drug conjugation could be used to achieve day(s)-or month(s)-long sustained delivery of PSs per dosing. ARTICLE HISTORY

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Oral delivery of a potent anti-angiogenic heparin conjugate by chemical conjugation and physical complexation using deoxycholic acid

Cited by 47 publications

References 32 publications

Antiangiogenic and anticancer effect of an orally active low molecular weight heparin conjugates and its application to lung cancer chemoprevention

Antiangiogenic and anticancer effect of an orally active low molecular weight heparin conjugates and its application to lung cancer chemoprevention

Poly-ion Complex of Chondroitin Sulfate and Spermine and Its Effect on Oral Chondroitin Sulfate Bioavailability

Drug delivery for bioactive polysaccharides to improve their drug-like properties and curative efficacy

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