Use of the intestinal and hepatic bile acid transporters for drug delivery

Swaan, Peter W.; Szoka, Francis C.; Oie, Shigeharu

doi:10.1016/0169-409x(95)00130-y

Cited by 31 publications

(17 citation statements)

References 120 publications

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“…The enterohepatic receptors in the ileum are responsible for circulating between 12-30 g of bile salts in a day, and the bile salts are reabsorbed in the terminal ileum with recovery efficiencies of up to 95% (15). C(3)-functionalized cholic acid derivatives have shown the ability to interact with molecular receptors in the ileum, aiding the delivery of molecules through the intestinal wall (16,17). Thus, we reasoned that a cholic acid derivative fitted with a DNA-binding domain might condense DNA and promote the intracellular delivery of DNA in a similar manner.…”

mentioning

confidence: 99%

Gastroprotection of DNA with a synthetic cholic acid analog

Niedzinski

Bennett

Olson

et al. 2000

Lipids

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The oral delivery of functional DNA to the gastrointestinal system would constitute a desirable, noninvasive method for potentially treating a variety of diseases. The digestive process, however, remains a formidable barrier. This dilemma may be addressed by using targeted liposomes both to protect the polynucleotide and to deliver the therapeutic DNA with high tissue specificity. The present study represents the initial steps toward developing a novel gene delivery system designed to interact with the enterohepatic receptors of the small intestine. Two cholic acid esters were synthetically modified at position C(3) to incorporate a DNA-binding domain. These novel compounds were evaluated for their ability to protect DNA from the nucleases found in gastrointestinal segments. Additionally, the compounds were screened as a component of a gene delivery vector. Formulations containing the new bile salt derivatives protected DNA from degradation for more than 2 h and were capable of transfecting cultured NIH 3T3 cells.

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mentioning

confidence: 99%

Gastroprotection of DNA with a synthetic cholic acid analog

Niedzinski

Bennett

Olson

et al. 2000

Lipids

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“…Earlier work from our laboratory and others have found that conjugates of peptides with cholic acid interact with and are transported by the human bile acid transporter [11,12]. The interaction was largely dependent on the ionization and the location of several ionizable group(s) on the conjugates.…”

Section: Introductionmentioning

confidence: 94%

Synthesis of Cholic Acid-Peptide Conjugates With A Negatively Charged Ester Linkage for Oral Delivery

Li¹,

Song²,

Oie³

et al. 2017

Med chem (Los Angeles)

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The progress in oral absorption of protein and peptide drugs has been hampered by the difficulty in transporting larger molecules across the gastrointestinal membrane. We are reporting here a study of the design and synthesis of cholic acid-peptide conjugates for peptide drug delivery through gastrointestinal track mediated by bile acid transporter. As principal samples, three small cholic acid-peptide conjugates containing a biodegradable ester bond via threonine linker have been synthesized. In order to introduce ester bond between cholic acid and peptides, conventional solid phase synthesis is not practicable, thus solution phase was employed. The threonine moiety was chosen to introduce a hydroxyl group, on which an ester bond can be formed with different peptides. The threonine moiety also provides the necessary negative charge adjacent to the C24 position as required for transport recognizing by the bile acid transporter in the ilue epicell. The synthetic process was based on DCC chemistry. By using catalytic amounts of N-hydroxysuccinimide the procedure for amide coupling was simplified and shortened while maintaining high efficiency. Esterification using ethyl acetate in the presence of triethylamine selectively introduced an ester bond at the C27 position giving higher yield with no protection on other three hydroxyls. The work also demonstrated that in solution phase synthesis of these peptide conjugates fluoride ion (F -) was more efficient than piperidine to cleave Fmoc from the amino group.Cell culture experiment showed the efficiencies of transporting of the conjugates and the dissociation of the conjugates detected by HPLC, suggesting that the cholic acid conjugates linked by degradable ester bond can be used as bigger molecule drugs delivering template. Further study would be designed by using more different linkers that would be also biodegradable bonds, such as thioester and so forth.

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“…The mixture of bile acids present in the body is very complex since they are commonly conjugated with the amino acids taurine and glycine, (ratio of taurine/glycine = 1/3) [14,15]. The pK a of bile acids is between 2 and 5 and so, under the conditions that prevail in the small intestine (pH = 7.0-9.0), these molecules are in their ionized form (also called bile salts) [16].…”

Section: Bile Acids and Cholesterol Homeostasismentioning

confidence: 99%

Polymeric bile acid sequestrants—Synthesis using conventional methods and new approaches based on “controlled”/living radical polymerization

Mendonça

Serra

Silva³

et al. 2013

Progress in Polymer Science

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a b s t r a c tPolymeric bile acid sequestrants have received increasing attention as therapeutic agents for the treatment of hypercholesterolemia. These materials are usually cationic hydrogels that selectively bind and remove bile acid molecules from the gastrointestinal tract, decreasing plasma cholesterol levels. Due to their high molecular weight, the action of bile acid sequestrants can be limited to the gastrointestinal tract, avoiding systemic exposure, which constitutes an advantage over conventional small-molecule drugs.Different polymers, such as vinyl polymers, acrylic polymers and allyl polymers have been used to prepare potential bile acid sequestrants based on conventional polymerization techniques. Also, much effort has been devoted to understanding the structure-property relationships between these polymers and their ability to bind bile acid molecules. The efficacy of these polymeric drugs can be ascribed to five major variables: (i) the density of cationic charges, (ii) the length and distribution of the hydrophobic chains, (iii) the polymer backbone flexibility, (iv) the degree of cross-linking and (v) the polymer shape.This review summarizes the major synthesis pathways that are employed in the preparation of this type of polymer therapeutics and the polymer structural key factors that are of relevance to enhanced therapeutic efficacy. Herein, new synthesis approaches, based on "controlled"/living radical polymerization techniques, are highlighted.

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Use of the intestinal and hepatic bile acid transporters for drug delivery

Cited by 31 publications

References 120 publications

Gastroprotection of DNA with a synthetic cholic acid analog

Gastroprotection of DNA with a synthetic cholic acid analog

Synthesis of Cholic Acid-Peptide Conjugates With A Negatively Charged Ester Linkage for Oral Delivery

Polymeric bile acid sequestrants—Synthesis using conventional methods and new approaches based on “controlled”/living radical polymerization

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