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Co-opting biology to deliver drugs.

ABSTRACT: The goal of drug delivery is to improve the safety and therapeutic efficacy of drugs. This review focuses on delivery platforms that are either derived from endogenous pathways, long-circulating biomolecules and cells or that piggyback onto long-circulating biomolecules and cells. The first class of such platforms is protein-based delivery systems--albumin, transferrin, and fusion to the Fc domain of antibodies--that have a long-circulation half-life and are designed to transport different molecules. The second class is lipid-based delivery systems-lipoproteins and exosomes-that are naturally occurring circulating lipid particles. The third class is cell-based delivery systems--erythrocytes, macrophages, and platelets--that have evolved, for reasons central to their function, to exhibit a long life-time in the body. The last class is small molecule-based delivery systems that include folic acid. This article reviews the biology of these systems, their application in drug delivery, and the promises and limitations of these endogenous systems for drug delivery.

SUBMITTER: Yousefpour P

PROVIDER: S-EPMC4251460 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Co-opting biology to deliver drugs.

Yousefpour Parisa P Chilkoti Ashutosh A

Biotechnology and bioengineering 20140721 9

The goal of drug delivery is to improve the safety and therapeutic efficacy of drugs. This review focuses on delivery platforms that are either derived from endogenous pathways, long-circulating biomolecules and cells or that piggyback onto long-circulating biomolecules and cells. The first class of such platforms is protein-based delivery systems--albumin, transferrin, and fusion to the Fc domain of antibodies--that have a long-circulation half-life and are designed to transport different molec ...[more]

PMID: 24916780

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Project description:Sulphur is an essential element for life and is ubiquitous in living systems. Yet how the sulphur atom is incorporated into many sulphur-containing secondary metabolites is poorly understood. For bond formation between carbon and sulphur in primary metabolites, the major ionic sulphur sources are the persulphide and thiocarboxylate groups on sulphur-carrier (donor) proteins. Each group is post-translationally generated through the action of a specific activating enzyme. In all reported bacterial cases, the gene encoding the enzyme that catalyses the carbon-sulphur bond formation reaction and that encoding the cognate sulphur-carrier protein exist in the same gene cluster. To study the production of the 2-thiosugar moiety in BE-7585A, an antibiotic from Amycolatopsis orientalis, we identified a putative 2-thioglucose synthase, BexX, whose protein sequence and mode of action seem similar to those of ThiG, the enzyme that catalyses thiazole formation in thiamine biosynthesis. However, no gene encoding a sulphur-carrier protein could be located in the BE-7585A cluster. Subsequent genome sequencing uncovered a few genes encoding sulphur-carrier proteins that are probably involved in the biosynthesis of primary metabolites but only one activating enzyme gene in the A. orientalis genome. Further experiments showed that this activating enzyme can adenylate each of these sulphur-carrier proteins and probably also catalyses the subsequent thiolation, through its rhodanese domain. A proper combination of these sulphur-delivery systems is effective for BexX-catalysed 2-thioglucose production. The ability of BexX to selectively distinguish sulphur-carrier proteins is given a structural basis using X-ray crystallography. This study is, to our knowledge, the first complete characterization of thiosugar formation in nature and also demonstrates the receptor promiscuity of the A. orientalis sulphur-delivery system. Our results also show that co-opting the sulphur-delivery machinery of primary metabolism for the biosynthesis of sulphur-containing natural products is probably a general strategy found in nature.

Project description:The design of adaptable drug delivery systems able to encapsulate and release drugs with different wettability has been attracting widespread interest. Additionally, many attempts have been made to tune hydrophobic/hydrophilic drug release kinetics over time, avoiding the so-called burst release. In this scenario, hydrogels resulting from the assembly of micellar structures showing a hydrophobic core and a hydrophilic shell could represent a promising alternative to design versatile drug vehicles. In this regard, this work aimed at designing new thermosensitive micellar hydrogels starting from a custom-made amphiphilic poly(ether urethane) (PEU). Specifically, a commercial triblock copolymer (Poloxamer® 407), selected to ensure the temperature-driven chain arrangement into micelles, was reacted with 1,6-diisocyanatohexane and 1,4-cyclohexanedimethanol. The successful PEU synthesis was proved by size-exclusion chromatography ( M¯ w 50000 Da) and infrared spectroscopy. Subsequently, the wettability-driven drug arrangement within the micelle network as well as the influence of drug-loading on the resultant formulation thermosensitivity was investigated by selecting ibuprofen (IBU) and ibuprofen sodium salt (IBUSS) as hydrophobic and hydrophilic drugs, respectively. Specifically, growing drug amounts were loaded into PEU solutions, and the average hydrodynamic micelle diameters and the critical micellar temperatures (CMT) were measured. Systems containing IBU at the highest tested concentration (i.e., 20 mg/mL) showed a significantly higher micelle average diameter (58.2 ± 4.7 nm) and a remarkably lower CMT (8.9°C) with respect to both the control (40.1 ± 1.4 nm and 21.6°C) and IBUSS-loaded formulations (37.3 ± 2.1 nm and 22.4°C). Then, the influence of drug encapsulation on the temperature at which micelles begin to aggregate was rheologically assessed, showing that IBU-loading induced a decrease in this parameter (14.6, 8.7, and 13.7°C for virgin, IBU-loaded, and IBUSS-loaded hydrogel, respectively). Finally, IBU and IBUSS releasing mechanism was analysed using the Korsmayer-Peppas model (n value of 0.63 ± 0.007 and 0.89 ± 0.003 for IBU- and IBUSS-loaded gels, respectively). Thanks to their micellar organisation, the here-developed hydrogel platform allowed the encapsulation of a high number of molecules with different wettability. Additionally, these systems exhibited tunable payload-releasing time without burst release and open the way toward the engineering of smart systems for the sustained co-delivery of multiple drugs in a target tissue/organ.

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Co-opting biology to deliver drugs.

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Co-opting biology to deliver drugs.

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