Albumin-based drug delivery: harnessing nature to cure disease

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Abstract

The effectiveness of a drug is dependent on accumulation at the site of action at therapeutic levels, however, challenges such as rapid renal clearance, degradation or non-specific accumulation requires drug delivery enabling technologies. Albumin is a natural transport protein with multiple ligand binding sites, cellular receptor engagement, and a long circulatory half-life due to interaction with the recycling neonatal Fc receptor. Exploitation of these properties promotes albumin as an attractive candidate for half-life extension and targeted intracellular delivery of drugs attached by covalent conjugation, genetic fusions, association or ligand-mediated association. This review will give an overview of albumin-based products with focus on the natural biological properties and molecular interactions that can be harnessed for the design of a next-generation drug delivery platform.

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Albumin as a drug carrier: design of prodrugs, drug conjugates and nanoparticles.

Felix Kratz (2008)

Albumin is playing an increasing role as a drug carrier in the clinical setting. Principally, three drug delivery technologies can be distinguished: coupling of low-molecular weight drugs to exogenous or endogenous albumin, conjugation with bioactive proteins and encapsulation of drugs into albumin nanoparticles. The accumulation of albumin in solid tumors forms the rationale for developing albumin-based drug delivery systems for tumor targeting. Clinically, a methotrexate-albumin conjugate, an albumin-binding prodrug of doxorubicin, i.e. the (6-maleimido)caproylhydrazone derivative of doxorubicin (DOXO-EMCH), and an albumin paclitaxel nanoparticle (Abraxane) have been evaluated clinically. Abraxane has been approved for treating metastatic breast cancer. An alternative strategy is to bind a therapeutic peptide or protein covalently or physically to albumin to enhance its stability and half-life. This approach has been applied to peptides with antinociceptive, antidiabetes, antitumor or antiviral activity: Levemir, a myristic acid derivative of insulin that binds to the fatty acid binding sites of circulating albumin, has been approved for the treatment of diabetes. Furthermore, Albuferon, a fusion protein of albumin and interferon, is currently being assessed in phase III clinical trials for the treatment of hepatitis C and could become an alternative to pegylated interferon. This review gives an account of the different drug delivery systems which make use of albumin as a drug carrier with a focus on those systems that have reached an advanced stage of preclinical evaluation or that have entered clinical trials.

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Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity.

D. Steinberg, S. Parthasarathy, T E Carew … (1989)

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Is Open Access

Efficacy and Safety Comparison of Liraglutide, Glimepiride, and Placebo, All in Combination With Metformin, in Type 2 Diabetes

Michael Nauck, Anders Frid, Kjeld Hermansen … (2009)

OBJECTIVE—The efficacy and safety of adding liraglutide (a glucagon-like peptide-1 receptor agonist) to metformin were compared with addition of placebo or glimepiride to metformin in subjects previously treated with oral antidiabetes (OAD) therapy. RESEARCH DESIGN AND METHODS—In this 26-week, double-blind, double-dummy, placebo- and active-controlled, parallel-group trial, 1,091 subjects were randomly assigned (2:2:2:1:2) to once-daily liraglutide (either 0.6, 1.2, or 1.8 mg/day injected subcutaneously), to placebo, or to glimepiride (4 mg once daily). All treatments were in combination therapy with metformin (1g twice daily). Enrolled subjects (aged 25–79 years) had type 2 diabetes, A1C of 7–11% (previous OAD monotherapy for ≥3 months) or 7–10% (previous OAD combination therapy for ≥3 months), and BMI ≤40 kg/m2. RESULTS—A1C values were significantly reduced in all liraglutide groups versus the placebo group (P < 0.0001) with mean decreases of 1.0% for 1.8 mg liraglutide, 1.2 mg liraglutide, and glimepiride and 0.7% for 0.6 mg liraglutide and an increase of 0.1% for placebo. Body weight decreased in all liraglutide groups (1.8–2.8 kg) compared with an increase in the glimepiride group (1.0 kg; P < 0.0001). The incidence of minor hypoglycemia with liraglutide (∼3%) was comparable to that with placebo but less than that with glimepiride (17%; P < 0.001). Nausea was reported by 11–19% of the liraglutide-treated subjects versus 3–4% in the placebo and glimepiride groups. The incidence of nausea declined over time. CONCLUSIONS—In subjects with type 2 diabetes, once-daily liraglutide induced similar glycemic control, reduced body weight, and lowered the occurrence of hypoglycemia compared with glimepiride, when both had background therapy of metformin.

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Author and article information

Contributors

Maja Thim Larsen: maja.thim.larsen@inano.au.dk

Matthias Kuhlmann: kuhlmann@inano.au.dk

Michael Lykke Hvam: mhvam@inano.au.dk

Kenneth A. Howard: kenh@inano.au.dk

Journal

Journal ID (nlm-ta): Mol Cell Ther

Journal ID (iso-abbrev): Mol Cell Ther

Title: Molecular and Cellular Therapies

Publisher: BioMed Central (London )

ISSN (Electronic): 2052-8426

Publication date (Electronic): 27 February 2016

Publication date PMC-release: 27 February 2016

Publication date Collection: 2016

Volume: 4

Electronic Location Identifier: 3

Affiliations

Interdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology and Genetics, University of Aarhus, Aarhus, Denmark

Article

Publisher ID: 48

DOI: 10.1186/s40591-016-0048-8

PMC ID: 4769556

PubMed ID: 26925240

SO-VID: 7413d4ae-c504-4a5f-97e0-7af4104c3d2a

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 14 December 2015

Date accepted : 17 February 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001825, Styrelsen for Forskning og Innovation;

Award ID: 102-2014-3

Award Recipient : Kenneth A. Howard

Custom metadata

Keywords: human serum albumin (hsa),drugs,albumin-binding,albumin fusions,half-life extension,intracellular delivery,neonatal fc receptor (fcrn),molecular medicine,targeted drug delivery

Data availability:

Keywords: human serum albumin (hsa), drugs, albumin-binding, albumin fusions, half-life extension, intracellular delivery, neonatal fc receptor (fcrn), molecular medicine, targeted drug delivery

Albumin-based drug delivery: harnessing nature to cure disease

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Most cited references 102

Albumin as a drug carrier: design of prodrugs, drug conjugates and nanoparticles.

Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity.

Efficacy and Safety Comparison of Liraglutide, Glimepiride, and Placebo, All in Combination With Metformin, in Type 2 Diabetes

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