Nanomedicine and Biomaterials
Experimental Medical Science
Faculty of Medicine
NANOPARTICLES FOR MAGNETIC DRUG TARGETING
The goal of targeted drug delivery is to concentrate the drug locally at the diseased tissue while maintaining a low concentration in the rest of the body. Magnetic targeting of drug-loaded magnetic nanoparticles by using extracorporeal magnets provides a mean to this effect. Due to the rapid decrease of the magnetic field with the distance and the large drag forces produced by the blood flow, the method works best for directing rather large (often micron-sized) particles to vessels of low blood flow located superficially. We are studying a method that overcomes the shortcomings of conventional magnetic targeting, namely implant-assisted magnetic targeting. Under the influence of an external magnetic field, a magnetizable implant will create locally a high-gradient magnetic field at the target site. The implant increases the magnetic force on injected magnetic particles significantly to allow the particles to be captured at the target site (i.e., the site of the implant). This means that (i) deeper locations in the body can be reached, (ii) nanosized particles can be applied, and (iii) large blood vessels with high flow rates can be targeted. We have developed magnetic nanoparticles loaded with tPA (tissue plasminogen activator), a thrombolytic biologic agent, and demonstrated in animal studies that the nanoparticles can be targeted to a cardiovascular stent, previously inserted by percutaneous coronary intervention (PCI), to dissolve an in-stent thrombosis. The movie below illustrates the concept of the method.
Kempe M et al. The use of magnetite nanoparticles for implant-assisted magnetic drug targeting in thrombolytic therapy. Biomaterials 2010, 31, 9499–9510. DOI:10.1016/j.biomaterials.2010.07.107
Kempe H, Kates SA, Kempe M. Nanomedicine’s promising therapy: magnetic drug targeting. Expert Review on Medical Devices 2011, 8(3), 291-294.
NANOPARTICLES FOR SUSTAINED DRUG RELEASE
Sustained drug release systems provide a prolonged drug release over time. The advantages include reduced in vivo drug concentration fluctuations, reduced overall dose, and higher patient compliance due to less frequent administration needs. The technique of molecular imprinting offers attractive opportunities to tailor selectivity and drug release profile of polymeric materials. During molecular imprinting, recognition sites are created by self-assembly of polymer building blocks around template molecules. After cross-linking the building blocks, the templates are extracted from the polymer network, leaving recognition sites that are complementary to the templates. The term “plastic antibodies” has been coined to describe the resultant recognitive polymers. We have developed molecularly imprinted nanocarriers for sustained release of the macrolide drug erythromycin. The drug has antibiotic, anti-inflammatory, and immunomodulating activities. Release studies in physiological buffer showed an initial burst release of a quarter of loaded drug during the first day and an 82% release after a week. The nanocarriers may potentially be included in bone cements, wound dressings, or implant coatings to promote sustained antibiotic and/or anti-inflammatory effects.
Kempe H, Parareda Pujolràs A, Kempe M. Molecularly imprinted polymer nanocarriers for sustained release of erythromycin. Pharmaceutical Research 2015, 32(2), 375–388. DOI:10.1007/s11095-014-1468-2
H Kempe, M Kempe. Molecularly imprinted polymers. In The Power of Functional Resins in Organic Synthesis, Fernando Albericio and Judit Tulla-Puche, Eds. Wiley-VCH, Weinheim, Germany, 2008: 15–44.
NANO- AND MICRO-SIZED SUPPORTS FOR SOLID-PHASE SYNTHESIS
Merrifield pioneered solid-phase synthesis on polystyrene supports in the 1960s. Since then, a range of different supports has been developed. One of these, the CLEAR support, was developed by Kempe and Barany in the mid 1990s and shortly thereafter commercialized by Peptides International. CLEAR is based on polyethylene glycol (PEG) and does not contain any polystyrene. It was developed to meet the need of a support that is compatible with a range of organic solvents as well as water and physiological media. We have more recently developed magnetic solid-phase synthesis supports in nano- and micro-sized ranges.
Kempe M, Barany G. CLEAR: A novel family of highly cross-linked polymeric supports for solid-phase peptide synthesis. J. Am. Chem. Soc. 1996, 118, 7083-7093. DOI:10.1021/JA954196S
Cederfur J, Kempe M. Development of wide-pore CLEAR supports for applications involving biological macromolecules. Polymer Bulletin, 2001, 46, 381-387. DOI:10.1007/s002890170046
Castro Franco AM, Kempe M. Wide-pore CLEAR: Resins for Solid-Phase Synthesis and Interactions of Resin-bound Ligands with Biological Macromolecules. In Innovation and Perspectives in Solid Phase Synthesis & Combinatorial Libraries, R. Epton, Ed.; Mayflower Scientific Ltd.: Kingswinford, England, 2004: 205-208.
Sasikumar PG Kempe M. Magnetic CLEAR supports for solid-phase synthesis of peptides and small organic molecules. Int. J. Peptide Res. Therapeut. 2007, 13, 129–141. DOI:10.1007/s10989-006-9056-x
Norén K, Kempe M. Multilayered magnetic nanoparticles as the support in solid-phase peptide synthesis. Int. J. Peptide Res. Therapeut. 2009, 15, 287–292. DOI:10.1007/s10989-009-9190-3
RECOGNITION ELEMENTS FOR DETECTION OF BETA-LACTAM ANTIBIOTICS
In animal husbandry, beta-lactam antibiotics are administered for therapeutic and prophylactic purpose to combat and/or prevent mastitis and other bacterial diseases. Due to the risk of development of antibiotic resistant bacterial strains, the inhibition of starter cultures in the dairy industry, and the potential risk of allergic reactions in hypersensitive human individuals, legislative authorities have established maximum residue levels allowed in foodstuffs. For this reason, there is a need for efficient detection methods. We have focused on the development of recognition elements by molecular imprinting. The work started in an FP5 EU collaborative project (CREAM).
Cederfur J, Pei Y, Zihui M, Kempe M. Synthesis and screening of molecularly imprinted polymer libraries selective for penicillin G. Journal of Combinatorial Chemistry, 2003, 5, 67-72. DOI:10.1021/cc020051n
Benito-Peña E, Moreno-Bondi MC, Aparicio S, Orellana G, Cederfur J, Kempe M.. Molecular engineering of fluorescent penicillins for molecularly imprinted polymer assays. Anal. Chem. 2006, 78, 2019–2027. DOI:10.1021/ac051939b
Kempe H, Kempe M. Influence of salt ions on binding to molecularly imprinted polymers. Anal. Bioanal. Chem. 2010, 396, 1599–1606. DOI: 10.1007/s00216-009-3329-0
Henrik Kempe and Maria Kempe. QSSR analysis of β-lactam antibiotics on a penicillin G targeted MIP stationary phase. Anal. Bioanal. Chem. 2010, 398, 3087–3096. DOI:10.1007/s00216-010-4254-y
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