Nanomedicine and Advanced Drug Delivery

Biography

Prof. Per Hansson has his expertise in colloidal systems of relevance for developing drug delivery systems. Most of his studies have dealt with polyelectrolytes and their interaction with colloids of opposite charge, in particularly phase transitions and phase separation in polyelectrolyte hydrogels in relation to the loading and release of amphiphilic drugs, proteins and peptides. He is currently investigating the self-assembling properties of amphiphilic drugs, and the fate of biomacromolecular drug formulations after injection into the subcutaneous tissue. This involves the development of in vitro methods to study the release from formulations and transport through the extracellular matrix. Hansson is leading the Pharmaceutical Physical Chemistry group at the Department of Pharmacy, Uppsala University, and the Parenteral Drug Delivery Platform of the Swedish Drug Delivery Forum

Abstract

Statement of the Problem: Microgels have the capacity to store large amounts of amphiphilic, peptide and protein drugs. This makes them interesting as delivery systems for drugs needing protection against degradation, and as components of slow-release and depot formulations for parenteral administration. Despite the fact that microgels are used clinically, e.g., to deliver doxorubicin in the treatment of liver cancer [1], little attention has been given to how the drug self-assembly inside microgels affects the release properties. The purpose of this study is to show that that the release of amphiphilic drugs is strongly influenced by self-assembly [2] and its effect on the swelling of the microgel network. Methodology & Theory: Loading and release of cationic amphiphilic drugs are investigate by means of micropipette-assisted microscopy of single microgels [2, 3] (Fig. 1) and μDiss apparatus studies. We have developed and evaluated two new models combining transport dynamics and thermodynamics of drug self-assembly, one for non- swelling responsive microgels based on the Nernst-Planck equation [2], and one for responsive networks handling coexisting phases with different degrees of network swelling. Findings: For two polyelectrolyte microgel systems, DC bead® used clinically, and polyacrylate microspheres (diameter: ~100 μm), the drug self-assembly has a profound effect on the loading and release kinetics as well as on the distribution of the drug inside the beads and the distribution between different beads in a suspension. The roles played by salt in the release medium and the responsiveness of the polymer network are highlighted. The micropipette technique is found to be a powerful in vitro method.  Conclusions & Significance: The results highlight the importance of the electric coupling of diffusive fluxes, the amphiphilic self-assembly and the responsiveness of the microgel. The results are important for the development of microgel drug delivery systems with improved release kinetics

Biography

Christoph Alexiou, in the year 2000 received his degree as an ENT-Physician and 2002 he changed to the ENT-Department in Erlangen, Germany, where he performed his postdoctoral lecture qualification (Habilitation). He is working there as an assistant medical director in the clinic and leads the Section for Experimental Oncology and Nanomedicine (SEON). Since 2009 he owns the Else Kröner-Fresenius-Foundation-Professorship for Nanomedicine at the Universityhospital Erlangen. He receives grants from the European Union, German Research Community (DFG), Ministry of Education and Science (BMBF) and Bavarian State Ministry of the Enviroment and Consumer Protection and is a member of the Executive Board of the European Technology Platform for Nanomedicine (ETPN). His research is addressing the emerging fields of  Diagnosis, Treatment and Regenerative Medicine using magnetic nanoparticles and the translation from basic research into clinical trials and published >150 papers in peer reviewed journals. He received for his research several national and international renowned awards

Abstract

Nanoparticles offer promising new possibilities for a multiplicity of medical applications including therapy and diagnosis of various diseases. Especially iron oxide nanoparticles provide a broad application spectrum as contrast agents, magnetic transporters, or heat carriers in hyperthermia treatment. While particles used for imaging should circulate for extended periods of time in the vascular system, nanoparticles designed for use as drug carriers should be efficiently taken up by the target cells. Importantly, nanoparticles for medical (and several other) applications must be biocompatible, meaning that after contact with cells no adverse effects are elicited. To translate basic findings into clinical trials several requirements such as detailed synthesis and characterization of the nanoparticles, nanotoxicological testings, ex vivo models to simulate in vivo conditions for appropriate adjustment of the necessary parameters and pre-clinical animal studies have to be addressed. These results are of pivotal importance to start with respective GMP production and approval, which is essential for translating these products into clinical trials (scheme). SEON (Section of Experimental Oncology and Nanomedicine) addresses these issues with a special focus on drug delivery in oncology (1,2,3,4,5,6) and their promising potential applications in cardiovascular (7,8), regenerative medicine (9), imaging (1,10) and infections (11). The aim is the translation of the preclinical results into clinical trials and the respective steps necessary to gain this ambitious object

Biography

Cesar Torres is a third-year PhD student at the University of Maryland, in College Park, MD, US.  He has a dual bachelor’s degree in Chemical Engineering and Chemistry, and a minor in Material Science & Engineering from the University of Idaho, in Moscow, ID, USA. As an undergraduate student, he participated in a summer research internship program at the Whitesides Group in Harvard University, working on nano-fabrication and soft-lithography.  As a PhD student, he is focused on the application of nanotechnology to controlled release systems in contact lenses.

Abstract

Statement of the problem: Ophthalmic diseases are most commonly treated with eye drops due to the low costs and self-administration. However, it has been reported that eye drops could deliver only about 5% of functional ingredients contained in a burst dosage since they suffer from tear drainage in addition to corneal and sclera barriers.  To address the limitations of eye drops, researchers have explored the use of therapeutic contact lenses. Nevertheless, a major limitation of contact lenses in drug delivery is that most of the drug absorbed is released within the first few hours, fact that limits the use for extended release.  The purpose of this study is to demonstrate the application of vitamin E diffusion barriers with ionic surfactants into contact lenses, in order to achieve controlled release of non-steroidal-anti-inflammatory drugs (NSAIDs).  Methodology: Silicone-hydrogel commercial contact lenses were soaked in ethanol solutions containing vitamin E and an ionic surfactant. Secondly, a NSAID was added to each lens by soaking the lenses in drug solutions for determined periods of time. The in vitro release experiments were carried by immersing the drug-containing contact lenses in phosphate buffer saline at physiological pH.  Results: Contact lenses containing vitamin E extend drug delivery up to a factor of 50, depending on the amount of vitamin E loaded and the physichochemical properties of the drugs.  Vitamin E in contact lenses acts as a diffusion barrier that retards the diffusion of the drugs to the release medium. Contact lenses containing both vitamin E and a long-chain cationic surfactant further extend drug delivery due to electrostatic interactions between the anionic NSAIDs and the surfactant.  Conclusion: Contact lenses containing vitamin E and cationic surfactants can provide extended release of NSAIDs, and could be potential biomaterials to be used for the treatment of ophthalmic diseases. However, ocular irritation and toxicity studies would be needed to evaluate the safety of the approach. 

Biography

Peptide-based vaccines: Dr. Hussein focus on the development of peptide-based vaccines against infectious diseases and cancer. This includes (1) synthesis of adjuvanting moieties for stimulation of immune system; (2) applying different methods for conjugation of peptides and lipids; (3) determination of the size, shape and charge of the self-assembled vaccine particles; (4) investigate the biological efficiency of vaccines in both in vitro and in vivo. Gene delivery: Currently, Dr. Hussein is working on the development of targeted nanoparticle delivery system to deliver the siRNA to cytoplasm. This delivery system includes peptide-based, micelles and/or liposome formulations

Abstract

Conjugation of multiple peptides by their N-termini is a promising technique to produce branched multiantigenic vaccines. We established a double conjugation strategy that combines a mercapto-acryloyl Michael addition and a copper-catalysed alkyne-azide 1,3-dipolar cycloaddition (CuAAC) reaction to synthesise self-adjuvanting branched multiantigenic vaccine candidates. These vaccine candidates aim to treat cervical cancer and include two HPV-16 derived epitopes and a novel self-adjuvanting moiety. This is the first report of mercapto-acryloyl conjugation applied to the hetero conjugation of two unprotected peptides by their N-termini followed by a CuAAC reaction to conjugate a novel synthetic lipoalkyne self-adjuvanting moiety. In vivo experiments showed that the most promising vaccine candidate completely eradicated tumours in 46% of the mice (6 out of 13 mice).

Biography

Glòria Garcia Ortega is a PhD student at the Universitat Autònoma de Barcelona whose work deals with lipo-based delivery systems for anticancer applications. The group where she stays focuses their research on the challenging area of bioinorganic chemistry (metallothioneins, synthesis of Cu and Pt chemotherapeutic complexes and metallosomes for biomedical applications). Her final Bachelor’s degree project lied on the synthesis, characterization and application of metal and metal-oxides nanoparticles. After her Master’s degree in Industrial Chemistry and Introduction to Chemical Research, she did an industrial research internship in order to develop nanocomposites for superconducting materials

Abstract

Metallosurfactants (MTS) are tensioactive metal complexes that gather properties of both constituents: the surfactant and the metal ion.^1,2These molecules exhibit self-assembly properties and, when mixed with phospholipids, are able to form stable vesicles, known as metallosomes, which size ranges from nanoparticles to microns. They have been proposed as reliable and efficient tools for drug delivery systems in cancer treatment.^3,4Although platinum drugs are widely used in the treatment of several types of solid tumors, the inclusion of Pt chemotherapeutic agents in such vesicles is reported to enhance their biocompatibility and allows to reduce immunogenicity and non-specific toxicity, diminishing side-effects in front of the free drug.^5,6

An unexplored Pt(II)-MTS family of linear anionic alkyl sulfonated ligands have been synthesised and fully characterised by several techniques (¹H-NMR, ¹³C-NMR, ¹⁹⁵Pt-NMR, ESI-MS, ICP-OES and ATR-FTIR). This particular MTS family bears the polar head group opposite to the coordinated Pt(II) centre, hence giving rise to a non-standard MTS structure.⁷The aggregation properties of both, the amphiphilic ligands and the corresponding Pt(II)-MTS have been studied by DLS and UV-vis, as well as by optical microscopy and cryo-TEM. Tensioactive ligands have not shown a suitable hydrophilic/hydrophobic moieties ratio to form aggregates by themselves. However, the coordination of some of these ligands to Pt(II) moiety allows their assembly in the micron-range (Figure 1). Mixed vesicles of Pt(II)-MTS and phospholipids at different concentrations have been obtained in aqueous media to study the Pt internalisation in the phospholipid bilayer and the metallosomes size.⁸Finally, preliminary cytotoxic studies have shown the potentiality of these compounds to be used as promising anticancer lipodrug candidates.

Biography

Hervé Hillaireau is Associate Professor of Pharmaceutical Technology at the School of Pharmacy of Université Paris-Sud since 2009. His research at Institut Galien Paris-Sud relates to the design and the toxicological evaluation of biodegradable nanoparticles as drug nanocarriers, with a focus on: (i) nanocarrier design for nucleoside/nucleotide analogues and nucleic acids delivery in anticancer and antiviral therapies; (ii) nanocarrier surface functionalization for molecular targeting; (iii) toxicological evaluation of biodegradable nanoparticles. He has been supervising or co-supervising 10 PhD theses. He is the author of 4 book chapters and 38 peer-reviewed international research articles, and has recently co-edited a special issue of Advanced Drug Delivery Reviews on Aptamers in therapeutics and drug delivery

Abstract

Nanomedicine hav brought tremendous hope of targeted and personalized medicine. In particular, they have improved the bioavailability of poorly soluble drugs, reduced side effects of several drugs, and enabled drug targeting to diseased tissues, especially in the field of cancer treatment. However, a widespread use of nanomedicine still faces several important impediments, especially in the case of hydrophilic drugs for several reasons. (i) Despite variable drug encapsulation efficiencies into nanocarriers, the drug loading achieved is generally low, which limits the drug dose and/or requires the administration of high amounts of excipients (eg. lipids or polymers forming the nanocarrier). (ii) The drug release is often poorly controlled and prone to the ‘burst release’ effect, and the stability of nanocarriers in physiological media may be unsatisfying, therefore limiting the targeting potential of nanomedicine. (iii) Each drug often requires a specific nanocarrier system, which is often challenging to scale-up, which dramatically limits the applicability into the industry and the clinics [1].

To address these limitations, we have designed a drug delivery platform tailored to hydrophilic drugs, especially nucleotides/nucleotide analogues. This platform relies on the preparation of chitosan-iron coordination complexes, which form nanogels in presence of hydrophilic drugs. Such nanogels act as nanocarriers of therapeutic nucleotides such as adenosine triphosphate (ATP), as well as nucleotide analogues such as azidothymidine triphosphate (AzT-TP).

Our group has first demonstrated the ability of triphosphate group-containing drugs to induce ionotropic gelation of chitosan. This was demonstrated using the nucleotide ATP and the nucleotide analogue AzT-TP. The resulting nanogels can be seen as nucleotide/nucleotide analogue nanocarriers, showing both efficient encapsulation and drug loading, up to 44% w/w [2]. To further investigate the potential of chitosan-metal complexes to improve the nanogel stability in physiological media, coordination complexes of chitosan and Fe(III) have been synthesized and used to form nanogels in presence of ATP, which clearly demonstrated a high resistance to physiological ionic strengths, increasing with the Fe(III) content. These results highlight the potential of metal association to chitosan to form nanogels with tunable stability and drug release profile [3].