Laser Optofluidics in Fighting Multiple Drug Resistance E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
This monograph is a collection of reviews that presents results obtained from new and somewhat unconventional methods used to fight multiple drug resistance (MDR) acquired by microorganisms and tumours. Two directions are considered: (i) the modification of non-antibiotic medicines by exposure to un-coherent, or laser optical radiation to obtain photoproducts that receive bactericidal or, possibly, tumouricidal properties and (ii) the development of new vectors (micrometric droplets of solutions containing medicinal agents) to transport medicines to targets based on optical and micro spectroscopic methods.
Chapters shed light on pendant droplets used for antibiotic drug delivery, the science of lasers and their interactions with fluids in pendant droplets and spectroscopic analyses of droplets used to treat MDR infections. It therefore equips researchers and medical professionals with information about tools that enable them to respond to medical emergencies in challenging environments.
The intended readership for this monograph includes graduate students, medical doctors, fluid physicists, biologists, photochemists, and experts in drug delivery methods employed in extreme conditions (such as those found in outer space and hypergravity conditions) who are learning about using techniques such as laser spectroscopy, biophotonics and optofluidics/microfluidics.
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Veröffentlichungsjahr: 2017
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Laser Optofluidics in Fighting Multiple Drug Resistance
Edited by
Mihail Lucian Pascu
Laser Department, National Institute for Laser,Plasma and Radiation Physics,Romania
BENTHAM SCIENCE PUBLISHERS LTD.
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PREFACE
This book is proposed as a synthesis of inter- and multi-disciplinary results about new and somewhat unconventional methods and means to fight multiple drug resistance acquired by microorganisms and tumours. Essentially, two are the main directions along which the book text is elaborated:
(i) Modification of non-antibiotic medicines by exposing them at un-coherent, or laser optical radiation so that from an initial compound that is not efficient in combating bacteria or tumours one obtains photoproducts which alone or by synergetic action receive bactericide or, possibly, tumouricide properties. Examples are given regarding several classes of medicines, pointing out particular compounds amongst cytostatics, phenothiazines, quinazolines and hydantoins and showing how the generated photoproducts may be identified by methods belonging to spectroscopy, microfluidics, optofluidics, chromatography and mass spectrometry.
(ii) Developing new vectors to transport medicines to targets based on optics and micro-spectroscopy methods. These vectors are microvolumetric droplets of water solutions that contain parent medicines and have two roles. First, is to allow fast modification of their content by exposing them to pulsed laser beams so that photoproducts with bactericide properties are generated via resonant interaction between one beam and one single droplet. The second, is splitting the droplet by its unresonant interaction with another laser beam having suitable properties, so that nano-droplets and micro-droplets are generated which contain the photoproducts and propagate at supersonic or, respectively, subsonic speeds towards the target.
The target readers of the book are medical doctors, physicists, optofluidics and microfluidics specialists, photochemists, biologists, laser spectroscopists as well as specialists in a broad area of domains ranging from delivery methods of medicines using different sorts of fabrics, to the use of multifunctional medicines in outer space missions, after passing hypergravity conditions. A particular target group is constituted by students experimenting in laser spectroscopy, biology, biomedicine, photochemistry, biophotonics and microfluidics since the book provides new and innovative information about behavior of liquid drops, foams, emulsions and bubbles at interaction with laser radiation and the possible applications of the results in the former mentioned fields.
The book is conceived not only as a coherent synthesis of new results, but also as a source of novel ideas, yet untreated, that are proposed to the readers as working variants in future research. This approach would allow, among others, a fast and flexible reaction in the fight against naturally or accidentally occurring multiresistant microorganisms and tumours, with fast enough results to allow a rapid deal with environment unexpected changes.
A particular interest is devoted to the use of laser spectroscopy and related methods for making available multifunctional drugs that may be applied for treatment of humans or for the decontamination of modules during space flights, in the conditions in which confined small spaces are used in isolation regime for long time intervals, as happens in interplanetary missions. Another subject of interest is the micro-lasers or micro-lasing droplets that emit in free space around them and may be used in a large area of biomedical and technological applications.
The editor would like to thank:
Dr. Tatiana Tozar for valuable assistance in placing the book text in the printing house template and for detailed checking of figures, tables, list of contributors and abbreviations.Dr. Andra Dinache for final overall critical reading of the text book.Dr. Viorel Nastasa for assistance in internet connections with the printing house.The Laser Spectroscopy Group of the National Institute for Laser, Plasma and Radiation Physics in Bucharest, for the team work that made possible harvesting together this book.List of Contributors
Introduction
Mihail Lucian Pascu1,2,*This book is triggered by the current progress in two emerging fields: (i) fighting multiple drug resistance acquired by microorganisms (in particular bacteria) by laser/optical means and methods and (ii) developing new transport vectors to deliver medicines to targets. Each of them is related to a – respectively - larger, distinct and self-consisting domain that undergoes also a current accelerated expansion.
The use of laser radiations to produce new substances from parent compounds is part of photochemistry which deals with generation of ultrapure products by interaction of molecules with photons of laser radiation. This is a chemistry in which chemical reactions are controlled instantaneously by the interaction of parent chemicals with laser beams, to yield new (photo) products, instead of using with the same purpose thermal/pyrotechnical procedures. The interaction produces either an inner modification of molecules structure which makes them more chemically active, or a break-up of molecules in radicals which interact with surrounding environment and/or between themselves and lead to new products. In both cases resulting materials are ultrapure due to the selective interaction of laser radiation with the molecular targets. This kind of procedure becomes very useful in pharmacology because it allows to produce in not too large quantities new and ultrapure medicines starting from substances already utilised in treatments.
The vectors considered in this book for possible transportation of medicines to targets are micro- and/or nano-droplets either directly generated by a capillary system or obtained by interaction of a laser beam with one single pendant droplet when the beam is not absorbed by droplets’ compounds and the light pressure on it dominates the interaction. The same kind of vectors may be droplets included in aerosols, where a particular distribution of theirs function of diameters/volumes may be produced.
The multiple drug resistance (MDR) which is also called multi-drug resistance or multiresistance of microorganisms that cause infections or even diseases may be defined as a state or property of a microorganism to resist antimicrobial drugs used either as single drugs or as “cocktails” of drugs. Depending on the kind of microorganisms, the medicines with respect to which MDR is acquired may be antibiotics, antifungal, antiviral or antiparasitic chemicals having functions and molecular structures originally conceived to efficiently eradicate the targets. Examples of most common MDR microorganisms which developed resistance are: Gram-positive (Staphyloccocus aureus) and Gram-negative (Pseudomonas aeruginosa, Escherichia coli) bacteria, viruses (HIV-Human immunodeficiency virus), fungi (Candida species, Scedosporium prolificans, Scedosporium apiospermum), parasites (Plasmodium falciparum and Plasmodium vivax producing malaria). Drug resistance was acquired from the very first antibiotic, penicillin (widely used since 1943, but tested before 1940) for which the resistance of Pneumococcus was reported in 1965, but the first resistance was reported in 1940, in the testing time interval, exhibited by Staphylococcus. Some antibiotics for which resistance of bacteria were shown as well as bacteria and respective years when resistance was mentioned are, as presented in SwitchYard Media [1]: tetracycline (utilised in 1950)/Shigella (resistance reported in 1959); erythromycin (introduced in 1953)/Streptococcus (1968); methicillin (introduced in 1960)/Staphylococcus (1962); gentamicin (introduced in 1967)/Enterocuccus (resistance first reported in 1979); vancomycin (first used in 1972)/Enterocuccus (1988) and Staphylococcus (2002); linezolid (introduced in 2000)/Staphylococcus (2001); ceftaroline (introduced in 2010)/Staphylococcus (resistance first reported in 2011).
A more complete description and a set of MDR related definitions (such as extensive drug resistance-XDR and pandrug-resistance-PDR) are introduced in Magiorakos et al. [2] as a result of a study made by the European Centre for Disease Prevention and Control (ECDC) and the Centers for Disease Control and Prevention (CDC) for creating a standardised terminology introduced to describe acquired resistance profiles in Staphylococcus aureus, Enterococcus spp., Enterobacteriaceae (other than Salmonella and Shigella), Pseudomonas aeruginosa and Acinetobacter spp.. Lists of antimicrobial categories were made using the expertise of the Clinical Laboratory Standards Institute (CLSI)-US, the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the United States Food and Drug Administration (FDA), as well. MDR was defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories, XDR as non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (bacterial isolates remain susceptible to only one or two categories) and PDR was defined as non-susceptibility to all agents in all antimicrobial categories.
On the other hand, one may speak about resistance of tumours and, in particular, malignant tumours to treatment with drugs belonging to several categories such as cytostatics, antibiotics, specifically designed (quinazolines, pyridinium) compounds, phenothiazines.
The delivery of medicines to targets is made using several procedures among which the local delivery of relatively large volumes (ml) and the systemic delivery through injections (usually one or more ml) are most common. In this book the introduction of drops and droplets as vectors to transmit the medicines to target tissues is described, taking into account the small volume (µl or less) of the delivered medicine which meets the needs to treat a particular system using the smallest necessary and possible quantity of drugs to avoid toxic and related to toxicity effects (photo-toxicity included). On the other hand, a single droplet in pedant/hanging/suspended position at interaction with laser beams, emitted either in pulsed regime or in continuous wave may be used in technological applications and a more general description of the optical properties of droplets is given in the book.
In general, a drop or droplet is a small quantity of liquid which may have different shapes (cylinder, sphere, ellipsoid or combinations of them in static or dynamic evolution) bounded completely or almost completely by free surfaces defined with respect to surrounding media (gases, liquids and high viscosity media immiscible with the droplet’s content and keeping it confined). The droplet may be generated in a hanging position with respect to a capillary in which case it is called pendant droplet or on a surface being called sessile droplet. If instead of generating a drop of liquid in gas environment one generates a small gas volume in a liquid, one may define a bubble as shown in de Gennes et al. [3]. One may also speak about a droplet in an emulsion or a bubble in a foam, or one may study droplets of emulsions or foams in pendant position in air or another media, for instance. All these physical entities are studied in microfluidics and constitute basic elements for applications in pollution control, dedicated industrial technologies and even outer space experiments.
The interaction of an optical beam with a droplet, a bubble, a liquid containing a bubble or a droplet of immiscible liquid with it, is treated by a relatively new field, the optofluidics which was coagulated mainly in the last 10-15 years. Optofluidics is a mixture of photonics and microfluidics (which deals with non-solid entities) that brings together light and non-solids to provide possible advanced technologies such as fluid waveguides, deformable lenses, microdroplet lasers, new photochemistry and low toxicity biomedicine (see [4-6]).
The coupling of optofluidics with the fight against MDR and its forms is the main idea behind this book which is conceived as a multi- and inter-disciplinary collection of data describing the authors’ main results in the field. So, the modification of existing medicines (antibiotics, non-antibiotics, cytostatics) for which MDR was acquired, by exposure to laser radiation to obtain photoproducts efficient against biological targets is reported. The process lasts as long as the sample is exposed to laser beam and the photoproducts are generated in minutes to hours if exposure is performed in bulk (1-2 ml volumes) or in, at most minutes if the irradiation of droplets (microvolumetric liquid entities with less than 10 µl volume) containing solutions of medicines is made.
The modification of molecular structures of parent compounds in liquid samples that interact with laser radiation is based on the absorption of laser beam by molecules in the droplet which is otherwise called resonant interaction because it is based on close values (resonance) of the energy difference between two molecular singlet states and the energy of laser beam photons.
If laser radiation is not absorbed by droplet materials, the interaction (usually called unresonant) generates only light pressure effects and produces mechanical effects on the droplet that may vary from changing its shape and producing vibrations to emission of smaller droplets having dimensions at nanoscale. Droplets at milli-, micro- and nano-scale may be used as vectors to transport medicines (parent compounds or photoproducts) to biological targets.
This is also function of the relation between the strengths/intensities of resonant and unresonant interaction effects of laser beams on one hand and the droplets contents, shapes and volumes on the other.
Fighting MDR acquired by bacteria, viruses, fungi, parasites and tumours can be made by working on the molecular structures of existing medicines which are not efficient anymore in treatments, via exposure to optical/laser radiation with the purpose to obtain new photoproducts efficient against targets that resist or are not too sensitive to the corresponding parent compounds. Further, generation of photoreaction products can be combined with droplets as new vectors to transport medicines to targets. In doing this, pendant droplets have the advantages of a minimal interaction with environment as well as with the generating capillary. On the other side, characterisation of compounds generated in droplets by optical means, i.e. spectroscopic investigations of the content of droplets that have very small volumes and contain very small quantities of substances to be analysed is another emerging field: micro- and nano-spectroscopy.
Starting from these general considerations, the book is conceived as a coherent collection of information about interdisciplinary and multidisciplinary research in the fast currently developing field devoted to applications of optically processed small volume samples in biomedicine and technology. The small volume samples are produced as droplets in pendant positions in different environment media.
In treating the subject, the description of pendant droplets is made from microfluidics (Chapter 2) and optofluidics (Chapter 3) points of view considering mainly single droplets in different media with which they do not mix, but also droplets containing foams or emulsions. Then, drop profile tensiometry results are shown that characterize liquid interfacial dynamics with emphasis on pendant droplets (Chapter 4) and an overview of dynamics and applications of pendant drops is shown in Chapter 5. To make the connection between the description of droplets and their biomedical applications, in Chapter 6 is presented an up-date about MDR acquired by microorganisms and tumours. Further, laser beam properties are introduced in Chapter 7 given that in the applications of interest here the single droplets interact with laser beams emitted in pulsed regime and many effects are directly related to laser beam shape, energy, time and space characteristics. Usually, the interaction takes place with a single pulse or with a controlled number of pulses. The next two chapters deal with unresonant (Chapter 8) and resonant (Chapter 9) interaction of laser beams described in Chapter 7 with droplets in pedant position. In the results shown here the droplets have microvolumetric dimensions and are hanged in air. The investigations of the effects of a laser beam on a single droplet utilise high speed optical recording, laser induced fluorescence and Raman spectra monitoring. In direct connection with resonant and unresonant interaction in Chapter 10 are described relevant data about surface tension and contact angles of microdroplets containing water solutions of medicines exposed to laser radiation either in bulk solutions or in droplets with the same content as bulk. Since droplets considered in the reported studies may contain solutions of medicines exposed to and modified by optical incoherent beams or laser beams prior to be generated as microdroplets, in Chapter 11 are shown results of the interaction of such beams with medicines water solutions in bulk. The studied medicines are part of the following categories: cytostatics (methotrexate and 5–fluorouracil), phenothiazines that are utilized normally as antipsychotic drugs (chlorpromazine-CPZ, promazine-PZ, thioridazine-TZ, promethazine-PMZ), quinazoline derivatives developed in Marseille for MDR experiments (BG 204, BG 1120, BG 1188), hydantoin derivatives developed in Krakow for MDR applications (SZ-2 is a typical compound). Here, emphasis is placed on the identification of new photoproducts generated from medicines molecules by exposure to optical radiation. The methods/techniques used with this purpose are standard UV-Vis optical absorption, laser induced fluorescence (LIF), phosphorescence based singlet oxygen detection, Raman scattering, Fourier transform infrared spectroscopy (FTIR) and thin layer chromatography (TLC).
In Chapter 12 results on studies regarding the processes that take place when a laser beam interacts with foams or emulsions in order to monitor their properties or to modify their content are shown. The substances considered here are vancomycin, oily vitamin A, polidocanol (aethoxyscklerol) and rhodamine 6G, separated or in combinations. Some of them are considered in interaction with surfactants such as xanthan gum and tween 80. Additionally, colourless and odourless glycerin is also used in experiments.
The next two chapters treat the applications of laser modified medicines in order to combat MDR acquired by microorganisms (Chapter 13) such as Gram-positive, Gram-negative bacteria and fungi as well as tumours (Chapter 14). As for the tumours, some of studied medicines interacted with optical incoherent radiation emitted by Hg or Xe lamps in cw regime and other were exposed to pulsed laser radiation emitted in UV by an nitrogen pulsed laser or in UV-Vis by a Nd:YAG laser coupled to nonlinear crystals. The tumours were, actually, psuedotumours produced on eye conjunctiva and treated with cytostatics (MTX, 5–FU) quinazoline derivatives (BG 204, BG 1120) and phentothiazine derivatives (CPZ).
A section dedicated to materials that may be used to deliver medicines to superficial tissues, such as skin or to clean infected hydrophobic surfaces, is Chapter 15 which deals with the interaction of medicines exposed to laser beams with fabrics/materials in view of biomedical applications.
Further, Chapter 16 is dedicated to droplets optofluidic properties in extreme conditions such as hypergravity (up to 20 g), having in mind applications in outer space or during trips towards outer space.
Another subject of quite largely foreseen perspective in optics of droplets and its applications is described in Chapter 17 which presents data about lasing properties of optically/laser pumped pendant droplets containing fluorophores such as laser dyes in view of scientific, technological and biomedical applications.
Finally, in Chapter 18 is shortly and synthetically discussed a new branch of spectroscopy which may be defined based on data such as those reported in some of the chapters of the book: droplet based spectroscopy as an alternative to bulky materials spectroscopy, when the drop and bulk materials are the same.
CONFLICT OF INTEREST
The authors confirm that this chapter content has no conflict of interest.
ACKNOWLEDGEMENTS
This work has been financed by the National Authority for Research and Innovation in the frame of Nucleus programme-contract 4N/2016 and the project PN-II-ID-PCE-2011-3-0922.
REFERENCES
[1]Timeline of antibiotic resistance produced by SwitchYard for The Food and Environment Reporting Network and Medium.. SwitchYard Media. Available at: http://switchyardmedia.tumblr.com/post/ 80782524007/timeline-of-antibiotic-resistance-produced-by[2]Magiorakos A.P., Srinivasan A., Carey R.B., Carmeli Y., Falagas M.E., Giske C.G., Harbarth S., Hindler J.F., Kahlmeter G., Olsson-Liljequist B., Paterson D.L., Rice L.B., Stelling J., Struelens M.J., Vatopoulos A., Weber J.T., Monnet D.L.. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance., Clin. Microbiol. Infect.2012; 18(3): 268-281. [CrossRef] [PubMed][3]de Gennes P-G., Brochard-Wyart F., Quere D.. , . Capillarity and wetting phenomena: drops, bubbles, pearls, waves. Springer Science & Business Media; 2003.[4]Pile D., Ligler F.. An interdisciplinary approach., Nat. Photonics.2011; 5(10): 569-569. [CrossRef][5]Fan X., White I.M.. Optofluidic microsystems for chemical and biological analysis., Nat. Photonics.2011; 5(10): 591-597. [CrossRef] [PubMed][6]Nastasa V., Samaras K., Andrei I.R., Pascu M.L., Karapantsios T.. Study of the formation of micro and nano-droplets containing immiscible solutions., Colloids Surf. Physicochem. Eng. Asp..2011; 382(1-3): 246-250. [CrossRef]Pendant Droplets – Microfluidic Approach
Viorel Nastasa1,2,Angela Staicu1,Mihail Lucian Pascu1,3,*Abstract
This chapter contains basic data about the microfluidic description of pendant droplets. Results are shown regarding the surface/interfacial tension measurements performed on water based solutions following the interaction with laser radiation. A synthesis is introduced of the main methods used to produce simple or complex droplets in different media. A method to evidence surface active products obtained after exposure of medicine solutions to laser radiation is presented. It consists in measuring in real time the dynamic interfacial tension at the interface between air and irradiated solution, when solution is in bulk form. The variation of dynamic interfacial tension is an indicator of the presence of laser produced amphiphilic molecules in solution. These results belong to series of reports dedicated to new methods used to fight multiple drug resistance developed by bacteria by decreasing the concentration of active compounds with bactericide effects. In line with microfluidic approach of droplets with µl volumes, surface tension measurements on DMSO-water mixtures containing a dye are presented.
NOTES
†Reprinted from A. Dinache, M. Boni, T. Alexandru, E. Radu, A. Stoicu, I. R.Andrei, A. Staicu, L. Liggieri, V. Nastasa, M. L. Pascu, M. Ferrari “Surface properties of Vancomycin after interaction with laser beams”, Colloid Surface A., vol 480, pp. 328-335, 2015.
‡Reprinted from A. Dinache, M. Boni, T. Alexandru, E. Radu, A. Stoicu, I. R.Andrei, A. Staicu, L. Liggieri, V. Nastasa, M. L. Pascu, M. Ferrari “Surface properties of Vancomycin after interaction with laser beams”, Colloid Surface A., vol 480, pp. 328-335, 2015.
CONFLICT OF INTEREST
The authors confirm that this chapter content has no conflict of interest.
ACKNOWLEDGEMENTS
This work has been financed by the Romanian National Authority for Research and Innovation in the frame of Nucleus programme-4N/2016 and projects PN-II- ID-PCE-2011-3-0922, 641/2013, PN III-P2-2.1-PED-2016-0420 and COST network MP1106.
