.jpg)
By
Dr. Carmen Alvarez-Lorenzo
Dr. Carmen Alvarez-Lorenzo, Dept. Farmacia y Tecnologia Farmaceutica, Facultad de Farmacia, Universidad de Santiago de Compostela, Spain. Corresponding author: carmen.alvarez.lorenzo@usc.es |
Over the last few years we have witnessed tremendous efforts in the design of advanced drug delivery systems (DDS) which are intended to make treatment with conventional drugs more cost-effective and to face up to the formulation challenges of the novel drug candidates, mostly from biotechnological sources. Ideally, a DDS should be able to release the drug at the appropriate site and at a rate that adjusts at every moment to the progression of the disease or to certain functions of the organism.
1 This purpose is barely fulfilled with the controlled release medicines that are mainly intended to provide a pre-established release profile for a prolonged period of time.
2
The “smart” or “intelligent” DDS that modulate drug release as function of specific biological/pathological signals or externally-applied stimuli are particularly profitable for:
- Labile drugs that require protection during the absorption and distribution towards the site of action
- Highly toxic drugs that should attain sufficient concentration at the target, but that should not affect healthy organs or cells
- Drugs that have to reach tissues, cells or cellular structures are hardly accessible from the blood stream
- Drugs that must be released at biorhythm-dependent rates.3
Intelligent DDSs require materials able to react to the stimulus triggering a response that should be predictable, reproducible, proportional to the intensity of the signal, and reversible. These materials have to be prepared
ad hoc for each specific application and, in many cases, their design is inspired in the structure and functions of biomacromolecules that participate in specific recognition, selective capture and controlled transfer of substances in the cells. The versatility of the synthesis procedures and the current level of the analytical techniques make the preparation of well-characterized polymers with a wide range of structures (multiblock, hyperbranched, cross-linked, hybrid) and functionalities possible. Stimuli-sensitive polymers should “sense” an external stimulus (e.g., light, heat, electrical or magnetic field, or compression) or an internal alteration of the biological microenvironment (pH or concentration of certain ions or molecules) and “act” undergoing a change in the solubility, the shape, the volume or the state of aggregation, which can be converted into a specific function.
4 If the stimuli-sensitive polymers respond to the signal in a reversibly way, specifically being activated when the stimulus is applied/appears and deactivated when it stops/disappears, they are referred as intelligent.
5 The stimuli-sensitive polymers can be arranged to form part of liposomes, polymeric micelles, polymersomes, films, hydrogels, carbon nanotubes or inorganic particles suitable for preparing medicines that can finely regulate the spatio-temporal release profile of drugs.
6 They can also be deposited on solid substrates, such as the surfaces of medical devices to create advanced drug/device combination products.
7
This feature reports on three research lines, lead by Carmen Alvarez-Lorenzo and Angel Concheiro, that are being currently carried out in the R&DPharma Group of the Department of Pharmacy and Pharmaceutical Technology at the University of Santiago de Compostela, Spain, with the financial support of Spanish and European agencies.
Stimuli-responsive polymeric micelles
Amphiphilic copolymers aggregate in water forming nanometric carriers with a hydrophobic core surrounded by a hydrophilic shell. The drug can be loaded either in the core or at the core/shell interface and, once administered to the body, the polymeric micelles spontaneously accumulate in tissues with enhanced permeability and retention as those inflamed, infarcted, or tumoral ones.
8 Furthermore, their size similar to the biological systems of transport makes polymeric micelles able to deliver the drug inside the cells. Both the core and the shell can be constituted by stimulus-responsive components. Intelligent polymeric micelles retain the drug while traveling in the blood stream, without premature leakage, until a change in the physiological conditions or the application of an external stimulus alters the hydrophilicity or conformation of the unimers.
9 The number of micelles that disintegrate or destabilize and, consequently, the drug release profile depends on the intensity of the stimulus. As soon as the stimulus stops, the micelles are re-formed and the release is interrupted (Figure 1a).
Fig. 1: Scheme of some stimuli-responsive structures useful for intelligent drug delivery.
Poloxamines are X-shaped copolymers of poly(ethylene oxide)-poly(propylene oxide) (PEO–PPO) blocks bonded to an ethylenediamine moiety. The PEO–PPO blocks confer temperature sensitiveness, while the ethylenediamine moiety provides pH-and ionic-strength-responsiveness.
10 These stimuli can alter the hydrophobic interactions that govern the self-assembly phenomena and, consequently, their performance as drug nanocarriers. Large micelles suitable for hosting drugs are formed at neutral-alkaline pH, while at acid pH they disassembly and the drug is released.
11 This behavior enables them to trigger the release when they reach damaged tissues (inflamed or tumoral) that have a microenvironment of lower pH than the healthy tissues. In fact, the poloxamine micelles have shown a good capability to withstand strong dilution processes, such as the one that occurs when a small volume of formulation is administered to the body via oral or parenteral routes. Nevertheless, even under a highly acidic conditions (low pH) such as that of the stomach, poloxamine micelles disassemble at a slow rate thanks to the temperature-driven hydrophobic interactions. This feature is being exploited for preparing more efficient oral formulations of the hypolipidemic drug simvastatin. The lactone form of simvastatin is a prodrug required for efficient intestinal absorption, but is poorly soluble in water and highly unstable in acidic environments. Incorporation to the poloxamine micellar solutions enhances (more than 100 times) the solubility and efficiently protects the lactone form even in a gastric-mimicking medium.
12
pH-responsive micelles have been also explored as carriers of labile antitumoral drugs, such as camptothecin.
13 The maintenance of the lactone form of camptothecin is crucial for the antitumor effect and the safety of the treatment. Grafting poly(acrylic acid) to PEO-PPO-PEO chains led to polymeric micelles that have an acidic pH in their interior, suitable for delaying the lactone hydrolysis. Tuning the ratio of EO/PO units it was possible to achieve high solubilization levels and to stabilize the drug in human serum.
14 These copolymers are suitable for preparing self-micellizable tablets that once in contact with the physiological fluids spontaneously disintegrate into the polymeric micelles.
15
Light can be applied as an external stimulus to switch drug release on and off at a specific site, offering a potential for release on demand in the targeted places of the human body that is otherwise difficult to achieve using other stimuli.
16 Polymeric micelles sensitive to light can be prepared from polymers bearing groups that assemble/disassemble as a function of wavelength. That is the case of the azobenzene groups, which modify their conformation from trans (hydrophobic) to cis (hydrophilic) when irradiated. The isomerization regulates the intra- and inter-molecular interactions between the polymer chains and thus the micellization/disassembly. In collaboration with Dr. Bromberg at MIT, we have evaluated a family of light-responsive copolymers able to self-associate under dark conditions forming micelles.
17 Under given light conditions, the copolymer chains modify their conformation, the micelles break and the drug is free in the medium. Furthermore, if a temperature-responsive copolymer with self-association properties is also present in the medium, it is possible to achieve a liquid system of low viscosity under dark conditions, that suddenly increases the viscosity when the light is applied at body temperature. Such a material could be useful in the development of a new drug delivery systems with a release rate able to be modulated with an external source of light (e.g. the sun light or, for internal areas, a laser beam).
18
Stimuli-responsive hydrogels
Hydrogels are three-dimensional polymer networks in which water can be imbibed at relatively high proportions. For a hydrogel to behave as a stimuli sensor and drug release actuator, its degree of cross-linking should be low enough to enable the polymeric network to undergo remarkable conformational changes due to the stimuli (namely swell/shrink), but high enough to maintain its functionality after several cycles. In general, the intelligent hydrogels release the drug when swollen, whereas the release becomes slower or even stops when they shrink. Our group has actively worked on the design of stimuli-sensitive hydrogels and interpenetrated networks endowed with the ability to recognize specific molecules.
6,19 To do that, the synthetic polymers require a properly designed sequence of monomers and cross-linkers that enables the memorization of a specific conformation, which revert back after being stretched and unfolded. We have adapted the molecular imprinting technology to the synthesis of hydrogels that possess active centers (receptors) capable of selectively taking up molecules. The conformation of the receptors can be deformed/re-constituted and, consequently, the affinity for the drug lost/recovered as a function of an external or a physiological signal. For example, dually pH- and temperature-responsive hydrogels can finely tune drug release through small conformational changes. Furthermore, the molecularly imprinted intelligent hydrogels have the extraordinary ability to re-capture the drug if this is not absorbed by the surrounding tissues. In this way, they can avoid side-effects caused by localised high drug concentrations. Bioinspired approaches are being applied for the screening of the monomers and their arrangement in the receptor pockets of the hydrogel. The idea is to imitate the active site of the natural target of the drug in the body in order to mime the non-covalent interactions responsible for the docking of the drug in the physiological receptor. This philosophy has been already successfully applied to design soft contact lenses that elute ophthalmic drugs in a sustained way.
20
Stimuli-responsive surfaces
Combination products that join together the performances of medical devices and drug release systems are attracting enormous attention in the therapeutic field. Medical devices play an important role in common diagnostic and therapeutic procedures and in the management of critically ill patients. For some applications, the insertion of the device should occur concomitantly to the systemic administration of drug/biologic products that act as coadyuvant of the treatment and prevent foreign-body reactions or other side-effects derived of the adherence of host proteins and cells or the proliferation of microorganisms.
21 Drug-eluting medical devices enable drug release at the required site and, consequently, the efficacy and the safety of the treatment are improved. In a joint collaboration with Dr. Bucio at UNAM, we have applied g-ray irradiation for the grafting of stimuli-responsive networks that regulate drug diffusion as a function of the surrounding conditions
22,23, resulting in medical devices with the capability of acting as DDS.
7 The functionalization may also improve hemocompatibility, change the protein pattern adsorption and inhibit biofilm formation.
24 In particular, surface modification with polymers bearing carboxylic acid groups (obtained by γ-ray grafting or plasma polymerization) has been shown suitable for loading antimicrobial drugs and to provide concentration levels above the minimum inhibitory concentration of common pathogens.
References
1
. K.Y. Lee, and S.H. Yuk, Prog. Polym. Sci. 32, 669 (2007).
2
. Y.W. Chien, and S. Lin, Clin. Pharmacokinet. 41, 1267 (2002).
3
. B.B.C. Youan, J. Control. Release 98, 337 (2004).
4
. D. Schmaljohann, Adv. Drug Deliv. Rev. 58, 1655 (2006).
5
. C. Alexander, and K.M. Shakesheff, Adv. Matter. 18, 3321 (2006).
6
. C. Alvarez-Lorenzo, and A. Concheiro, Mini-Rev. Med. Chem. 8, 1065 (2008).
7
. C. Alvarez-Lorenzo, E. Bucio, G. Burillo, and A. Concheiro, Expert Opin. Drug Deliv. 7, 173 (2010).
8
. V. Torchilin, Adv. Drug Deliv. Rev. 63, 131 (2011).
9
. N. Rapoport, Prog. Polym. Sci. 32, 962 (2007).
10
. C. Alvarez-Lorenzo, A. Rey-Rico, A. Sosnik, P. Taboada, and A. Concheiro, Frontiers in Bioscience E2, 424 (2010).
11
. C. Alvarez-Lorenzo, J. González-López, M. Fernández-Tarrio, M.I. Sández-Macho, and A. Concheiro, Eur. J. Pharm. Biopharm. 66, 244 (2007).
12
. J. González-López, C. Alvarez-Lorenzo, P. Taboada, A. Sosnik, I. Sández-Macho, and A. Concheiro, Langmuir 24, 10688 (2008).
13
. C. Alvarez-Lorenzo, A. Sosnik, and A. Concheiro, J. Drug Deliv. Sci. Tec. 20, 249 (2010).
14
. R. Barreiro-Iglesias, L. Bromberg, M. Temchenko, T.A. Hatton, C. Alvarez-Lorenzo, and A. Concheiro, J. Control. Release 97, 537 (2004).
15
. L. Bromberg, T.A. Hatton, R. Barreiro-Iglesias, C. Alvarez-Lorenzo, and A. Concheiro, Drug Dev. Ind. Pharm. 33, 607 (2007).
16
. J. Jiang, X. Tong, D. Morris, and Y. Zhao, Macromolecules 39, 4633 (2006).
17
. C. Alvarez-Lorenzo, S. Deshmukh, L. Bromberg, T.A. Hatton, I. Sandez-Macho, and A. Concheiro, Langmuir 23, 11475 (2007).
18
. C. Alvarez-Lorenzo, L. Bromberg, and A. Concheiro, Photochem. Photobiol. 85, 848 (2009).
19
. C. Alvarez-Lorenzo, and A. Concheiro, J. Control. Release 80, 247 (2002).
20
. A. Ribeiro, F. Veiga, D. Santos, J.J. Torres-Labandeira, A. Concheiro, C. Alvarez-Lorenzo, Biomacromolecules 12, 701 (2011).
21
. A. Dwyer, Semin. Dialysis 21, 542 (2008).
22
. J.C. Ruiz, C. Alvarez-Lorenzo, P. Taboada, G. Burillo, E. Bucio, K. De Prijck, H.J. Nelis, T. Coenye, and A. Concheiro, Eur. J. Pharm. Biopharm. 70, 467 (2008).
23
. A. Contreras-GarcÃa, C. Alvarez-Lorenzo, A. Concheiro, and E. Bucio, Radiat. Phys. Chem. 79, 615 (2010).
24
. A. Contreras-GarcÃa, E. Bucio, A. Concheiro, and C. Alvarez-Lorenzo, React. Funct. Polym. 10, 836 (2010).
Disclaimer: The views expressed here are those of the interviewee and do not necessarily represent the views of AZoM.com Limited T/A AZoNetwork the owner and operator of this website. This disclaimer forms part of the
Terms and conditions of use of this website.
.
.jpg)
