Current options for drug deliveryto the spinal cordFilippo Rossi, Giuseppe Perale, Simonetta Papa, Gianluigi Forloni &Pietro Veglianese††Dipartimento di Neuroscienze, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy
Introduction: Spinal cord disorders (SCDs) are among the most devastating
neurological diseases, due to their acute and long-term health consequences,
the reduced quality of life and the high economic impact on society. Here,
drug administration is severely limited by the blood--spinal cord barrier
(BSCB) that impedes to reach the cord from the bloodstream. So, developing
a suitable delivery route is mandatory to increase medical chances.
Areas covered: This review provides an overview of drug delivery systems used
to overcome the inaccessibility of the cord. On one side, intrathecal adminis-
tration, either with catheters or with biomaterials, represents the main route
to administer drugs to the spinal cord; on the other side, more recent
strategies involve chemical or electromagnetic disruption of the barrier and
synthesis of novel functionalized compounds as nanoparticles and liposomes
able to cross BSCB.
Expert opinion: Both the multifactorial pathological progression and the
restricted access of therapeutic drugs to the spine are probably the main
reasons behind the absence of efficient therapeutic approaches for SCDs.
Hence, very recent highlights suggest the use of original strategies to
overcome the BSCB, and newmultidrug delivery systems capable of local con-
trolled release of therapeutic agents have been developed. These issues can
be addressed by using nanoparticles technology and smart hydrogel drug
delivery systems, providing an increased therapeutic compound delivery in
the spinal cord environment and multiple administrations able to synergize
treatment efficacy.
Keywords: biomaterials, blood--spinal cord barrier, central nervous system, hydrogels,
nanoparticles, spinal cord
Expert Opin. Drug Deliv. (2013) 10(3):385-396
1. General consideration on spinal cord disorders
Spinal cord disorders (SCDs) remain one of the most devastating conditions inneurological diseases that, in the severe form, can lead to the loss of productivelife years and a high economic impact on the society. SCDs can be categorizedinto traumatic pathology of the spine such as spinal cord injury (SCI), degenera-tive pathology such as amyotrophic lateral sclerosis (ALS) and spinal muscularatrophy and myelopathy associated with tumors, inflammatory and infectivedisease [1-3]. All of them show peculiar symptoms that might include pain, lossof sensation, numbness, muscle weakness and motor inactivity [1-3]. Althoughthe concepts of injury and degeneration of many SCDs are well supported, clinicaltrials of potential agents have been disappointing [4-7]. In fact, SCDs treatmentrepresents a challenging biomedical puzzle for two important reasons: i) manySCDs are characterized by a multifactorial pathophysiology (i.e., genetic altera-tions, inflammation, altered immunoresponse, excitotoxicity and oxidative stress)making successful single drug development difficult [1-3] and ii) the restricted
access to the spinal cord (SC) environment limits the efficacyof potential drugs (blood--spinal cord barrier, BSCB) [8,9].
2. BSCB restrictions
SC is isolated from the rest of the body by a filter or barriercalled BSCB that plays a protective and regulatory role on themolecular exchange between SC parenchyma and bloodstream.This makes a biochemical and immunological environment inthe SC capable of reducing the vulnerability to pathologicalinsults and limiting potential damage [9]. On the other hand,from a therapeutic point of view, this impermeable barrierlimits or blocks the entrance of potential drug that need togain access to the SC [10]. BSCB is assembled around SCcapillaries as a multilayer cell structure composed of innernon-fenestrated endothelial cells, which forms an impermeablewall by tight junction proteins (claudin, zonula occludens pro-tein and cingulin), followed by basal lamina and pericytes up toastrocytes with prolonged end-feet processes [9]. Pericytes andbasal lamina are important for the maturation, remodelingand maintenance of endothelial cells and wall assembly [9].Whereas, astrocyte foot processes play a key role in modulatingthe BSCB phenotype via secretory mechanism [9]. Additionalefflux transport proteins and degrading enzymes are involvedin the cross-restriction of molecules between the bloodstreamand the nervous system environment, such as multidrugresistance protein, P-glycoprotein and breast cancer resistance
protein which are located in the luminal side able to drainback unacceptable molecules [11]. Moreover, degradingenzymes may eliminate molecules transported inside the cyto-sol of the endothelial cells [11], further limiting the crossinginto the environment of the SC. New evidences suggest thatBSCB shows morphological and functional differences in com-parison to blood--brain barrier, such as glycogen deposits,increased permeability to some cytokines and reduced adher-ence and tight junction proteins [8]. A deep understanding ofthe permissive rules capable of regulating the moleculesexchange between bloodstream and SC environment remainsa fundamental key point to reconsider the conventional andnonconventional routes of drug delivery (systemic and intra-thecal (IT) administration) and an increased effort is requiredto interpret these mechanisms.
3. Conventional delivery strategy
Common practice methods to administer pharmacologicalcompound in central nervous system (CNS) are based onoral, intravenous (IV) and intraarterial (IA) delivery(see Figure 1). Oral and IV pharmacological interventionsare particularly indicated to treat neuropathic central painand management of spasticity related to SCDs, whereas IAdelivery is indicated to treat tumors. Different medications,administered orally or intravenously, are used in clinical prac-tice to treat neuropathic pain, such as anticonvulsivant agentgabapentin and pregabalin, which are considered as the first-line treatment for SCI neuropathic pain [12]. Both mimicthe neurotransmitter gamma-aminobutyric acid (GABA)increasing the activity of inhibitory neurons which in turnnegatively regulate the transmission of the nociceptive signals.Alternative pain treatment is provided by antidepressants(amitriptyline [13]) and analgesics (morphine [14] or cloni-dine [15]) which act, respectively, on adrenergic and serotonin-ergic receptors increasing the serotonin neurotransmitters [16],or on opioid receptors [17], both potentiating the inhibition ofpain signals. Other pharmacological treatments, orally or IVadministered, regard the clinical manage of the spasticity asso-ciated with the SCDs [18]. These treatments are directed tomodulate dysfunctions in the excitatory (glutamate) or inhib-itory (GABA and glycine) neurotransmission [19] underlyinghypertonic muscle spasm. An approved drug to treat the spas-ticity associated with multiple sclerosis and SCIs is the orallyadministered baclofen [20], an analog of GABA that bindsGABA B receptors in the SC, which is able to decrease therate of muscle spasms and stretch reflex. However, a promis-ing alternative route of administration to treat spasticity isrepresented by IT administration by slow chronic infusionof baclofen that results in a marked increase in efficacy andreduced side effects compared to oral treatment [21]. Otherdrugs used to treat spasticity are imidazoline molecules,such as tizanidine and clonidine, which have an agonisticactivity on noradrenergic alpha 2 receptors, resulting in directimpairment of excitatory amino acid release from spinal
Article highlights.
. SCDs remain one of the most devastating conditions inneurological diseases that, in the severe form, can leadto the loss of productive life years and high economicimpact on the society.
. SC is isolated from the rest of the body by a filter orbarrier called BSCB that plays a protective and regulatoryrole but, from a pharmacological point of view, thisimpermeable barrier limits or blocks the entrance ofpotential drug that needs to gain access to the SC.
. IT direct injection or infusion in the CSF with minipumpsis a common strategy to cross the barrier, but it shows apoor distribution of therapeutic compounds into the SCparenchyma and several iatrogenic side effects.
. Hydrogels could be used as IT drug delivery systems inSCDs: they are able to provide sustained delivery ofhydrophilic drugs and remain localized in situuntil degradation.
. Drug loading within polymeric NPs represents anattractive alternative as they could be functionalized tocross the BSCB, to exhibit high cell selectivity andsustain the release of hydrophobic drugs.
. A combined multitarget approach by using differentsmart biomaterials (NPs loaded in hydrogels) could bethe new frontiers of a tailored delivery solution tocontrol and progressively release drugs in situ increasingmedical chances.
This box summarizes key points contained in the article.
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interneurons, which in turn reduce the spasticity. In addition,other drugs derived from clinical experience are currently usedto manage spastic events such as benzodiazepines (diazepamand clonazepam), which facilitate the postsynaptic action ofGABA inhibiting anomalous excitatory signal that lead tospasticity. An alternative to the oral and IV administration isthe IA delivery. This particularly was indicated to treat SCtumors with the advantage of injecting locally high concentra-tion of chemotherapic drug in the tumor [22]. Larger doses ofdrugs that diffuse into the CNS can be administered with theabovementioned conventional oral and IV administration.Furthermore, IV and IA are used to deliver drugs directlyinto the bloodstream, avoiding its first-pass metabolism.However, many limitations drastically reduce the applicabilityof the abovementioned administrations: i) limited access tothe SC environment (BSCB), ii) the half life of the drug inthe plasma and iii) potential drug side effects. Based on this,nonconventional strategies have been developed and are stillbeing developed. Recent research has, indeed, increasinglyfocused on the development of new delivery tools aiming attreating SCDs, thus, providing new opportunities to over-come the SC barrier and increasing the potential therapeuticefficacy of them. Based on a more immediate application onsevere and localized form of SCDs, these new deliverystrategies will be widely commented for spinal disorderssuch as SCI.
Drug delivery directed to the CNS is particularly difficult dueto BSCB that is effective in the transport of nutrients buttightly prevents the passage of most drug therapeuticsdelivered systemically, as abovementioned [9]. In fact, it hasbeen demonstrated that 100% of large molecules (> 500 Da)and 98% of small molecules (< 500 Da) are rejected [23]. This
emphasizes the need for other methods to overcome theBSCB, and new approaches have been developed (see Figure 2).
4.1 BSCB disruption by chemical substances,
ultrasound or electromagnetic radiationChemical compounds, such as mannitol hypertonic solution,are used to temporally increase the permeability of endothelialcells producing a higher blood osmotic pressure which in turnpromotes drug entrance [24,25]. As alternative, compoundscapable of interacting with bradykinin receptors (bradykinin,alkylglycerols and labradimil) [26,27] are clinically used. Thesemodulating intracytoplasmatic calcium level up to leach outthe intercellular tight junctions of the endothelial cells thatare capable of permeabilizing BSCB. Mannitol has beenfound effective and quite safe for treating CNS tumors [25].Whereas, more complications can arise by using bradykininreceptors targeting drugs, due to the widespread distributionof these receptors in the body. In order to target specificarea of the CNS with potential drugs, alternative methodshave been developed, such as ultrasound and electromag-netic radiation that are capable of inducing transientcavitation between the endothelial cells by thermal lesion ormicro-bubble generation [28].
4.2 Pharmacological approach based on the synthesis
of various different compounds for promoting the
BSCB crossingLow molecular weight drugs [29], cationic form of drugs thatmay easily enter the CNS [30], high lipophilic prodrugs [31,32]
or drugs chimerized with peptides [33] that mimic crossingendogenous molecules are all potential drugs that can crossthe BSCB. In addition, therapeutic drugs can be furtherchemically modified and/or combined with transport vectorsincluding peptides (insulin, transferrin or lectins) [33],cyclodextrins [34] or monoclonal antibodies directed totransferrin [35,36] or insulin receptors [37] to exploit the
Conventional delivery strategy
Advantages: -Non invasive treatment -Possible diffuse treatment of the SC-Avoid first-pass metabolism
Disadvantages: -Limited access to the SC environment -Limited half-life of the drug in the plasma -Potential side effects
Advantages: -Non invasive treatment -Safe and less expensive -Possible diffuse treatment of the SC
Disadvantages: -Limited access to the SC environment -The intestinal wall and liver chemically metabolize many drugs, decreasing the amount of drug reaching the bloodstream -Potential side effects
BL
OOD STREAM
Oral deliveryIntravenous-intraarterial delivery
Figure 1. Schematic overview of conventional delivery strategies to treat SCDs: IV, IA and oral routes.
Current options for drug delivery to the SC
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BSCB crossing permissions. Whereas, other compoundshave been recently developed and directed to low densitylipoprotein receptor, the latter involved in the internali-zation of many endogenous ligands in the CNS [38], whichrepresent a promising entry door for drugs into the SCenvironment [10].
4.3 Functionalized nanoparticles that are able to
penetrate the BSCBRecently, one of the most significant achievements was thedemonstration that functionalized nanoparticles (NPs) canpenetrate through the BSCB and can be used for drug deliveryto the CNS [39]. To achieve this, various materials andsynthetic approaches are being investigated. Several cell-penetrating peptides, such as transactivating-transductionpeptide, were found to be capable of penetrating the barrier,and their attachments to the surface of liposomes and NPswere used to facilitate internalization of these nanostructures
into the CNS [40,41]. Moreover, poly(butyl cyanoacrylate)NPs can penetrate the barrier via apolipoprotein-mediatedtransport, showing neuroprotective efficacy once functional-ized with enzymes (superoxide dismutase) and antibodies(N-methyl D-aspartate receptor 1) [42]. Hence, recentadvances in polymer science have provided a huge amountof innovations, underlining the increasing importance of thesesystems in biomedical applications [42-46]. Indeed, due to theirversatility in terms of size, potential surface and hydrophilic orlipophilic characteristics, polymeric NPs lead relevant advan-tages in drug delivery by increasing the selectivity of drugsand by controlling their release during the time [47,48]. Fur-thermore, NPs are considered a primary vehicle for targetedtherapies because of their ability to pass biological barriers,enter and distribute within cells by energy-dependentpathways [40,49]. So far, many studies have shown that NPsproperties, such as size and surface, can influence how cellsinternalize and uptake them [49]. Once uptaken, NPs may
-Mannitol hypertonic solution-Compounds that interact with bradykinin receptors (bradykinin, alkylglycerols and labradimil)
Advantages: -Minimally invasive
Disadvantages:-Mannitol can cause acute tubular necrosis, hyper- natremia, hypokalemia, and hypotension due to increased loss of electrolyte poor water via osmotic diuresis-Bradykinin can cause side effects for the widespread distribution of its own receptors in the body .
Ultrasound and electromagnetic radiation
Synthesis of new drugs for promoting BSCB crossing-Low molecular weight drugs, cationic form of drugs, high lypophilic pro-drugs-Drugs chimerized with peptides (insulin, transferrin, lectins)-Drugs directed to low density lipoprotein receptor
Advantages: -Selective modulation of BSCB at a prefered site and not for the global CNS-BSCB permeability rapidly reversed
Disadvantages:-The mechanism by which the barrier is modulated is not completely understood -Non reproducible BSCB permebility is obtained with similar treatment
Advantages: -Diffuse treatment of the CNS -Reduced drug concentration used
Disadvantages:-High cost of developing new drugs -Limited half-life of the drug in the plasma-Possible reduced efficacy of the drugs linked to the carrier
Functionalized nanoparticles
Advantages: -Diffuse treatment of the SC -Increased access to the SC environment -Cell specific targeting
Disadvantages: -Low hydrophilic drug loading capacity -Accumulation in perypheral organs and macrophagic cells
Astrocyte
Endothelium
Basal lamina
Tight junction
Perycite
Blood
BSCB
IIIIIIIIIIIIIII
IIIIIIIIIIIIIII
IIIIIIIIIIIIIII
IIIIIIIIIIIIIII
IIIIIIIIIIIIIIIIIIIIIII
IIIIIII
Figure 2. BSCB is assembled around SC capillaries as a multilayer cell structure composed of inner non-fenestrated
endothelial cells, which forms an impermeable wall by tight junction proteins, followed by basal lamina and pericytes up to
astrocytes with prolonged end-feet processes. Different delivery strategies have been developed to overcome BSCB as the
use of: chemical substances, specific new drugs, functionalized NPs, ultrasound and magnetic radiation.
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act as a drug depot within cells and could be useful in achiev-ing therapeutic dosing via targeted therapies, establishingsustained-release drug profiles and protecting therapeuticcompounds from efflux or degradation [50]. Receptor-mediated endocytosis could be the potential filter for evengreater selectivity in cellular targeting. The cellular membraneis dotted with a myriad of receptors, which extracellularlyinteract with their respective ligands (or with NPs whose sur-face is functionalized with ligands) transducing a signal to theintracellular space. This signal can trigger a multitude ofbiochemical pathways and, furthermore, it may also causeinternalization of the ligand and its appended NPs via endo-cytosis. In this direction glial cell line-derived neurotrophicfactor loaded in NPs can be uptaken by neural cells (gliaand neurons) and retained in the cells for prolonged timeperiods inducing an increase of neuronal survival and improv-ing locomotion function in SCI animal model [51]. However,NPs, for their own specific features, have a short half timewhen injected in the organism, between 1 and 3 h, sometimeslimiting their therapeutic efficacy only to macrophages [52].One attractive alternative, to reduce the uptake kinetics, isto functionalize NPs with synthetic polymers creating cova-lent bonds: polyethylene glycol (PEG) is the most widelyused polymer for this purpose. The attachment of PEG chainsto NPs can sterically hinder its access to macrophages surfacereceptors and subsequently delay their uptake: PEGylatedNPs have an increased half life in the bloodstream. Further,in vivo paradigms showed that PEGylated NPs also signifi-cantly reduced the formation of reactive oxygen species andthe process of lipid peroxidation of the cell membrane [43,53].Moreover, the use of NPs can also optimize the delivery ofmethylprednisolone (MP), the only FDA approved drug forSCI treatment, providing a diffusive barrier and enhancingits neuroprotective properties [54]. The use of NPs as carriersfor neuroprotective agents was also considered for prostaglan-din E1 [55]: its sustained delivery significantly prevented celldeath, induced angiogenesis and improved blood flow,thereby preserving the remaining cells and recruiting the func-tion in spinal diseases. In addition, hepatocyte growth factorreleased through NPs contributes to neuroprotection, anti-apoptosis and angiogenesis around lesion site [55]. In thesame way, the delivery of cerebrolysin (i.e., a mixture ofdifferent neurotrophic factors as brain-derived neurotrophicfactor, glial cell line-derived neurotrophic factor, nerve growthfactor, ciliary neurotrophic factor and other peptide frag-ments) shows promising results too if carried by NPs [56].Thus, the direct injection of colloidal NPs suspension intoinjury site is one attractive alternative, but several concernsarise: injected NPs very often leave the zone of injection asthey are not confined by any support, and easily extravasateinto the circulatory torrent, migrating all over the body toliver and spleen [54]. According to these critical issues, severalstudies have suggested that to associate hydrogels with NPs,provided a targeted therapy that is able to maximize theefficacy of neuroprotective agents and minimize their side
effects [57-59]. Indeed, NPs delivery through hydrogel matricesis also used for the delivery in situ of neuroregenerative agents:anti-Nogo A antibodies [60] and neurotrophin-3 [61]. In addi-tion, proteins [62] and growth factors [63] physically entrappedin NPs and loaded in hydrogels showed suitable release pro-files. However, this promising and already available nanotech-nology still implies new efforts to assess the biocompatibilityand manage potential risk associated with the exposure ofNPs for humans and environment [64].
5. Brain delivery administration
Alternative strategy for bypassing the BSCB is the intra-ventricular injection of drugs directly into the CSF(see Figure 3). Drugs can be administered using an Ommayareservoir device implanted subcutaneously in the scalp andconnected to the ventricle via an outlet catheter. The intra-ventricular injection shows several advantages: i) a directinjection into the CSF bypassing the BSCB, ii) a reduceddosage of drugs used limiting potential the side effects andiii) a longer drug life in the CSF minimizing protein bindingand enzymatic activity associated with drugs in plasma.However, various disadvantages of this route of administra-tion have been showed such as a slow rate of drug distribu-tion within the CSF and potential side effects associatedwith the increased intracranial pressure for the fluidinjection. For these reasons, this intraventricular deliveryroute is proposed to reach high concentration of drugs inimmediately adjacent parenchyma [65].
6. Intrathecal administration
6.1 Catheters and implanted minipumpsIT drug delivery has been clinically used as an alternativeroute of drug administration to the systemic and oral ways,expanding the medical options available to physicians totreat the SC (see Figure 3) [66,67]. IT delivery is proposed asa direct way to release compounds with a single or continu-ous infusion directly into the cerebrospinal fluid (CSF) atthe level of the SC. A direct injection of drug is clinicallypossible into the spinal space corresponding to the intersticebetween the pia mater and the arachnoid membrane, with-out great iatrogenic exacerbation of the patient’s medicalcondition [68,69]. Unfortunately, a direct injection or infu-sion in the CSF shows a poor distribution of therapeuticcompounds into the SC parenchyma, reaching only theouter part of it. CSF is produced in the choroid plexus inthe brain and moves in a pulsatile manner to the SC; CSFthen returns to the vascular system by venous sinuses viathe arachnoid granulations [70]. CSF is produced at a rateof 0.2 -- 0.7 ml/min and it is renewed within 5 h [70]. Forthese reasons the injected therapeutic compounds returnquickly in the bloodstream and the BSCB again representsa strong limitation to a diffuse pharmacological treatmentof the SC. For the abovementioned limits, IT is particularly
Current options for drug delivery to the SC
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indicated for acute and chronic pain (cancer pain, reflexsympathetic dystrophy, causalgia, chronic pancreatitis andsciatica) and spasticity management (SCI and multiplesclerosis) [21,68,69,71-75]. In fact, this route of administrationhas been proposed ever since the 1970s for a direct deliveryof morphine yields or baclofen directly on the outer struc-ture of the SC including somatosensory ascending path-ways [21,71,73]. Nociceptive neurons are located in thesuperficial dorsal horn corresponding to lamina I (thatrespond exclusively to noxious stimulation and project tothe brain) and II (substantia gelatinosa, composed of someexcitatory and inhibitory interneurons able to respond tonoxious stimuli). For these reasons, the dorsal outer regionof the SC represents an important therapeutic target forthe treatment of the pain. The sensitization of nociceptors,after injury or inflammation, results from the release ofseveral substances, such as acetylcholine, serotonin, bradyki-nin, histamine, leukotrienes and substance P by the damagedtissue. Drugs delivered through IT are able to modulate therelease of these chemicals, thus seems to be a promisingapproach to counteract the associated neuropathic pain. Infact, in these clinical treatments, IT delivery showsvarious additional therapeutic advantages compared toconventional routes: a more localized immediate pharmaco-logical activity, a greater control of drug delivery, rapidreversibility and reduced side effects [69]. Various IT delivery
systems, including external catheters and implanted mini-pumps, are in use [73]. Unfortunately, some side effectsregarding the placement of the catheters were described,such as obstruction, leakage, breakage and dislodgment. Inaddition, hemorrhage, CSF leaks and infections, such asgranulomas, were observed too [73].
6.2 HydrogelsSignificant recent advances in new original injectablebiomaterials (hydrogels) represent an interesting therapeuticnovelty to release biologically active compounds directlyinto the IT space, due to their ability to remain localizedin situ [76,77]. Hydrogels are three-dimensional networksof hydrophilic homopolymers, copolymers or macromerscross-linked to form insoluble polymeric matrices [78]. Thesepolymers, generally used above their glass transition temper-ature (Tg), are typically soft and elastic due to their thermo-dynamic affinity with water. They are often used in tissueengineering because they are hydrophilic, biocompatibleand their drug release rates can be controlled and triggeredby interactions with biomolecular stimuli [79]. In particular,hydrogels present several additive characteristics that makethem excellent drug delivery vehicles [77,80,81]; for example,mucoadhesive and bioadhesive characteristics that allowremaining in situ, enhancing drug residence time and tissuepermeability [82]. Furthermore, hydrogel dimensions play a
Non-conventional delivery strategy: Brain and intrathecal delivery
Intraventricular injection Advantages: -Direct injection into the CSF-Reduced dosage of drugs limiting potential side effects Disadvantages: -Slow rate of drug distribution within the CSF -Potential side effects associated to the increased intracranial pressure for the fluid injection
Catheter
HydrogelNPs
Mini pumpsAdvantages: -More localized immediate pharmacological activity -Greater control of drug delivery -Rapid reversibility-Reduced drug side effects
Disadvantages: -Obstruction, leakage, breakage and dislodgment of catheter-Possible hemoarrage and infections-Limited drug diffusion into the spinal cord
HydrogelAdvantages: -Localized and controlled pharmacological activity -High biocompatibility-Reduced side effects
Disadvantages: -Low hydrophobic drug loading capacity -Limited control of low steric hidrance drug delivery
Hydrogel+NPsAdvantages: -Independent delivery kinetic of different drugs-Hydrophobic and hydrophilic drug loading capacity-Localized multi-pharmacological activity Disadvantages: -Possible elevated NPs uptake from resident macrophagic cells (microglia)
Brain delivery Intrathecal delivery
Hydrogel
Ommaya reservoir
Figure 3. Schematic overview of nonconventional delivery strategies to treat SCDs: brain and IT delivery routes.
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key role, being relatively deformable and readily conform tothe shape of any space to which they are confined [78]. More-over, their possible compositional and mechanical similaritywith the native extracellular matrix give them the opportu-nity to serve as dual-purpose devices, acting as a supportingmaterial for cells during tissue regeneration as well as deliver-ing a drug payload [83]. In SCI repair the necessity to avoidrisks due to surgery is mandatory and it is a fundamental con-dition to provide low invasive placement and in situ forminggels. Drug-loaded hydrogels are injected intrathecally andremain localized at the site of injection, delivering the loadeddrugs to the SC [77,84-87]. In general, some issues should beconsidered in incorporating compounds in hydrogel systems:i) the loading capacity of the material; ii) the distributionrelates to the way the compounds is dispersed, which willinfluence the release kinetics; iii) the binding affinity, whichdefines how tightly the compounds binds the system andthat must be sufficiently low to allow release, but highenough to prevent uncontrolled release; iv) the release kine-tics, whose control allows the appropriate dose of growthfactor to reach the target over a given period of time; v) thelong-term stability, for which the system should be enabledto maintain the structure and activity of the compoundsover a prolonged period of time; vi) the economic viability,as far as such biomaterials must be easy to manufacture, tohandle and be cost-competitive. For example, they are usedto accelerate the release of sparingly soluble drugs as nimodi-pine, tuning the release profile in accordance to the therapeu-tic concentration needed [88]. Nowadays, in SCI repair, theonly approved treatment in the acute phase is the administra-tion of MP [58]. MP has been shown to reduce acute oxidativestress and inflammation resulting from a secondary damagecascade initiated by the primary physical injury to the SC.However, MP systemic administration showed modest effi-cacy in neuroprotection and severe dose-related side effects,such as wound infection and pulmonary embolus, and itsutility is presently questioned. Then, alternative MP deliveryhas been suggested, such as by hydrogel, showing a morelocalized release and long-term efficacy in animal models [89].In addition, several other drugs, working as neuroprotectiveagents, were loaded within gels showing high bioactiv-ity [90,91], reducing cavitation and preserving a greaternumber of neurons in the damaged cord. Furthermore,hydrogels are extremely versatile in terms of chemistry [92]
and hence polymer chains could be functionalized to havebetter in vivo performances [93-96]: Macaya et al. [95] function-alized collagen hydrogels with genipin, increasing cell viabil-ity, while Vulic et al. [96] covalently bonded hydrogel chainswith protein precursor to have a tunable release system.Hydrogels work as carrier and should be designed as tempo-rary structures having desired geometry and physical,chemical and mechanical properties adequate for implanta-tion into chosen target tissue. Nevertheless, care must betaken not only to ensure complete biocompatibility of bothintermediate and final degradation products but also to
provide a degradation kinetic compatible with host tissueintegration, to allow proper and viable tissue regenerativeprocesses [97]. Moreover, between IT strategies, nanowiredrelease systems are gaining increasing interests in the lastyears: drugs can be attached with nanowires and coated onpolymeric or metallic films, showing high ability to reachdesired areas of the brain or SC in high quantities [98,99].Experiments carried out show that novel therapeutic com-pounds, once linked to nanowires and applied over the trau-matized cord, result in enhancement of the neuroprotectionand improvement in functional outcome: a local applicationwhen administered with titanium dioxide (TiO2) nanowires(30 -- 50 nm) is able to show pronounced beneficial effectson barrier dysfunction and neurite outgrowth [100,101].
7. Conclusions
Drug administration in SCDs is severely limited by the pres-ence of BSCB and the physical inaccessibility of the cord.Since most therapeutic molecules do not cross the BSCB,oral and IV. deliveries cannot be used and alternatives, suchas local IT delivery by catheters and minipumps, have beenadopted. In this field, an original use of biomaterials, such ashydrogels, could help in providing sustained in situ drug deliv-ery, thus avoiding risks and side effects due to surgery relatedto catheters and implanted minipumps. Other strategies havebeen proposed to cross BSCB, including chemical disruptionof the barrier and synthesis of functionalized compounds phar-macologically active or carriers, such as NPs and liposomes,which can penetrate into the SC environment. These findingsindicate that material science, in conjunction with bio- andnano-technologies, can develop novel specifically designeddevices that are able to maintain drug levels within a desiredrange, satisfying the need for fewer administrations, optimaluse of the drug and increased patient compliance.
8. Expert opinion
Many preclinical studies have been proposed to find potentialtreatments for SCDs. Unfortunately, many of them showedno relevant efficacy when translated to clinical trials [4-7].A possible reason could be that most strategies proposed haveused treatments directed toward a single pathophysiologicalmechanism and only few attempts to find effective combina-tion therapies (neuroprotective and neuroregenerative) werecarried out to improve the outcome [102-104]. Other reasonscould be associated with the confined pharmacological treat-ment of a conventional drug administration, mainly due tothe low concentration achieved in CNS (for BSCB restrictions)and/or potential unacceptable side effects of prolongedtreatments. Consequently, new efforts are directed to developinnovative strategies and drug delivery tools to overcomeBSCB or to perform effective drug delivery directly in eitherCSF or SC parenchyma. The deep understanding of thefundamental mechanisms regulating BSCB crossing restriction
Current options for drug delivery to the SC
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toward SC represents the most relevant key question for nonin-vasive delivery strategies, such as, for example, conventionaladministration. This is particularly relevant for SCDs charac-terized by a spread degeneration that involves many cord seg-ments, such as motor neuron disease (ALS), myelopathiesassociated with the altered immunoresponse (multiple sclero-sis), inflammatory and infective diseases. As alternative, arecently performed approach to locally administer the drugsinto specific SC sectors involves continuous infusion by mini-pumps: this is particularly indicated for pain events or spasticityrelated to SCI or myelopathy associated with localized tumorgrowing (morphine analogs, baclofen and chemotherapeuticdrugs) [21,68,69,71-75]. Various advantages are associated withthese routes of administration such as immediate drug efficacyand limited side effects. Unfortunately, various drawbacksrestrict the applicability of this route of administration, suchas limited drug diffusion into the SC segment and CSF clear-ance of about 5 h: higher doses and repeated injections arehence required. Furthermore, problems due to surgery andcatheter placement are frequently reported [73]. More recently,newly engineered scaffolds have gained greater interest inSCDs. SCI, for its own neuropathological features (focalizedtraumatic event), represents a particularly good applicablecandidate for engineered scaffolds that is capable of carryingsubstances (drugs, antibodies, peptides or other proteins). Inthis framework, medicine and engineering work together inbetter defining the promising therapies using interdisciplinaryknowledge to design and construct novel scaffolds that areable to maintain drug levels within a desired range, satisfyingthe need for fewer administrations and optimizing drug con-centration and patient compliance. Furthermore, a promisingcombined therapeutic approach, with different drugs loadedsimultaneously inside the same scaffold to be placed in theSC, is supported from new smart hydrogels opportunelysynthesized to independently control loaded drugs releasekinetics [76,77]: recent research has, for example, focused itsattention on multifunctional therapies directed to counteractmultiple degenerative mechanisms of SCI, trying to releasenot only neuroprotective but also neuroregenerative agents.Here, promising neuroregenerative agents are chondroitinaseABC (chABC) and NT-3: respectively, a bacterial enzymethat is able to digest chondroitin sulfate glycosaminoglycansand a neurothrophine, both of which can promote axonalregeneration and sprouting supporting functional recovery invarious animal models [80]. However, chABC and NT-3 deli-veries are severely limited due to their deactivation and biodis-tribution [80,105,106]. In general, if injected as a solution, it isextremely difficult to retain them at the injury site because oftheir rapid diffusion into extracellular fluids [107]: for instance,a single injection of neurotrophic factors in vivo has a limitedhalf life of about 30 min, and multi-injection rather than asingle injection would hence be needed to provide aneuroprotective effect. These drawbacks can be overcome byusing hydrogels, providing local sustained release that cancontrol longer administration of selected drugs, thus relevantly
increasing treatment efficacy [80,105,106,108]. Moreover, neuro-trophic factors as brain-derived neurotrophic factor [109-112],ciliary-neurotrophic [113], epidermal [114] and fibroblast [76,96,114]growth factors are important promoting factors for neuralregeneration which can be smartly delivered using hydrogels.It has been demonstrated that neurotrophic factor treatmentsimprove neuronal survival, regeneration of nerve fibers, differ-entiation and synaptogenesis [110]. In recent years, there hasbeen growing interest in developing nanoscaled delivery tools,specifically addressed to biomedical application, such as, forexample, controlled topic drug delivery: the interdisciplinarynature of this strategy spans from nanofabrication to bioengi-neering, from neurobiology to pharmacology and it furtherprovides a great opportunity to improve current methodsto treat the SCDs through innovative drug therapeuticapproaches. Different routes of administration are considered:systemic administration using functionalized NPs are able toovercome the BSCB restriction [40-42], these particularly areindicative for a wide application such as in diffuse cellulardegeneration processes (ALS) in SCDs, and localized delivery,such as the degenerated part of specific segment of the SC(SCI or carcinomatous myelopathy). Furthermore, a combinedapproach by using different smart biomaterials (e.g., multipoly-meric approach using both hydrogels and NPs) could representtoday’s new frontiers of a tailored delivery solution to controland progressively release different drugs in either CSF or SCparenchyma. Indeed, the ability to remain localized in situ,together with the possibility of controlling the delivery ofhydrophilic high steric hindrance molecules, typical of hydro-gels, could be combined with the cell selectivity and with thepossibility of tuning the release of hydrophobic drugs, typicalrole of NPs. Several recent studies have investigated theseaspects trying to combine the advantages of both systems:MP [54], antibodies [60] and growth factors [63] were incorpo-rated in NPs and then loaded into hydrogels to provide asustained release into the final target tissue, aiming at increasingmedical recovery chances.
In conclusion, an ideal drug delivery platform must achievelocalized and sustained release and a favorable risk/benefit ratioin order to be adopted clinically for SCDs treatment. In partic-ular, all the following characteristics in developing deliverytools have to be considered: i) biocompatibility; ii) controlledbiodegradability; iii) easy injectability; iv) complete controlover material formulation and hence complete rationalizationin terms of physicochemical properties; v) ability to sustainmultiple drugs delivery, at the same time and with differentkinetic profiles; and vi) total absence of any chemicalinteractions between moieties of materials and drugs.
Declaration of interest
Author’s research is supported by Fondazione Cariplo, GrantNo. 2010/0639. The authors state no conflict of interestand they have not received any payment in preparation ofthis manuscript.
F. Rossi et al.
392 Expert Opin. Drug Deliv. (2013) 10(3)
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AffiliationFilippo Rossi1,2 PhD, Giuseppe Perale1,2 PhD,
Simonetta Papa1 MS, Gianluigi Forloni1 PhD &
Pietro Veglianese†1 PhD†Author for correspondence1Dipartimento di Neuroscienze,
