Urological Science 23 (2012) 70e77

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Urological Science
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Mini review

Intravesical therapy for lower urinary tract symptomsq CME

Credits

Jayabalan Nirmal a, Yao-Chi Chuang b, *, Pradeep Tyagi a, Michael B. Chancellor a

a
Department of Urology, William Beaumont Hospital, Royal Oak, Michigan, USA
b
Department of Urology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan

a r t i c l e i n f o a b s t r a c t

Article history: Intravesical (local) therapy for diseases emanating from the bladder is similar to the commonplace
Received 11 September 2011 management of ocular diseases using eyedrops. The existing intravesical therapy involves administering
Received in revised form dosage forms directly into the bladder (through a catheter). This mode of treatment is routine in the
27 October 2011
bladder cancer by instillation of bacillus CalmetteeGuérin to provoke the body’s own natural defenses
Accepted 6 December 2011
Available online 24 August 2012
against invasion by proliferating cancer cells in the bladder. Although convenient, the conventional
routes of administration for treating diseases such as interstitial cystitis/painful bladder syndrome (IC/
PBS) and overactive bladder (OAB) are less acceptable to patients owing to side effects, which may
Keywords:
cystitis
further exacerbate the disease symptoms. Intravesical therapy has demonstrated varying degrees of
intravesical therapy efficacy and safety in treating IC/PBS and OAB. In recent years, intravesical delivery of biotechnological
overactive bladder products including neurotoxins using a liposome platform demonstrated immense promise for lower
urinary tract symptoms. This review considers the current status of intravesical therapy in lower urinary
tract diseases with special attention to novel drug-delivery systems.
Copyright Ó 2012, Taiwan Urological Association. Published by Elsevier Taiwan LLC.
Open access under CC BY-NC-ND license.

1. Introduction intravesical drug delivery (IDD) with respect to specific diseases

and novel drug-delivery systems.
Intravesical therapy/drug delivery is widely used as a first-line
treatment for delaying or preventing the recurrence of bladder
2. LUTS
cancer.1,2 Given the success of this approach in oncology, it would
be wise to apply the lessons learned over the decades in treating
2.1. Interstitial cystitis/painful bladder syndrome
bladder cancer to improve the treatment of lower urinary tract
(LUT) and its symptoms (LUTS). The advertising slogan “applying
Interstitial cystitis/painful bladder syndrome (IC/PBS) is
the medicine directly where it hurts,” heard often in mass media for
a chronic disease characterized by suprapubic/bladder discomfort.
over-the-counter drugs, is apt for promoting wider acceptance of
It is accompanied by urinary frequency, urgency, or nocturia, in the
this line of therapy for LUTS. Instillation of drugs in the bladder
absence of infection or other pathological conditions. Little is
provides a high concentration of drugs locally at the disease site in
known about the pathogenesis of IC; however, it was proposed that
the bladder without an increase in systemic levels, which can
a dysfunctional epithelium allows the transepithelial migration of
explain the low risk of systemic side effects. However, drug delivery
solutes, such as potassium, which can depolarize subepithelial
to bladder tissues by the intravesical routes is constrained by the
afferent nerves and provoke sensory symptoms. In addition,
impermeability of urothelial cells, a short duration of action, and
localization of a high number of activated mast cells in the bladder
the need for frequent administration.3e5 The lining of the urinary
and dysfunction of the superficial layer of the extracellular matrix,
bladder has the most impermeable barrier in the human body. The
the glycosaminoglycan (GAG) layer, were demonstrated to be
following review of the literature describes the status of
related to IC.6,7 The result of these potential etiologies involves
neurogenic inflammation, primary afferent nerve overactivity, and
central nervous system sensitization, all of which interact to
perpetuate pain. Pain-sensing C fibers are located within the
* Corresponding author. Department of Urology, Kaohsiung Chang Gung
uroepithelium and submucosa of the bladder and can be activated
Memorial Hospital, Chang Gung University College of Medicine, 123 Ta-Pei Road,
Niao-Song, Kaohsiung 833, Taiwan.
by either a GAG layer deficiency or release of histamine via mast
E-mail address: chuang82@ms26.hinet.net (Y.-C. Chuang). cells. Because of the multifactorial nature of the disease, improved
q There are 2 CME questions based on this article. therapeutic outcomes can be achieved using multimodal treatment

1879-5226 Copyright Ó 2012, Taiwan Urological Association. Published by Elsevier Taiwan LLC. Open access under CC BY-NC-ND license.
http://dx.doi.org/10.1016/j.urols.2012.07.005
 J. Nirmal et al. / Urological Science 23 (2012) 70e77
through pharmacological and nonpharmacological approaches
acting via different mechanisms.8,9
2.2. Overactive bladder
Overactive bladder (OAB) is defined as a symptom complex
comprised of urinary urgency, with or without urgency inconti-
nence, usually with frequency and nocturia.10 There are four main
hypotheses to explain the pathophysiological basis for OAB. The
neurogenic hypothesis is based on observations that altered neural
control induces bladder overactivity by altering sensory activity,
reducing inhibition, or inappropriately triggering the voiding reflex
and increasing the efferent drive.11 The myogenic hypothesis states
that myocytes from the urinary bladder of patients have increased
spontaneous activity that allows excitation to propagate widely
through the bladder wall.12 The basis for the peripheral autonomy
theory is that cellular interactions in the LUT determine the blad-
der’s functional state; both spontaneous excitation and wider
propagation can result from activity in various cell types such as
muscle, interstitial, urothelial, and neuronal cells.13 The afferent
hypothesis focuses on the sensory basis of OAB, suggesting that
alterations in the central transfer or sensory transduction leads to
increased afferent “noise,” and therefore, an increased awareness of
bladder filling.14 In OAB, the release of acetylcholine from urothe-
lium during the storage phase of micturition can activate musca-
rinic receptors in the urothelium. Activated muscarinic receptors
trigger the release of urothelial ATP and nitric oxide, which results
in the activation of the afferent pathway. Thus, blockade of uro-
thelial muscarinic receptors could indirectly act to reduce afferent
nerve activation and therefore decrease OAB symptoms. Oral
antimuscarinics are the mainstay of pharmaceutical management
of OAB, competitively inhibiting either all muscarinic receptors
(oxybutynin) or selectively the M3 receptor (darifenacin and
solifenacin).15,16
3. Intravesical delivery for LUTS
3.1. Rationale for intravesical delivery
Although a large number of therapeutic agents are available for
treating bladder diseases, most of them are administered through
the per-oral route and hence fail to have a sufficient effect at the
disease site. Systemic administration of these therapeutic agents
requires administration of large doses, but only a small fraction
actually reaches the bladder, and the undesired biodistribution
Fig. 1. Schematic representation describing approaches for intravesical delivery. EMDA ¼ electromotive drug administration; GAG ¼ glycosaminoglycan.
71
increases side effects. IDD involves the direct administration of
bioactive agents into the urinary bladder through a catheter (Fig. 1).
The anatomy of the urinary bladder allows relatively uncompli-
cated access and manipulation with a catheter, and hence localized
treatment options have enormous potential. Delivery of a thera-
peutic agent directly into the bladder greatly improves the expo-
sure of the affected bladder lining to the agent, and this is of even
greater significance in the case of drug-resistant targets that
require a much higher dose of the drug.17,18
3.2. Constraints to intravesical delivery
IDD is associated with some intrinsic limitations. Periodic
voiding of urine washes out drug solutions instilled in the bladder.
This greatly reduces the residence time of the drug in the bladder
and hence requires frequent dosing. A further complication of IDD
is the progressive dilution of the instilled drug solution due to
filling up of urine in the bladder. To overcome this problem, strat-
egies such as emptying the bladder before drug instillation,19
suppressing the rate of urine production by the kidneys, and
regulating fluid intake before and after drug administration can be
utilized. In addition, the drug’s molecular weight, ionization,
concentration, and exposure time of treatment were proposed as
major factors for determining the rate of transurothelial drug
absorption. An ideal intravesical agent was postulated to have
a molecular weight of >200 amu, negligible ionization between pH
6 and 7, and a partition coefficient in the critical ranges of either
approximately 0.4e0.2 or 7.5e8.0. Recent phase III randomized
clinical trials for intravesical mitomycin demonstrated that elimi-
nating the residual volume, overnight fasting, doubling the mito-
mycin concentration to 40 mg in 20 mL, and urinary alkalinization
using oral bicarbonate resulted in a doubling of the durable tumor-
free rate at 5 years.20 As is the case with intravesical mitomycin, the
acidic urinary pH is also a limiting factor in intravesical epirubicin
(EPI) and doxorubicin (DOX) therapy.21 Another major determinant
in the therapeutic success of intravesical therapy is the degree of
drug lipophilicity, which allows penetration through cell
membranes. Paclitaxel, a highly lipophilic compound, achieves
greater intraurothelial concentrations than either mitomycin or
DOX.22
3.3. Bloodeurine barrier
To elicit a therapeutic effect following intravesical delivery into
the urinary bladder, the drug has to cross a watertight barrier
72 J. Nirmal et al. / Urological Science 23 (2012) 70e77
between the blood and urine. The bloodeurine barrier, called the
urothelium, is the tightest and most impermeable barrier in the
human body (Fig. 1).23 The urothelium, responsible for a multitude
of physiological activities, is not only effective in blocking the entry
of urine contents but is also equally effective in blocking the entry
of instilled drugs.3,4 It sits at the interface between the urine and
underlying connective tissue where it forms a barrier preventing
the unregulated exchange of solutes, ions, and toxic metabolites.
The permeability to substances such as water, ammonia, and urea,
which normally cross membranes relatively rapidly, is extremely
low in the urothelium.3,4 It has exceptionally high transepithelial
resistance ranging from 10,000 to >75,000 Ucm2 owing to para-
cellular resistance of tight junctions pooled with apical plasma
membrane transcellular resistance.24,25 Urothelial tight junctions
are comprised of a dense network of cytoplasmic proteins (zonula
occludens-1), cytoskeletal elements, and transmembrane proteins
(occludin and claudins) and have the highest recorded paracellular
resistance of all epithelia measured to date.26 In addition, the apical
plasma membrane of the urothelium contains specific proteins,
uroplakins, which account for the transcellular resistance. Electron
microscopic analysis of umbrella cells lying at the luminal surface of
the urothelium showed a hexagonal arrangement of uroplakins,
where six subunits of each particle are tightly joined together to
form a complete hexagonal ring, with lipids contained in the
central cavity.27 The low permeability of the urothelial barrier is
believed to result from the peculiar protein array and tight junc-
tions between umbrella cells. The urothelial barrier restricts the
movement of drugs after intravesical administration and also
restricts the action of the active drug fraction in the urine. Hence,
many drugs fail to reach the bladder at desired therapeutic levels
and ultimately lack pharmacological effects.27,28
4. Intravesical therapeutics for LUTS
4.1. GAG analogs
Intravesical delivery of GAG analogs such as hyaluronic acid
(HA), heparin, and chondroitin sulfate (CS), restores the barrier
function lost due to epithelial dysfunction in interstitial cystitis. HA
itself is an important component of the urothelium, and sodium
hyaluronate is used to replenish bladder GAG when treating IC. HA
inhibits leukocyte aggregation and migration, and adherence of
immune complexes to polymorphonuclear cells.29,30 From a clinical
study involving 48 patients, it was evident that intravesical heparin
(104 units/10 mL sterile water, three times a week for 3 months)
controlled symptoms of IC with continued improvement even after
1 year of therapy.31 When used in conjugation with hydro-
distention therapy, both HA and heparin prolonged the beneficial
effects of hydrodistention in patients with a small functional
bladder capacity. HA was found to be more effective compared with
heparin. In contrast to no improvement in the control group, there
was a significantly higher rate of improvement at 6 and 9 months in
the HA group relative to the heparin group (50% vs. 20%, p < 0.05).
Improvements in the number of times voiding per day (e1.8  2.5,
p < 0.01), a visual analog scale (e0.9  1.1, p < 0.01), and bladder
capacity (16  18 mL, p < 0.01) were more significant in the HA
group at 9 months relative to no improvement in the heparin
group.32 Hauser et al investigated CS binding to the bladder uro-
thelium in a mouse model of urothelial acid damage. CS was labeled
with Texas Red, and the efficacy of restoring the barrier function
was determined by intravesically instilling 86Rb, a potassium ion
mimetic, through the urothelium into the bloodstream. The results
demonstrated that CS preferentially binds to damaged urothelium
and restores the impermeability barrier. Maximum efficacy was
achieved with a dose of 400 mg CS per instillation.33
4.2. Dimethyl sulfoxide
A 50% aqueous solution of dimethyl sulfoxide (DMSO; RIMSO-
50) is widely used to treat IC because of its analgesic, anti-
inflammatory, and muscle-relaxant properties.34 Both early and
classic forms of IC respond to RIMSO-50, and it also has an influence
on conduction and neurotransmission in sensory nerves.35e38
RIMSO-50 is accepted as being moderately effective and safe for
relieving symptoms or urgency and pain in IC.39 Intravesical
instillation of DMSO in animal models demonstrated direct corre-
lations of the drug concentration and contact time with the bladder
with the anti-inflammatory effects without a change in the bladder
capacity or systemic toxicity. DMSO can penetrate tissues without
damaging them and is used to enhance the transport of chemo-
therapeutic drugs such as cisplatin, DOX, and pirarubicin into
bladder tumors.40
4.3. Drug cocktails
Because of the multifactorial nature of IC, combination therapy
utilizing drugs with different mechanisms of action is a reasonable
approach. Parsons et al demonstrated the effect of mixing different
ratios of heparin with lidocaine in drug cocktails for treating
patients with IC. The treatment response evaluated at different
time points showed a reduction in pain and urinary urgency in
most patients. Relief from symptoms 2 weeks after treatment
suggested that the efficacy was retained beyond the duration of the
local anesthetic activity of lidocaine.41
4.4. Vanilloids
Compounds related to capsaicin and an ultrapotent analog,
resiniferatoxin (RTX), collectively referred to as vanilloids, interact
at a specific membrane recognition site (the vanilloid receptor)
expressed almost exclusively by primary sensory neurons involved
in nociception and neurogenic inflammation. Interest in using
vanilloids for intravesical therapy in IC is based on the putative
mechanism of action, as well as on clinical and nonclinical obser-
vations. Suprapubic pain, the major symptom and cause of
morbidity in patients with IC, is believed to be primarily mediated
by afferent type-C sensory neurons in the bladder. C fibers may also
become mechanosensitive, producing increased urinary frequency
and urgency in IC. Vanilloids are used to downregulate sensory
nerves in the IC bladder, thereby mitigating the pain response. RTX
is an ultrapotent analog of capsaicin that may have improved
tolerability and enhanced efficacy compared with capsaicin. RTX
resulted in a more favorable ratio of desensitization to initial
excitation compared with capsaicin in animal models of pain
behavior.42,43 In a rat model, intravesical RTX (0.01 mM) reversibly
desensitized bladder afferents for 3 weeks, and a 0.1-mM dose
resulted in sustained desensitization for at least 4 weeks. In
patients with neurogenic bladder problem, intravesical RTX and
capsaicin were comparably effective; however, RTX is better toler-
ated. A randomized, placebo-controlled study utilizing 18 patients
with hypersensitive bladder disorders showed that a single intra-
vesical administration of RTX (0.01 mM) significantly improved
pain, urinary frequency, and nocturia at 1 month, and urinary
frequency at 3 months following treatment.44
4.5. Antimuscarinics
Recent reports showed that intravesically administered anti-
cholinergic agents, apart from blocking muscarinic receptors in the
bladder, may also act by blocking the bladder-cooling reflex
mediated by C fibers with an incomplete neurogenic lesion and
 J. Nirmal et al. / Urological Science 23 (2012) 70e77
neurogenic detrusor overactivity (NDO).45 Intravesical oxybutynin
(1.25 mg/5 mL, twice a day) was shown to be a relatively safe and
effective therapeutic option for children with neurogenic bladders
who experienced intolerable side effects or were unresponsive to
oral antimuscranics.46 Intravesical delivery of oxybutynin was
proven to be suitable for patients who have an OAB and suffer from
side effects of the metabolite, N-desethyl-oxybutynin, following
per-oral administration.47,48
4.6. Neurotoxin
The use of botulinum neurotoxin A (BoNT-A) to treat LUT
dysfunction has expanded in recent years, and the off-license usage
list includes PBS, NDO, idiopathic detrusor overactivity (IDO), and
LUTS resulting from bladder outflow obstruction. There are two
commonly used preparations of BoNT-A: BOTOX (onabotuli-
numtoxinA) and Dysport (abobotulinumtoxinA). BoNT-A, the most
popularly used BoNT, acts by cleaving the soluble N-ethyl-
maleimide-sensitive fusion attachment protein receptor (SNARE)
protein, SNAP-25, and inhibiting the release of various neuro-
transmitters at the presynaptic vesicle by binding to the synaptic
vesicle protein, SV2, during neurotransmitter exocytosis. BoNT-A
was successfully used to treat IC and OAB through a cystoscopi-
cally guided injection. However, instillation of this high molecular
weight toxin has to be localized because any systemic absorption
can prove fatal. Pretreatment of the urothelium with protamine
sulfate (PS) to improve its permeability to BoNT-A was attempted in
rats.49,50 The cationic PS interacts with the anionic GAG layer,
leading to a slight increase in permeability of the urothelium.51
Instillation of neurotoxins into the bladder is an accepted
approach to achieve chemical neuromodulation of afferent neuro-
transmission underlying IC and OAB. However, neuromodulation
by instilled neurotoxins is suboptimal, possibly due to protein
degradation by proteases and proteinases in the urine, dilution by
urine, or poor uptake of the BoNT solution into the urothelium.
4.7. Antisense oligodeoxynucleotide and gene therapeutics
Until recently, there has been little research carried out on gene
and antisense oligodeoxynucleotide (ODN) therapy for the urinary
tract. Most of the previous work focused on urinary tract malig-
nancies such as bladder and prostate cancers. However, this situ-
ation has changed radically in the past few years. Interest in gene
therapy for urinary tract dysfunction is due to the potential market
size that urological diseases represent as well as the fact that the
LUT is ideally suited for minimally invasive molecular medicine
therapy owing to a lower risk of systemic toxicity. Overexpression
of nerve growth factor (NGF) was linked to inflammation of the
bladder and to the pathogenesis of IC. Tyagi et al52 investigated the
potential of intravesical instillation of antisense ODNs for localized
reduction of NGF expression in the urinary bladder. Antisense ODNs
were replaced with antisense peptide nucleic acid (PNA) to improve
the stability, and tethering with a TAT peptide sequence was used to
facilitate penetration into the bladder. Cystometrograms (CMGs)
exhibited significantly reduced bladder contraction frequency in
the antisense PNA-treated rats compared to rats treated with the
control. NGF immunoreactivity was also reduced in the urothelium
of antisense PNA-treated bladders. These findings demonstrated
the feasibility of using TATePNA conjugates for intravesical anti-
sense therapy.
In our previous studies, we also showed that overexpression of
NGF in the bladder and bladder afferent pathways is directly
involved in the emergence of hyperexcitability of C fibers, leading
to the pathology of OAB.53 Based on research findings by our group,
the intrathecal application of NGF antibodies results in reduced
73
NGF levels in bladder afferent pathways, and is able to normalize
bladder/urethral function in spinal cordeinjured rats.54 Similar
clinical outcome was reported with systemic administration of
monoclonal human NGF antibodies (tanezumab) in IC patients.55
Although the systemic administration of antibodies was able to
reduce pain, it encumbered patients with safety concerns such as
paresthesia, hypoesthesia, and arthralgia. The results revealed that
NGF is a viable drug target, and the fact that the intravesical route
can avoid systemic side effects prompted alternative approaches for
targeting NGF. As it is likely that the major pathology of OAB is
driven by NGF, targeting the intracellular synthesis of NGF in the
bladder is a promising therapeutic alternative. The proof of the
concept of this approach was demonstrated by suppression of
bladder overactivity by the local instillation of an antisense agent
against NGF based on the PNA backbone.52,56
One mechanism by which bladder pain is induced was postu-
lated to involve chronic tissue inflammation that can lead to
functional changes in C-fiber afferents. It was previously reported
that endogenous enkephalins are expressed in bladder afferent and
efferent pathways to inhibit micturition.57,58 Yokoyama et al59
examined the efficacy of targeted and localized expression of
enkephalin in afferent nerves, which innervate the bladder, using
herpes simplex virus (HSV) vectorebased gene transfer in bladder
pain and hyperactivity. A replication-defective HSV-1 vector, SHPE,
engineered to carry the human preproenkephalin (hPPE) transgene
to the bladder and its sensory nerves was used. The results of this
study indicated that HSV vectors injected into the bladder wall
were transported through bladder afferent pathways and
expressed hPPE. After SHPE bladder inoculation, the bladder
hyperactivity induced by nociceptive stimuli (i.e., capsaicin) was
reduced via naloxone-dependent opioid mechanisms. In addition
to this, nociceptive freezing behavior induced by intravesical
capsaicin was also suppressed in association with increased bladder
capacity after SHPE treatment. These data illustrate that enkephalin
gene therapy for bladder pain response is feasible and achieves
a physiological decrease in bladder irritative responses, and gene
transfer using replication-defective HSV vectors may offer new
hope for treating refractory IC. Gene therapy strategies for OAB may
include suppression of bladder muscle activity or neural pathways
that trigger the micturition reflex. Kþ channel gene therapy for
urinary incontinence is under development (by Christ et al).60
Intravesical instillation of naked pcDNA/hSlo (complementary
DNA) causes overexpression of bladder Kþ channels that may
inhibit OAB.60
5. Nano approaches to intravesical delivery
Because of the limited permeability of the bladder wall and
undesired side effects of chemical enhancers, the IDD approach is
amenable to modulating the release and absorption characteristics
of instilled drugs by coupling them to novel carriers such as lipo-
somes, microspheres, nanoparticles (NPs), and so forth. Strategies
involving NPs and in situ gels for IDD are depicted in Fig. 1.
5.1. Vesicular systems: liposomes
Liposomes are lipid vesicles composed of synthetic or natural
phospholipids that self-assemble to form bilayers surrounding an
aqueous core. They can incorporate small drug molecules, both
hydrophilic and hydrophobic, macromolecules, and even plas-
mids, and show greater uptake into cells via endocytosis.61
Intravesical liposomes, even without drugs, have therapeutic
effects on IC patients, mainly due to their ability to form
a protective lipid film on the urothelial surface. Fraser et al62
examined the effect of intravesically administered liposomes of
74 J. Nirmal et al. / Urological Science 23 (2012) 70e77
L-a-phosphatidylcholine:cholesterol at ratio of 2:1 in a rat model
of hyperactive bladder. PS was used to mimic the interstitial
cystitis state, followed by a KCl and acetic acid infusion to serve as
an irritant. The cystometrographic results showed that the
hyperactivity induced by PS/KCl was partially reversed by treat-
ment with liposomes/KCl, showing a significant change in the
intercontraction interval (ICI) from 15.8  1.4 minutes with the
control KCl solution to 2.7  1.0 minutes with PS/KCl and finally an
increase to 4.4  1.2 minutes with liposome treatment. Similarly,
the irritant effect induced by acetic acid was reduced by liposome
treatment, with ICI values changing from 15.3  2.2 minutes with
saline to 6.7  1.5 minutes with the liposome formulation. The
possible mechanism of action of liposomes is the formation of
a lipid film on the urothelium that protects it from penetration by
irritants. Additionally, liposomes can augment the barrier prop-
erties of the urothelium by stabilizing neuro membranes of
damaged nerves and reduce their hyperexcitability. In addition,
liposomes composed of phospholipids can exert anti-
inflammatory effects by initiating local lipid signaling and
affecting mast cell activity. Encouraged by the efficacy of empty
liposomes as a therapeutic agent for intravesical therapy of IC/PBS,
Chuang et al recently published information on the clinical safety
and efficacy of liposomes in IC/PBS patients.63 In an open-labeled
prospective study of 24 IC/PBS patients, the effect of intravesical
liposomes was compared with oral pentosan polysulfate sodium.
Statistically significant decrease in pain, urgency, and the
O’LearyeSant symptom index were observed in the liposome
group. None of the patients reported urinary incontinence,
retention, or infection due to liposome instillation. Intravesical
instillation of liposomes was found to be safe for IC with potential
improvement after one course of therapy for up to 8 weeks.
Intravesical liposomes appear to be a promising new treatment for
IC/PBS, and future large-scale placebo-controlled studies are
needed to verify results of the pilot study.
A potent immunosuppressive effect of tacrolimus encouraged
its topical application to achieve a local anti-inflammatory effect.
However, its poor aqueous solubility presents challenges in
formulating biocompatible instillations. Liposomal tacrolimus
significantly inhibited cyclophosphamide-induced inflammatory
cystitis through modulating interleukin-2, prostaglandin E2, and
prostaglandin E receptor 4(EP4) function. These findings support
the investigation of local tacrolimus in cases of IC refractory to
conventional therapy.64 A study conducted by the authors’ labo-
ratory evaluated the potential of liposomes as a vehicle for the
intravesical delivery of the neurotoxin, capsaicin, for treating IC.
Capsaicin is a water-insoluble hydrophobic drug, so its instillation
requires the use of ethanolic saline to enhance urothelial penetra-
tion, but this can damage bladder tissues. The efficacy of liposome-
encapsulated capsaicin was evaluated by measuring the micturition
reflex in normal rats under urethane anesthesia.65 The CMG trac-
ings showed that liposomes were able to deliver capsaicin with an
efficacy similar to ethanolic saline. Tissue histological and
morphological studies, however, revealed that toxicity to the
bladder was drastically reduced. In the context of toxins instilled in
the bladder, fat-soluble neurotoxins such as capsaicin can be inte-
grated into the phospholipid bilayer, and water-soluble neurotoxins
such as botulinum can be protected within the aqueous compart-
ment of liposomes.66 Liposomes can co-opt the native vesicular
traffic ongoing in the bladder, necessary for periodic expansion of
the bladder lining during urine storage phases, which may provide
a favorable environment for drug delivery. Liposomes can mimic
these vesicles and thereby aid in improving the delivery of cargo
across the blood-urine barrier. Encapsulation of BoNT inside lipo-
somes protected it from urinary degradation without compro-
mising the efficacy in a rat model. Immunohistochemical detection
confirmed the liposome-mediated transport of BoNT into the uro-
thelium.67 Animal studies indicate that liposomes can restrict BoNT
delivery to the detrusor muscle and avoid the risk of retention and
incomplete bladder emptying.
5.2. Polymeric NPs
Polymer-based NPs offer a variety of compositions, all of which
provide a variable degree of drug loading and release by changing
the parameters of the chemical nature and cross-linking reactions
involved. The encapsulated drug is released in a controlled manner
by either diffusion, erosion, or a combination of both.68 Although
a large number of synthetic polymers can be used to form NPs, those
which are biocompatible and biodegradable are used for drug-
delivery purposes. Chang et al69 studied poly(ethyl-2-
cyanoacrylate) epirubicin nanoparticles (EPI-NPs) in bladder
cancer cell lines (T24 and RT4). The NPs greatly improved the
penetration of EPI into the bladder wall, as commercial aqueous
formulations of EPI have very low efficacy. Adhesion of the NPs to
bladder samples was evaluated using a diffusion cell. Histological
staining showed that the formulation caused no structural damage
to the urothelium. Tissue analyses also showed higher penetration
and accumulation of the EPI-NP formulation in tissues compared
with those of the free drug. A large number of polymers such as
polycaprolactone, polyacrylates, polylactic acid, polyglycolides can
be formulated into nanocarriers for intravesical applications.70
5.3. Magnetic NPs
NPs developed using magnetic compounds have immense
potential as both targeted drug carriers and for diagnostic
imaging.71 Magnetic NPs can be used as contrast agents to visualize
diseased regions of the bladder, by targeting specific regions of the
bladder using a magnetic field to localize drug-loaded magnetic
particles.72,73 The core of these NPs can be coated with an organic
or inorganic shell to allow drug adsorption or for ligand attachment
to their surface. However, the size and properties of these particles
need to be optimized for intravesical delivery. A recent study by
Leakakos et al74 used magnetic targeted carriers (MTCs, with
particle sizes of approximately 0.5e5 mm) to deliver the anticancer
drug, DOX, into the bladder wall. The MTCs contained an iron
component to allow targeting by a magnet and an activated carbon
component to adsorb the drug. These particles were evaluated in
transitional cell bladder carcinomas in swine bladder, and the study
results showed greater accumulation of magnetic particles at the
region of the bladder closest to the external magnet. Thus, magnetic
guiding of such particles can provide site-specific intravesical
delivery of drugs.
5.4. Dendrimers
Dendrimers are core-shell macromolecules made up of highly
organized layers of monomers that make up branches surrounding
a core. Successive branches (called generations) can be added to
increase the molecular size and number of available surface
groups.75 Dendrimers have a narrow size distribution, highly
ordered structures, availability of a large number of functional
groups for attachment of targeting ligands and drug molecules, and
a high degree of control over drug-release properties.76e79
Recently, François et al evaluated the possibility of utilizing 5-
amino levulinic acid (5-ALA)eloaded dendrimers to decrease the
photobleaching of the fluorophore, protoporphyrin IX (PpIX), and
to improve the visualization and specificity during cystoscopy.
Intravesical administration of 5-ALA dendrimers in rats resulted in
PpIX synthesis which was much more selective toward the tumor
 J. Nirmal et al. / Urological Science 23 (2012) 70e77
as opposed to 5-ALA or hexyl derivative ALA (h-ALA). In vitro
experiments showed that there was prolonged and sustained PpIX
synthesis with reduced photobleaching compared to h-ALA-
induced PpIX. These are primary indicators that 5-ALA den-
drimers can possibly overcome drawbacks of 5-ALA/h-ALA
fluorescenceeguided cystoscopy.80
5.5. Nanocrystalline silver
Boucher et al investigated the effect of nanocrystalline silver in
experimental bladder inflammation. Nanocrystalline silver or
phosphate-buffered saline was introduced intravesically into rat
bladders for 20 minutes followed by vehicle or PS and lipopoly-
saccharide. Nanocrystalline silver was not effective at <1%. Intra-
vesical administration of nanocrystalline silver (1%) decreased
urine histamine, bladder tumor necrosis factor-a, and mast cell
activation with no toxic effects. The effects were apparent even
4 days later and may be useful for IC.81
6. Mucoadhesive approaches to intravesical delivery
6.1. Polymeric hydrogels
Major progress in IDD is the use of hydrogels to serve as drug
depots on the bladder wall. This eliminates the need for repeated
infusions of drug solutions, in which the drug is mostly washed out
when voiding urine. Large varieties of biocompatible, bioactive
polymeric hydrogels are available which can remain attached to the
bladder wall even after urine voiding. A recent study by Tyagi et al82
involved in vivo evaluation of a fluorescein isothiocyanate (FITC)-
and misoprostol-loaded thermosensitive polymeric hydrogel in
a rat model. Thermosensitive polymers can be used to first inject
the hydrogel in its liquid form, which then forms a gel in situ inside
the bladder cavity at an elevated body temperature. The triblock co-
polymer, poly(ethylene glycol)epoly[lactic acid-co-glycolic acid]e
poly(ethylene glycol), was modified to make it more hydrophobic
in nature so as to enable it to withstand urine components. Results
of the study showed that the injected gel did not obstruct urine
outflow, proving that it attached itself as a thin layer onto the
bladder wall. The prolonged excretion (over 24 hours) of FITC in the
urine suggested that the hydrogel did not get washed off during
urine voiding. Another aspect of this gel is its reversible gelling
property, which enables easy removal of the gel from the bladder
by simple washing with saline at room temperature. Efficacy
studies showed that the misoprostol trapped in the hydrogel
maintained its biological activity and successfully reduced incon-
tinence in rats. Although there have been few studies on such
systems, there are a large number of potential polymeric gel
systems that can be explored. Translating this method for use in the
human bladder involves a number of unique challenges such as (1)
the gels need to be designed for the higher capacities of the human
urinary bladder; (2) the gels should form a uniform thin layer inside
the bladder at the affected site; (3) the gels should have optimal
contact with the urothelial surface to allow for strong adherence;
and (4) mechanical properties of the gels should also allow them to
resist detachment by shear forces of urine flow and stretching of
the bladder wall.18
6.2. Mucoadhesive NPs
IDD systems can be made more effective by using mucoadhesive
materials that can attach to the mucous membrane of the urothe-
lium. This allows the formulation to be retained at the site for
a longer duration and ensures sustained and enhanced contact with
the mucous layer. Mucoadhesive formulations can also be used to
75
coat and protect damaged tissue surfaces or even to increase
penetration of therapeutic agents into the cell lining.83 Mucoad-
hesive formulations must meet three basic criteria: the carrier
should rapidly adhere to the bladder wall, the carrier must not
obstruct the flow of urine or any of the normal functions of the
bladder, and it should be able to remain attached to the affected site
even after urine is voided.84 A number of biomolecules, such as
chitosan, carbomers, and cellulose derivatives, were identified as
having mucoadhesive properties, among which chitosan is widely
used for permeability enhancement of drug solutions through the
urothelium. Chitosan has many properties advantageous for intra-
vesical delivery, as it is biodegradable, biocompatible, and poly-
cationic and has reactive amine and alcohol groups.85 Derivatives of
chitosan are used to treat IC using the sulfated form N-sulfonato-
N,O-carboxymethylchitosan (SNOCC) to encapsulate and transport
5-aminosalicylic acid (5-ASA) into the rat bladder wall. The
inflammation and urinary frequency was found to be reduced using
a combination of 3% SNOCC with 5-ASA.86 The SNOCC coats the wall
of the bladder while chitosan enhances permeation of the anti-
inflammatory agent into the bladder lining. In a recent study,
chitosanethioglycolic acid (TGA) NPs were evaluated as carriers for
intravesical delivery. Because of its thiol groups and disulfide
bonds, chitosaneTGA NPs showed greater stability, superior
mucoadhesion, and more sustained and more controlled release
than the corresponding unmodified chitosan particles. The adhe-
sion of prehydrated chitosaneTGA NPs to the urinary bladder
mucosa under continuous urine voiding was 14-fold higher
compared with unmodified chitosan NPs. Release studies indicated
more sustained trimethoprim release from covalently cross-linked
particles compared with unmodified chitosanetripolyphosphate
NPs over a period of 3 hours in artificial urine at 37  C. The study
revealed that the chitosaneTGA IDD system may prove to be useful
carriers for local drug applications in the urinary bladder, which
increases the residence time of the drug at the target site and
enables sustainable delivery for an extended period.87
7. Electromotive drug administration
The desire to increase the penetration of drugs instilled into the
bladder has also tempted exploration of electromotive drug
administration (EMDA). In a recent study, patients suffering from
urge syndrome with and without urge incontinence (25.6% OAB
wet, 20.0% OAB dry, and 54.4% mixed urinary incontinence) and
non responsive to oral anticholinergic drugs underwent EMDA
therapy performed once in every 4 weeks for a period of 3 months.
EMDA significantly improved urodynamic parameters, the quality
of life as evaluated with the King’s health questionnaire, and pad
usage in patients with urge syndrome and therapy-resistant IDO as
evident from a micturition chart over 48 hours.88
8. Conclusions
Future development of novel drug-delivery systems as
a delivery platform for intravesical administration of drugs can
improve the efficacy and safety of pharmacotherapy for bladder
diseases. The latest developments in the field of nanotechnology
bring this mode of therapy to the forefront as a new hope for
disease management in the LUT.
Conflicts of interest statement
Yao-Chi Chuang, Pradeep Tyagi and Michael B. Chancellor are
consultants for Lipella Pharmaceuticals Inc.
76 J. Nirmal et al. / Urological Science 23 (2012) 70e77
Source of Funding
None.
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