Drug Delivery in Clinical Urology - Molecular Pharmaceutics (ACS

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Drug Delivery in Clinical Urology Alice Crane, Sudhir Isharwal, and Hui Zhu Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.8b00383 • Publication Date (Web): 20 Jun 2018 Downloaded from http://pubs.acs.org on June 21, 2018

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Molecular Pharmaceutics

Current Therapeutic Strategies in Clinical Urology Alice Crane MD PhD, Sudhir Isharwal MD, and Hui Zhu* MD PhD All Authors: Glickman Urological and Kidney Institute Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, OH 44195

*Corresponding author Hui Zhu Phone: 216-645-6467 Email: [email protected]

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Abstract: The field of urology encompasses all benign and malignant disorders of the urinary tract and the male genital tract. Urological disorders convey a huge economic and patient quality-oflife burden. Hospital acquired urinary tract infections in particular are under scrutiny as a measure of hospital quality. Given the prevalence of these pathologies, there is much progress still to be made in available therapeutic options in order to minimize side effects and provide effective care. Current drug delivery mechanisms in urological malignancy and the benign urological conditions of overactive bladder (OAB), interstitial cystitis/bladder pain syndrome (IC/BPS), and urinary tract infection (UTI) will be reviewed herein. Both systemic and local therapies will be discussed including sustained release formulations, nanocarriers, hydrogels and other reservoir systems, as well as gene and immunotherapy. The primary focus of this review is on agents which have passed the pre-clinical stages of development.

Table of Contents Graphic:

Keywords: overactive bladder; interstitial cystitis; urinary tract infection; bladder cancer; kidney cancer; prostate cancer; intravesical therapy; hydrogels; nanocarriers


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I Introduction: In an era with an increasing array of available treatment options, it has become of utmost clinical importance to refine therapeutic strategies in order to optimize efficacy while limiting systemic toxicity. Urologic therapies, as in most areas of medicine, often carry a high rate of undesirable side effects leading to diminished quality of life and potentially high rates of patient non-compliance. For some benign disease processes such as overactive bladder (OAB) and interstitial cystitis (IC), a patient may be faced with morbid surgery if they do not respond to or cannot tolerate the available treatment options. Bothersome side effects are often due to systemic effects outside of the organ of interest. Several strategies exist in order to avoid or minimize these “off-target” effects. The first and the simplest approach is direct delivery of the drug to the location of the pathology. For disease processes affecting the bladder, instillation or injection of the drug through a catheter or cystoscope (camera) inserted through the urethra may be used (“intravesical delivery”). The bladder is seemingly optimized for local drug delivery due to its characteristics as a hollow storage organ and easy access. However, the physiology of the urinary tract also poses some unique challenges for medication delivery (Figure 1).

Fig. 1 Challenges in drug delivery to the bladder and therapeutic delivery mechanisms to overcome each barrier. “First pass metabolism” refers to metabolism by the liver prior to delivery at the target site. LiRIS - lidocaine-releasing intravesical system



The urothelium is a transitional epithelium with the luminal surface comprised of a unique layer of umbrella cells. These umbrella cells are covered with uroplakins and a hydrophilic mucin layer made up of glycosaminoglycans (GAGs)3. This forms a tight impermeability barrier which restricts the uptake of therapeutic agents following intravesical delivery4. The same impermeability of the urothelium that prohibits systemic absorption of urinary waste stymies therapeutic agents that require bladder wall penetration for maximal efficacy. In addition, the constant production and washout effect of urine limits drug dwell time. Many systemic side effects can also be circumvented by bypassing metabolism of orally administered drugs by the liver prior to target organ delivery (“first pass metabolism”). Testosterone delivery for symptomatic hypogonadal (“Low T”) men is an interesting example as original oral formulations were extensively metabolized by the liver and required excess dosing to achieve therapeutic levels1. Subsequent attempts at chemical modification of the molecule to bypass first pass metabolism led to significant hepatotoxicity2. Currently, no oral formulations of testosterone are FDA approved while a variety of alternative delivery mechanisms have been developed including patches, gels, injections and a long-acting implantable drug delivery system (Testopel). Drug delivery in oncology adds its own unique challenges. Urologic malignancies, like other solid tumors, show therapeutic resistance via several well-known mechanisms including drug export pumps, deregulation of DNA repair limiting apoptosis, and tumor metabolism of chemotherapy drugs. In addition, the penetration of antitumor drugs is hampered by the tumor microenvironment which limits the efficacy of chemotherapy at the target tissue (Figure 2).

In order for chemotherapy to be maximally effective, it must be distributed to the tumor via vascular access, cross the vascular wall, permeate through the interstitium and reach a sufficient concentration to affect the target cellular processes. However, the tumor vascular network is often altered, the vascular walls immature, the interstitium often poor due to hypercellularity of tumor cells, and diffusion is limited due to intratumoral pressure. In comparison to normal tissues, tumor cells are generally located farther


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away from blood vessels which requires drugs to travel further in order to penetrate tumor cells. These barriers to drug penetration lead to modest efficacy of most chemotherapeutic regimens and to high dose toxicity. Improved drug delivery to overcome these challenges could improve cancer outcomes and is an important area of active research. Exciting advances have been made in drug delivery that address many of the above challenges inherent to urinary tract and tumoral drug delivery5. Mechanisms of drug delivery to be reviewed herein include controlled-release delivery mechanisms including indwelling bladder reservoir devices, liposomal and nanoparticle vehicles, protein carriers, and immunotherapy, among others. Advances in drug delivery for the prevalent benign urologic conditions overactive bladder (OAB), interstitial cystitis/bladder pain syndrome (IC/BPS), and urinary tract infection (UTI) as well as for urologic malignancies are specifically discussed. These widespread urologic disorders severely impact patient quality of life (QoL) and contribute heavily to healthcare burden. More sophisticated drug design and advanced targeting will help increase the efficacy of

available therapeutics while minimizing side effects thus increasing patient QoL and compliance. The ideal characteristics of drugs and delivery systems for each disease process are delineated in Figure 3.

II Current Therapeutics and Advances in Drug Delivery in Benign Urology IIa Overactive Bladder Syndrome Overactive bladder (OAB) is an extremely common benign urologic condition defined by the International Continence Society (ICS) as the presence of “urinary urgency, usually accompanied by frequency, nocturia, with or without urgency urinary incontinence, in the absence of …obvious pathology”6. The estimated prevalence of OAB is between 7-43% and the



urinary symptoms associated with this syndrome have a large impact on patient quality of life. Current treatment strategies carry with them undesirable side effects and only moderate efficacy - causing a subset of patients to progress to more morbid procedures 7-10.

Advances in Available Oral Agents for Overactive Bladder The mainstay of OAB treatment is anticholinergic medication which is characterized by dry mouth and constipation and carries only a modest improvement in symptoms leading to poor patient adherence11. The more recently developed β3 agonists, which increase sympathetic norepinephrine-mediated bladder capacity, may be better tolerated12. However, many patients still fail oral medications even with anticholingeric/β3 agonist dual therapy. The simplest method to improve the side effect profile of these medications is to alter the kinetics of oral drug delivery. Extended release anticholinergics for OAB have been shown to have a decreased incidence of dry mouth without a decrease in efficacy which leads to an increase in patient compliance13. Indeed, the American Urological Association (AUA) guidelines recommend the use of extended release formulations over immediate release14. Patches, gels and intravesical instillation (delivery of drug via a urethral catheter directly into the bladder) are available alternative routes of administration. The most common drug available for intravesical instillation is oxybutynin chloride/hydrochloride with other agents including trospium chloride, propiverine, and atropine. In a study by Madersbacher and Jilg, 75% of the patients who did not experience side effects with intravesical instillation had class anticholinergic side effects when subsequently given the corresponding oral formulation15. Advances in Intravesical Therapy for Overactive Bladder When patients with OAB fail therapy with anticholinergics and/or β3 agonists, an effective and common alternative option is onabotulinumtoxinA (botox) intravesical injections14. Botox works by binding to synaptic vesicle glycoprotein 2A and inhibiting acetylcholine exocytosis into the synapse, causing muscle paralysis and, in the case of OAB, mitigating the sensation of urgency carried by afferent nerves and increasing bladder storage capacity mediated by efferent nerves16-17. Due to the impermeability of the bladder urothelium, current formulations of botox must be delivered via injection directly into the bladder wall. There is also a high rate of urinary retention (inability to empty the bladder) requiring self-catheterization by the patient and of urinary tract infection (UTI)18. In patients with a non-neurologic cause of OAB, rates of urinary retention are up to 35%19. Because of this, attempts are underway to minimize the invasiveness of botox delivery in hopes of decreasing the frequency and/or intensity of side effects. In 2004 Tyagi et al introduced a liposomal carrier for intravesical instillation which was first tested in an UTI model20. This method of delivery was subsequently tested for OAB 21. Liposomes are vesicles that can adsorb to cell surfaces and fuse with the cell membrane, acting as a vehicle for drug delivery and enabling drugs to penetrate the watertight urothelium without physical injection4,22. The rationale for liposomal-mediated delivery is trifold. First, many


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patients are unwilling to accept multiple injections under local anesthesia. Secondly, Kuo et al hypothesized that liposomal delivery of botox would have less penetration than injection and affect the urothelial sensory nerves without affecting the actual detrusor contractility, preventing treatment-related detrusor underactivity21. Lastly, extravesical extravasation of the botox toxin has been demonstrated when delivered by injection, although the clinical significance of this extra-vesical toxin in unknown23. A proof-of-concept double-blind randomized pilot study by Kuo et al demonstrated that intravesical Lipotoxin instillation reduced frequency episodes in patients failing prior oral therapy without any instance of urinary retention or UTI in a total of 24 patients21. Prophylactic antibiotics were given for three days after the procedure. Decreases in frequency and urgency episodes were decreased in the Lipotoxin group with efficacy of 50% at 1 month and 28% at 3 months. However, Lipotoxin instillation did not change the occurrence of urinary incontinence episodes. A larger double-blind randomized placebo-controlled trial by Chuang et al enrolling 62 patients (31 in treatment arm) demonstrated similar results with lipobotulinum toxin24. Treated patients had less frequency and urge severity than the placebo arm but no difference in urge episodes or urgency incontinence. Although treatment effects are modest, this may be a promising avenue for patients with milder OAB and unwillingness to selfcatheterize. An alternative approach to penetration of the bladder urothelium without the need for direct injection is the use of chemical or physical means to increase the permeability of the urothelium. Dimethyl sulfoxide (DMSO) is an organic solvent that can be used to denude the urothelium and has been shown in pig bladders to increase the permeability of instilled agents25. Physical approaches include electromotive drug administration (EMDA) and shock wave. EMDA of botox has shown promise in a pediatric population with neurogenic bladder secondary to myelomeningocele26. It relies on a current passed between an electrode-tipped urinary catheter and external patches to increase the permeability of the urothelial lining, allowing more efficient penetration. In a 2011 study of 15 children, urodynamic parameters including bladder capacity and mean maximal detrusor pressure improved with electromotive delivery of botox while incontinence episodes decreased in most patients26. The majority of children also saw improvement in their fecal incontinence. Recently, long-term durability out to 6 years has been shown with this method of delivery27. The availability of less invasive and less frequent drug administration is especially important in the pediatric population where general anesthesia and lifetime treatments are required. Low-energy shock waves (LESW) have also been shown to increase the permeability of tissues temporarily and the feasibility of using LESW for intravesical botox administration has been assessed in rats28. Another tactic to bypass the invasiveness of injection-based delivery is to increase the dwell time of the active drug in the bladder. Thermosensitive hydrogel is an aqueous solution in a liquid state at room temperature which becomes semi-solid at body temperature. A doubleblind randomized pilot study by Krhut et al in 2016 demonstrated a decrease in severity of urge episodes with intravesical instillation of botox embedded in TC-3 hydrogel29. This suggests that botox can exhibit some efficacy without bladder lining penetration if a therapeutic concentration is sustained in the bladder.



IIb Interstitial Cystitis/Bladder Pain Syndrome Interstitial cystitis/bladder pain syndrome (IC/BPS) is a symptom complex with the unifying theme of pain. Most frequently, IC/BPS patients experience pain upon bladder filling, but levator spasm, perineal pain and extra-genitourinary pain are not uncommon30-31. The Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction definition of IC/BPS is an “unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder, associated with lower urinary tract symptoms of longer than six weeks duration, in the absence of infection or other identifiable causes”32. IC/BPS is more common in women with an estimated prevalence of 2.7-6.5% versus men with an estimated prevalence of 2.9-4.2%33-34. As a chronic and difficult to treat pain disorder with varied patient presentation, IC/BPS is a frustrating syndrome for both patients and providers and, like OAB, carries a significant detriment to patient QoL35. There has been no single satisfactory therapeutic agent for all phenotypes and patients often require multimodal therapy to manage their symptoms (Table 1). In addition, intravesical drug delivery is a key component to many treatments for IC/BPS although catheterization and instillation may be painful and/or ineffective for many of these patients. Advances in drug delivery in this disorder seek to increase efficacy, minimize side effects and/or decrease the intensity, discomfort and frequency of treatment.

Current Intravesical Therapy in Interstitial Cystitis/Bladder Pain Syndrome Urothelium Repair and Denuding Agents The pathophysiology of IC/BPS is poorly understood, which poses a challenge to targeted drug development and delivery. Patients with IC/BPS are thought to have a defect in their urothelial lining which allows potassium and urinary toxins to penetrate the urothelium and cause symptoms of discomfort with possible additional roles for chronic inflammation and neurogenic hyperactivity36. Several current intravesical therapies include components of the GAG layer including heparin, hyaluronic acid, and chondroitin sulfate37. Interestingly, given its ability to denude the epithelium, DMSO has also been used to treat IC/BPS as an antiinflammatory and analgesic agent though it has been reported that some patients experience a flare of symptoms when first placed on DMSO instillation38. Liposomal Drug Delivery As with OAB treatment, liposome delivery has been investigated as a minimally invasive drug delivery mechanism in IC/BPS. For IC/PBS specifically, liposomes alone can exert antiinflammatory effects and are thought to be able to coat and repair damaged urothelium39. Several small prospective studies have found liposomal instillation to be safe and effective in reducing urgency and pain40-42. One open-label study compared liposomal instillation to a current accepted oral therapy (pentosan polysulfate (PPS)) and found an equal decrease in urinary frequency and nocturia and a significant decrease in urgency and pain in the liposome group40.


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Botox is a recommended fourth-line treatment according to AUA guidelines but, as discussed, is currently only available via intravesical injection into the bladder wall43. This is particularly problematic in this pain sensitive population and thus liposome delivery of botox is of interest in IC/BPS. . However, a recent two-center prospective study with instillation of lipsome encapsulated botox versus placebo did not show a significant improvement in the therapeutic group44. Like many studies in IC/BPS, there was a large placebo effect which highlights the need for carefully controlled studies in this patient population. Slow Release Intravesical Reservoirs Another advance in drug deliveryfor IC/BPS is the lidocaine-releasing intravesical system (LiRIS) which was developed for sustained delivery of local anesthetic. Nickel et al reported significant reductions in pain, urgency, voiding frequency, and improvement in diseasespecific questionnaires in 16 women with IC/BPS. Additionally, resolution of Hunner’s lesions, which are lesions of the bladder wall seen in a subset of IC/PBS patients, were seen in 5/6 women and reductions in pain were seen several months past the two week dwell time of the device45.

Table 1: Current and Upcoming Oral and Intravesical Therapeutics in Interstitial Cystitis/Bladder Pain Syndromea Agent Recommended

Discouraged

Emerging

Lineb

Route

RCTs

nd

2

Oral

Cimetidine

2nd

Oral

Hydroxyzine PPS

2nd 2nd

Oral Oral

Van Ophoven, 200446 Thilagarajah, 200147 Sant, 200348

DMSO

2nd

Instillation

Heparin

2nd

Instillation

Lidocaine Botox

2nd 4th

Instillation Intradetrusor

Long-term antibiotics BCG

-

Oral

-

Instillation

-

Oral

Peters, 199759;Mayer, 200560 None

-

Instillation

Nickel, 201245

Amitriptyline

Long-term Glucocorticoids LiRIS


Holm-Bentzen, 198749;Mulholl and, 199050;Parsons ,199351;Sairane n, 200552 Perez-Marrero, 198853; Peeker, 200054 Parsons, 201255 Nickel, 200956 Kuo & Chancellor, 200957 Warren, 200058


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Liposome

-

Instillation

Lipsome/Botox

-

Instillation

Chuang, 200940 Chaung and Kuo, 2017 44,c

a

Based on AUA Guidelines on Interstitial Cystitis43 1 line therapy consists of education, stress management, and behavioral modification 3rd line therapies are not discussed and include low-pressure hydrodistension and fulguration of Hunner’s lesions c Negative trial RCT – Randomized controlled trial PPS – pentosanpolysulfate LiRIS - lidocaine-releasing intravesical system

b st

IIc Urinary Tract Infection Urinary tract infection (UTI) is an enormous healthcare burden and ranges from a simple bladder infection in healthy young women to devastating and potentially fatal urosepsis in susceptible populations. In addition, the commonplace use of urinary catheters complicates efficacious drug delivery in the setting of catheter-associated urinary tract infections (CAUTIs) due to the introduction of a foreign object and the formation of crystals and bacterial biofilms. Urinary stents are also often used in urology which are usually made of copolymer material and placed in the ureter to relieve obstruction from external compression by malignancy, urinary stone disease, ureteral strictures, or retroperitoneal fibrosis. They are also used as an adjunct to post-surgical healing for upper urinary tract surgery or as a prophylactic measure to aid intraoperative identification of ureteral injuries during high-risk pelvic procedures. Unfortunately, catheters and stents provide a platform for the rapid development of bacterial colonization and urine cultures poorly reflect colonized organisms61. Urinary Tract Infections Associated with Catheters and Stents Antibacterial and Commensal Bacteria Coatings To combat challenging catheter-associated infections, the use of antimicrobial and antifungal impregnated catheters has been explored, but with mixed clinical benefit62. Antibioticimpregnated catheters may delay the presence of detectable bacteria in the urine but have not shown benefit in long term catheterization63. A large randomized controlled trial comparing silver alloy-coated catheters and nitrofural antimicrobial-impregnated catheters versus standard catheters enrolling > 6000 patients showed no effect of silver alloy-coated catheters and a nonclinically significant reduction in CAUTI with impregnated catheters. Furthermore, there was greater patient discomfort with antimicrobial coated catheters64. Catheter varnishes may provide a more reliable drug-release mechanism than impregnation. The first poly(meth)acrylate was available in 1955 (EUDRAGIT® L and EUDRAGIT® S) with pharmaceutical applications following approximately a decade later65. Kinetic studies of chlorhexidine and thiazolidinedione-8 (TZD-8) have been performed and show promise in sustained drug delivery with ammonio methacrylate copolymer type A (Eudragit®RL) or ethylcellulose varnishes66-67. Chlorhexidine has anti-biofilm properties while TZD-8 is an anti-quorum sensing molecule. Quorum-sensing is a pathogen signaling mechanism regulating biofilm formation in response to outside stimuli68.


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An interesting variation on coated catheters is bacterial coating with a genetically engineered strain of Escherichia Coli to simulate the effect of naturally present commensal bacteria to “crowd out” pathogenic bacteria69. Several small studies have shown a decrease in symptomatic UTIs with both bacterial coating of the urinary catheter and with bacterial inoculation of the bladder69. There has also been promising preliminary data regarding the above delivery techniques in the setting of ureteral stents70-71. Intravesical Phage Therapy Urease-secreting uropathogens such as Proteus Mirabilis not only form biofilms but alkalinize the urine through ammonia production. This causes calcium and magnesium phosphates to precipitate and form encrustations which become embedded in the biofilm matrix on the urinary catheter. A three-phage cocktail used by Nzakizwanayo et al was shown in an in vitro model to both treat existing infection with P Mirabilis and prolong time to catheter blockage as well as prevent biofilm formation in early-infection models72. The mechanism behind bacteriophage therapy is specific docking with target pathogenic bacteria followed by infection of the bacteria cell by the phage and triggering of host cell lysis. Lysis of the host releases virion progeny which can re-infect bacterial cells73. Phage therapy is a promising alternative in the face of increasing anti-microbial resistant organisms and is an accepted therapy in Eastern Europe with commercial cocktails available. It should be kept in mind, however, that bacterial strains can harbor resistance to phage cocktails though targeted lytic activity can be increased after directed bacteriophage adaptation73. Prevention of Urinary Tract Infection in the Setting of Prosthetic Devices Urology is a field that makes use of prosthetic devices – namely, the inflatable penile prosthesis (IPP) and the artificial urinary sphincter (AUS) for male erectile dysfunction (ED) and stress urinary incontinence (SUI), respectively. The insertion of prosthetics poses a similar problem as catheters and stents with the important difference that infection of a prosthetic device requires surgical removal. To combat seeding of the foreign body being inserted, antibiotic coating with rifampin and minocycline (InhibiZone [IZ]) was introduced. It has shown to be effective in IPP devices74 but has not shown to be effective in prevention of AUS infections and/or erosions75. Slow Release Intravesical Reservoirs For non-complex UTIs without the introduction of foreign bodies, several reservoir systems have been investigated to minimize side effects and increase local drug concentrations76. Preliminary results with thermosensitive hydrogels have shown a tenfold higher intravesical drug concentration than with conventional methods5. Another delivery system that functions as a reservoir platform is the technique of microencapsulation. Labbaf et al successfully engineered microencapsulated gentamicin in polymethylsisesquioxane (PMSQ) capsules77. PMSQ was chosen due to its biocompatibility and non-toxicity. Coaxial electrohydrodynamic forming (CEHDF) was used to make the capsules. This approach can be conducted under ambient parameters and involves two different liquids



flowing through a device containing two aligned coaxial needles. The polymer solution flows through the outer needle while the drug solution flows through the inner needle while an electric field focuses the liquid stream into a jet which forms microcapsules upon dispersion. The advantage of microencapsulation delivery is hypothesized to be the ability to deliver antimicrobials intracellularly. Several uropathogens including E Coli and Enterococcus Faecalis can reside in the cytoplasm of urothelial cells, thus shielding themselves from the host immune system78. Labbaf et al showed that PMSQ microencapsulated gentamicin can effectively penetrate human bladder cells and convey killing activity against E faecalis77. Biomimicry Similar to phage therapy discussed above, biomimicry techniques also seek to penetrate the bladder urothelium and target intracellular bacterial reservoirs. A majority of uropathogenic E Coli produce adhesive filaments (type 1 pili) with a subunit called FimH which binds to mannose-containing glycoprotein host receptors. This is the mechanism of invasion into uroepithelial cells by these pathogens. Lectins are a group of carbohydrate-binding proteins that may be able to mimic this process and improve drug delivery to treat UTIs79. Preliminary studies have also been conducted using liposomal vehicles drug modified by the lectin wheat germ agglutinin to enhance intracellular uptake and targeting80. Nanoparticles Several different candidate nanoparticle-based agents have been studied. Silver nanoparticles are limited by their toxicity and concerns for environmental persistence. Gold nanoshells (AuNSs), which consist of a dielectric core surrounded by a gold shell, are inert at body temperature but can be engineered for photothermal ablation by converting absorbed energy from near-infrared (NIR) light to heat. Khantamat et al demonstrated the ability of AuNSs to adhere to silicone surfaces and destroy E Faecalis in an in vitro model81. AuNSs have also shown efficacy against multi-drug-resistant (MDR) bacteria82. Magnetic core shell nanoparticles (MCSN) have also been shown to have activity against MDR bacteria and have greater tissue penetration than AuNSs83. A MCSN composed of an iron oxide core coated with a silica shell functionalized with conjugated amine groups was shown to trap uropathogenic E Coli upon the application of a radiofrequency current83. Bacteria were killed within 30 minutes, presumably due to loss of membrane potential and dysfunction of membrane-associated complexes. Other nanocomposites investigated include zinc oxide and rifampicin-loaded copper nanoparticles84-85. Nanoparticles alone or as a delivery vehicle for antibiotics are still in early stages. There is no standardized dosing for these agents and the potential for toxicity, particularly neurotoxicity, remains uncertain86. III Current Therapeutic Strategies in Urologic Malignancy Urologic malignancies are among the top 10 most common cancers diagnosed in men and women, impacting the lives of millions of people worldwide. Prostate cancer is the second most common cancer diagnosed in men in the United States while kidney cancer is the 6th most common and bladder cancer is the 9th most common in both sexes. Although many


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chemotherapeutic drugs are currently available, effective targeting of drugs to malignant cells in vivo without significant systemic toxicity remains elusive.

. Slow Release Drug Delivery Several anticancer drug molecules have short half lives in the body and effectively controlling their release is critical to their successful clinical application. To circumvent this problem, drug molecules have been embedded in biodegradable or non-biodegradable polymers, providing drug stability and slow elution87. The composition of the embedding polymer can be controlled to alter drug kinetics. This strategy has been effectively used in prostate cancer hormone therapy. Prostate cancer in its initial stages is sensitive to testosterone and treatment involves chemical castration. Hormone therapy when taken orally is extensively metabolized by the liver and is essentially ineffective. However, with advancements in drug delivery, these drugs were integrated with polymers to control the release rate and duration of activity. This approach has formed the basis of injectable drug therapies such as Lupron and Zoladex. Hormone therapy delivered in this way provides effective therapy lasting one to six months88-89. Intravesical Therapy in Bladder Cancer As with benign bladder conditions, bladder cancer therapy has been particularly challenging among urological cancers due to the limitations of intravesical delivery. However, intravesical therapy is the first-line treatment for non-invasive bladder cancer and this direct administration into the bladder largely avoids systemic side effects. The two most commonly used intravesical therapies are chemotherapy with Mitomycin C (MMC) and immunotherapy with Bacillus-Calmette-Guerin (BCG). Chemotherapy with MMC reduces tumor recurrence by preventing tumor cell implantation after surgical resection of bladder tumor and by a direct cytotoxic effect. In contrast, BCG therapy leads to immunostimulation of T cells against tumor antigens to reduce recurrence and progression. These therapies are delivered to the bladder on a weekly basis via a urinary catheter and must be left in place for 1-2 hours. However, some patients are not able to tolerate the catheter placement and/or the necessary drug dwell time of 12 hours. Additionally, since the exposure of the urothelium to these therapies is restricted to a short duration, the activity against the tumor cells is limited. The effectiveness of current intravesical therapies is at best modest and efforts are underway to increase drug concentration in the bladder and enhance penetration of the bladder lining. Passive diffusion of drugs instilled into the bladder can be enhanced by the application of electrokinetic forces. Under the influence of an electric field, the diffusion rate of drug molecules can be increased. EMDA has been applied to drive the intravesical chemotherapy uptake by the bladder cancer cells with good results. Due to increased effectiveness, the dwell time of the chemotherapy can be significantly reduced (30 mins vs. 2hrs), which is advantageous for the comfort of the patient90. Di Stasi et al, in a prospective randomized control trial, compared the effectiveness of EMDA MMC with MMC standard instillation and BCG for



high-risk non-muscle invasive bladder cancer in the adjuvant setting. Patients received a 6-week induction course followed by 1 year of maintenance therapy. At 6 months after therapy, a complete response of 58% was noted with EMDA MMC compared to 31% with passive instillation and 64% with BCG. Due to this comparative similar effectiveness with BCG in highrisk disease patients, EMDA MMC provides an alternative for patients who are not able to tolerate BCG. The same investigator group, in a follow-up study, compared alternative EMDA MMC and BCG to BCG alone with induction therapy followed by one-year maintenance therapy. After a median follow-up duration of 88 months, patients in the EMDA MMC alternating with BCG therapy group had significantly lower recurrence rate (42% vs 58%) and longer disease-free interval than the BCG alone therapy (69 months vs. 21 months)91. A prospective randomized trial (NCT01920269) comparing EMDA MMC to MMC with passive diffusion and surgical resection of bladder tumor alone with 6 weeks of induction therapy followed by one year of maintenance therapy is currently in progress. The primary endpoint of the study is disease free interval and secondary endpoints include time to progression, diseasespecific-survival, and overall survival. Although EMDA has been shown to increase the efficacy of chemotherapy, due to the complex nature of delivering electrokinetic forces, the application of this technique in clinical practice has not been widespread. Slow Release Intravesical Drug Delivery in Bladder Cancer Chemotherapeutic molecules can be embedded in a gel polymer that stays in the bladder for several micturition cycles and thus delivers a prolonged therapeutic concentration of the drug. These formulations also obviate the need for repeated catheterizations and thus decrease patient discomfort and increase patient compliance. The uptake of drugs through the urothelium can also be improved by chemical enhancers such as DMSO. Chemotherapies such as doxorubicin and cisplatin have been successfully administered with DMSO with increased uptake22. However, this increased permeability also resulted in unwanted side effects such as painful and frequent urination92. Aqueous solutions of poly(ethylene glycol-b-[DL-lactic acid-co-glycolic acid]-bethylene glycol) (PEG-PLGA-PEG) triblock copolymers are in free flowing liquid form at the room temperature but form viscous gel at body temperature93. These hydrogel formulations are particularly important in cases where repeated direct instillations of the drugs are challenging. RTGel is one such reverse-thermal gelation hydrogel. Its clinical application is currently under study in case of upper tract urothelial cancer after efficacy and safety was proved in the preclinical studies94. Gene Therapy in Bladder Cancer Adenoviruses are an investigational approach to targeted drug therapy. INSTILADRIN® (instiladrin nadofaragene firadenovec) is a non-replicating adenovirus carrying the human IFN alpha2b gene. The IFN alpha2 protein has activity against superficial bladder cancer but its efficacy is limited by dwell time and unstable concentrations in the urothelium. When combined with excipient Syn3, the recombinant adenovirus (rAd-IFN) results in transduction of the virus into the bladder wall and the IFN alpha2b gene is incorporated into cellular DNA leading to


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heavy expression of IFN alpha2b95. A phase III trial is currently enrolling patients with high-risk BCG unresponsive NMIBC. Nanoparticles in Bladder and Kidney Cancer As in in benign disease, a multitude of different nanoparticles are under investigation for drug delivery in urologic oncology. Recently, Voss et al conducted a phase II trial of a nanoparticle-drug conjugate in patients with advanced metastatic renal cell carcinoma in addition to bevacizumab versus the current standard of care96. The trial was negative and the agent (CRLX101) abandoned in renal cell carcinoma (RCC). However, it is encouraging that the combination was well-tolerated by patients if a more effective nanoparticle conjugate is developed in RCC. Better success was seen in non-invasive bladder cancer with intravesical instillation of nanoparticle albumin bound (nab) paclitaxel for BCG unresponsive cancer97. 75% of the 28 patients in this phase II trial had failed at least two prior treatments and 35.7% of patients responded with durable results out to one year. A different nanotechnology approach being investigated in animal models is nanochemothermia which refers to magnetic nanoparticle/chemotherapy conjugates that are heated by an alternating magnetic field. In a murine model, methotrexate-coupled magnetic nanoparticles (MNP) were more effective in destroying bladder cancer cells than MNP alone98. Novel nanobiotechnology tools are also around the corner with new research into exosomes as diagnostic and therapeutic delivery tools99. Exosomes are 30-100nm sized vesicles that are released into the extracellular space and carry proteins, nucleic acids, lipids, and metabolites reflective of their cell of origin. Exosomes and other extracellular vesicles are an enticing biologically active alternative to synthetic nanoparticles with the potential to exhibit specific tissue tropism. Immunotherapy in Bladder and Prostate Cancer Bladder cancer in particular has had a long history of immunotherapy treatment with BCG being the standard of care for decades for non-invasive disease . New advances include oportuzumab monatox which is an anti-neoplastic single chain variable fragment of a monoclonal antibody that binds to epithelial cell adhesion molecule (EpCAM). In 2012, a phase II trial was conducted for 46 BCG unresponsive patients with oportuzumab monatox demonstrating a 44% complete response rate100. Seven patients remained disease-free at 18-25 months follow-up. Prostate cancer, though it has a relatively “immunologically cold” tumor microenvironement, has also had its share of immunological advances. The only approved therapy is Sipuleucel -T which confers a 4 month survival advantage in castrate-resistant prostate cancer101. Sipuleucel-T is a type of cancer vaccine that consists of autologous antigen-presenting cells (APCs) that have been activated ex vivo with a recombinant fusion protein fused to granulocyte-macrophage colony-stimulating factor. Chimeric antigen-receptor (CAR)engineered T cell therapy, which has been clinically successful in hematological malignancies, is in early stages of investigation in prostate cancer102.



IV Conclusion While advances have been made in drug delivery and therapeutics in all areas of urology, bladder pathology in particular has been an intense area of study due to the unique opportunity for direct instillation of drugs into the bladder. Efforts are underway to increase drug dwell time in the bladder, enhance urothelium penetration, and decrease systemic side effects for both benign and malignant conditions. The majority of promising delivery mechanisms still remain in Phase 2/3 trials with combination therapies and novel techniques constantly emerging. It remains to be seen which therapeutic approaches offer a durable response with minimal toxicity.

Acknowledgement: The authors received no specific funding for this work.

References:


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Drug Delivery in Clinical Urology - Molecular Pharmaceutics (ACS

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