Journal of Controlled Release 284 (2018) 144–151
Contents lists available at ScienceDirect
Journal of Controlled Release
journal homepage: www.elsevier.com/locate/jconrel
Review article
Use of iontophoresis for the treatment of cancer
a,⁎
James D. Byrne , Jen Jen Yeh
b,c,d
, Joseph M. DeSimone
T
b,c,e,f
a
Harvard Radiation Oncology Program, Boston, MA 02114, USA
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
d
Division of Surgical Oncology, Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
e
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
f
Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695, USA
b
c
A R T I C LE I N FO
A B S T R A C T
Keywords:
Iontophoresis
Chemotherapies
Devices
Drug delivery
Cancer
Despite major advancements in cancer treatments, there are still many limitations to therapy including off-target
effects, drug resistance, and control of cancer-related symptoms. There are opportunities for local drug delivery
devices to intervene at various stages of cancer to provide curative and palliative benefit. Iontophoretic devices
that deliver drugs locally to a region of interest have been adapted for the treatment of cancer. These devices
have shown promise in pre-clinical and clinical studies for retinoblastoma, skin, bladder, and pancreatic cancers.
Herein, we review iontophoretic devices used in the management of cancer.
1. Introduction
The 2018 estimate for new cancer diagnoses is 1,735,350 and
cancer deaths is 609,640 [1]. Treatment of invasive cancer is largely
determined by tumor histology, cancer stage, patient preference, and
performance status. The primary treatment modalities include surgery,
chemotherapy, and radiation therapy. For most solid tumors, surgery
has remained the optimal therapy. Depending upon the cancer type,
surgery may be feasible in only a small subset of patients [2–5, 7, 8].
Other modalities can be combined with surgery, including chemotherapy and radiation therapy. However, these therapies can be
associated with major side effects including fatigue, diarrhea, xerostomia, and secondary malignancies [9]. As such, there is room for
improvement in current cancer therapy.
Local delivery of chemotherapies could provide curative or palliative benefit at various stages of cancer along with reduction of drug side
effects [10]. In addition, this treatment could be an adjunct to surgery,
radiation, and even systemically administered chemotherapy. An advantage to local delivery is the administration of agents that are too
toxic when delivered systemically [10, 11]. Of the various methods for
local chemotherapy delivery, iontophoresis has gained interest because
of the control of drug delivery [12, 13].
Iontophoresis is a method of drug delivery where a mild electric
current is applied around a drug reservoir to improve drug transport
into the adjacent tissue. At least two electrodes, known as the anode
and cathode, are required for drug delivery with one located in or in
⁎
Corresponding author at: Harvard Radiation Oncology Program, Boston, MA 02114, USA.
E-mail address: jdbyrne@partners.org (J.D. Byrne).
https://doi.org/10.1016/j.jconrel.2018.06.020
Received 19 April 2018; Received in revised form 14 June 2018; Accepted 14 June 2018
Available online 15 June 2018
0168-3659/ © 2018 Elsevier B.V. All rights reserved.
proximity to a drug reservoir, as seen in Fig. 1. Parameters that influence iontophoretic drug delivery includes size of the electrode and
quantity and time of current application [12]. These devices have been
used in a variety of areas including oncology, anesthesia, sports medicine, nail fungus, and cosmetic treatments [11, 14–18].
Herein, we review the iontophoretic devices used to treat cancer.
The focus is on both pre-clinical and clinical studies that showcase
improvement above current therapy. In addition, we examine the barriers for iontophoretic drug delivery, challenges for clinical translation,
and potential opportunities for further advancement.
2. Barriers to iontophoretic drug delivery
2.1. Physiological and biological barriers encountered by iontophoresis
The tumor environment provides a significant barrier for drug
transport. Tumors develop with an abundance of extracellular matrix
(ECM). The large amount of ECM contributes to an abnormal tissue
architecture of the tumor, and there is an abnormal growth of blood and
lymphatic vessels. Tissue density, as a result of the ECM, may impede
iontophoretic drug transport into and through tumors. Furthermore,
abnormal vasculature may lead to deficiencies in oxygen and nutrients
and the accumulation of metabolic byproducts in areas of the tumor
[19, 20]. Regions of the tumor that have high accumulation of metabolic acids may have less cellular uptake of weakly basic chemotherapies, such as doxorubicin, resulting in lower drug efficacy [21].
Journal of Controlled Release 284 (2018) 144–151
J.D. Byrne et al.
Fig. 1. Schematic representation of iontophoresis. The application of an electric potential generates ion flow between the anode (positive electrode) and cathode
(negative electrode). Adapted with permission from reference [12].
Other barriers that influence iontophoretic drug transport include
drug concentration and quantity of applied current. The quantity of
drug delivered by iontophoresis is not always linearly correlated to
drug concentration. This is a function of the physicochemical properties
of the drug as well as formulation additives, which may complicate
drug transport. As the concentration of a drug increases, additives in the
formulation become competing ions that diminish the transport of the
drug [12]. In addition, increasing the concentration of certain lipophilic
cations, such as nafarelin, can inhibit electroosmosis through an effect
from the hydrophobic surface being near to a positively charged component [27]. There seems to be a saturation effect up to a certain applied current for drugs. Tissue toxicity also limits quantity of applied
current and, more importantly, current density. For example, there is a
maximum tolerated current density of 0.5 mA/m2 for transdermal drug
delivery due to skin irritation [28]. For cancer treated with iontophoresis, the maximum tolerated current density may be limited by the
normal tissue adjacent to the tumors.
Drug formulation plays a key role in iontophoretic drug transport.
Each of the parameters must be accounted for when evaluating the preclinical and clinical utility of a drug for iontophoresis.
Barriers for iontophoretic drug transport also depend upon the location of the tumor and placement of the iontophoretic device. For
example, transdermal devices must deliver drug through the stratum
corneum, which functions to protect the body against environmental
toxins, dehydration, and infection. The stratum corneum is a major
parameter that modulates transport. For this reason, methods to reduce
or eliminate the stratum corneum have been investigated to improve
iontophoretic drug transport [22]. For intravesical delivery, the bladder
wall is relatively thin in comparison to skin; however, the major delivery challenge is the chemical environment of the bladder. As the
bladder collects urine, dilution of the drug may reduce exposure and
efficacy of the treatment [23, 24]. Overall, it is a matter of overcoming
these barriers that will enable successful drug delivery using iontophoresis.
2.2. Drug formulation and device-related barriers for iontophoresis
There are formulation and device parameters that may act as barriers to iontophoretic drug delivery, including the type of iontophoresis,
pH of the drug solution, drug ionization and charge, tissue charge, drug
concentration, and applied current. To understand the impact of these
parameters, the two major iontophoretic transport mechanisms, including electrorepulsion and electroosmosis, must be delineated.
Electrorepulsion involves charge-charge repulsion at the drug-electrode
interface, and electroosmosis is a solvent flow mechanism induced by
the current flow into tissue [25]. Adjusting the formulation and device
parameters can result in differences in the relative importance of
electrorepulsion and electroosmosis for the iontophoretic delivery of a
drug.
The physicochemical properties of a drug molecule and the pH of
the drug solution have a direct impact on drug ionization and charge,
tissue charge, and the type of iontophoresis that enables optimal drug
transport. For example, increasing the pH of a weak base reduces the
ionic fraction of the drug, which impacts transport in multiple ways. As
the pH approaches the pKa for the weak base, the relative contribution
of electrorepulsion to anodic ionotophoresis (anode-to-cathode) is reduced as there are less ions in solution. At pH values above the isoelectric point of tissue, such as skin, results in negatively charged tissue,
and electroosmosis contributes more to transport of the weak base as a
function of the negatively charged tissue [12]. Conversely, a higher
solution pH for a weak acid, such as 5-fluorouracil, will increase the
relative contribution of electrorepulsion when using cathodal (cathodeto-anode) iontophoresis [26]. The physicochemical properties of a drug
molecule are critical in distinguishing the form of iontophoresis and the
formulation pH most ideal for transport.
3. Approaches for iontophoretic drug delivery
The iontophoretic delivery of anti-cancer agents can be categorized
according to the device location. Devices have been developed for the
following approaches: transdermal, transpapillary, intravesical, transscleral, and peri-pancreatic. Out of these different approaches, only
devices used in transdermal and intravesical drug delivery have been
tested clinically. The rest of the devices have been evaluated in preclinical studies. A summary of all routes of delivery and the drugs delivered can be found in Table 1.
3.1. Transdermal
There has been a substantial quantity of work evaluating the
transdermal iontophoretic delivery of drugs for skin cancers. This may
be due to the ease of device delivery and testing. The broad range of
agents tested for transdermal iontophoresis include small molecule
chemotherapies, ALA for photodynamic therapy, vaccines and immunotherapy, and gene silencing with oligonucleotides [10, 29–50].
The versatility of agents delivered by iontophoresis is showcased in the
transdermal route of delivery.
Small molecule chemotherapies are among the most straight-forward drugs to deliver using iontophoresis due to size and stability. A
variety of small molecule chemotherapies have been delivered in pre145
5-FU
Cisplatin
Cisplatin
Bleomycin
Vinblastine
Doxorubicin
Doxorubicin
ALA
ALA esters
gp-100 peptide
KVPRNQDWL
CpG-ODN
Miproxifen phosphate
Transdermal
Transdermal
Transdermal
Transdermal
Transdermal
Transdermal
Transdermal
Transdermal
Transdermal
Transdermal
Transpapillary
146
*
6.0
MMC
MMC
δ-ALA
MMC
MMC
MMC
Carboplatin
Carboplatin
Gemcitabine
FOLFIRINOX (Leucovorin,
5-FU, irinotecan,
oxaliplatin)
Intravesical
Intravesical
Intravesical
Intravesical
Intravesical
Intravesical
Transscleral
Transscleral
Peri-pancreatic
Peri-pancreatic
20 mg/mL
10 mg/mL leucovorin 14.0 mg/mL
5-FU 14.4 mg/mL irinotecan 5 mg/
mL oxaliplatin
5.5–6
14.0 mg/mL
1.4–14.0 mg/mL
0.4 mg/mL
0.4 mg/mL
0.4 mg/mL
0.50%
0.8 mg/mL
0.4 mg/mL
0.1 mg/mL
0.5% (wt/wt)
0.5 mg/mL
*
1–100 mM
15 mM
1.6 mg/mL
*
3 mg/mL
10 mg/mL
5% (wt/wt)
*
1 mg/mL
Drug concentration
*
5.5
5.8
*
*
*
6.45
MMC
6.55
*
*
6.5
7.4
~7.0
5.5
*
*
*
5.5
*
*
Drug pH
Intravesical
Transdermal
Drug
Route of delivery
10 min
20 min
2 mA
20 min
5 min
30 min
30 min
30 min
20 min
20 min
30 min
15 min
120 min
60 min
180 min
360 min
120 min
360 min
20 min
3 min
10 min
360 min
10 min
20–30 min
Time
2 mA
5.0 mA/cm^2
2.57 mA/cm^2
20 mA
20 mA
20 mA
15 mA
15 mA
20 mA
5 mA
0.5 mA/cm^2
0.4 mA/cm^2
0.4 mA/cm^2
0.4 mA
0.4 mA
0.5 mA
0.5–1.5 mA
2 mA
4 mA
0.5 mA
4 mA
0.5–1.0 mA
Current or
current density
7
14
1
6
1
3
6–12
1
8
1
1
5
4
9
1
1
1
1–9
6
1
1
8
5
Number of
treatments
Pre-clinical
Pre-clinical
Pre-clinical
Pre-clinical
Clinical
Clinical
Clinical
Clinical
Clinical
Pre-clinical
Pre-clinical
Pre-clinical
Pre-clinical
Pre-clinical
Pre-clinical
Pre-clinical
Pre-clinical
Clinical
Clinical
Clinical
Pre-clinical
Clinical
Clinical
Pre-clinical
or clinical
Tumor growth inhibition after iontophoretic treatment above
and near tumor in mouse model of melanoma
Significantly higher AUC for intrapapillary delivery compared to
oral administration
Iontophoresis increased MMC delivery 6-fold into viable human
bladder compared to passive diffusion
Iontophoresis increased MMC delivery 4–6-fold into viable
human bladder at all depths compared to passive diffusion
Disease free-interval was 14.5 months for iontophoresis of MMC
compared to 10.5 months for MMC instillation only
5 of 6 patients were disease free at 10–16 months, 1 of 6 patients
recurred after 10 months
58% patients with CR at 6 months and median time to
recurrence was 35 months
Patients treated with sequential BCG and iontophoresis of MMC
had higher disease-free interval, lower recurrence, progression,
overall mortality, and disease-specific mortality compared to
BCG alone
Intravesical iontophoresis of MMC before TURBT reduced
recurrence rates and enhanced the disease-free interval
compared to intravesical passive diffusion of MMC after TURBT
and TURBT alone
50% of treated eyes exhibited control at carboplatin
concentration 7.0 mg/mL
Iontophoresis increased carboplatin in retina, choroid, and optic
nerve compared to IV therapy
Iontophoresis of gemcitabine resulted in tumor shrinkage
compared to only tumor growth inhibition for IV delivery
Iontophoresis of FOLFIRINOX induced more tumor shrinkage
compared to only IV delivery
CR in 96.2% of patients
CR in 26.7% of lesions, PR in 46.7% of lesions, and minimal
response in 26.7% of lesions
PR in 100% of patients
CR in 100% of patients
CR in 29.0% of lesions, PR in 71.0% of lesions
Doxorubicin formulated in chitosan gels improved diffusion to
deeper skin layers
Iontophoresis of DOX-SLNs delivered 56% of total drug into
viable epidermis
Increasing ALA concentration at pH 7.4 improves drug delivery
Delivery of methyl-ALA resulted in 7-fold increase in SC and 18fold increase in viable skin compared to ALA
Tumor growth inhibition in mouse model of melanoma
Outcomes
70
10
67
66
60
59
58
56
55
54
53
51
47
46
40
42
38
36
33
34
37
29
31
Ref.
Table 1
Summary of all the routes of delivery and the different anti-cancer agents tested. Abbreviations: 5-FU – 5-fluorouracil, ALA – aminolevulinic acid, AUC – area under the curve, BCG - Bacillus Calmette-Guerin, CpG-ODN –
CpG-oligodeoxynucleotides, CR – complete response, DOX-SLN – doxorubicin-loaded solid lipid nanoparticles, MMC – mitomycin C, PR – partial response, TURBT – transurethral resection of bladder tumor.
J.D. Byrne et al.
Journal of Controlled Release 284 (2018) 144–151
Journal of Controlled Release 284 (2018) 144–151
J.D. Byrne et al.
delivery of bleomycin and vincristine [34, 35]. In one such example, the
iontophoretic delivery of bleomycin was pursued for the treatment of a
patient with an extensive verrucous carcinoma of the face. The treatment was performed where the anode was a hollow plastic tip containing cotton soaked with bleomycin solution and placed over the
region of interest; the cathode placed on the ipsilateral upper arm.
Discrete treatments were performed every other day for a total of 6
treatments. The region of interest was biopsied 3 months after treatment and revealed only moderate fibrosis and minimal chronic inflammation but no malignant cells. Findings from a physical exam
within 6 months of treatment demonstrated no residual disease [34].
Kaposi sarcoma lesions in patients with human immunodeficiency virus
were treated using the iontophoretic delivery of vinblastine. Thirty-one
lesions in 6 patients resolved after treatment [35].
The iontophoretic delivery of doxorubicin-filled matrices and nanoparticles has been investigated. Doxorubicin strongly interacts with
the stratum corneum, which causes transdermally delivered drug to
remain in the skin's superficial layer making this form of delivery
challenging. Various formulations of doxorubicin, including water and
gel formulations, were evaluated for transdermal delivery. It was found
that the iontophoretic delivery of doxorubicin in water showed slightly
better delivery compared to drug formulated in hydroxyethylcellulose
or chitosan gels. However, the majority of drug delivered in the water
formulation was delivered to the stratum corneum. Doxorubicin formulated in chitosan gels enabled deeper transport into the skin, likely
due to the chitosan interacting with negative charges of the skin [38].
In addition, the same group evaluated the iontophoresis of ~175 nm
doxorubicin-loaded solid lipid nanoparticles (DOX-SLNs) through the
skin. They hypothesized that encapsulating doxorubicin in SLNs would
enable deeper transport into the skin. Fifteen times less doxorubicin
was found in the stratum corneum using DOX-SLNs compared to the
water formulation of doxorubicin; however, there was a two-fold improvement in transport of doxorubicin to deeper parts of the skin using
DOX-SLNs compared to the water formulation of doxorubicin [39]. The
antitumor potential was evaluated in a mouse model of SCC. The iontophoretic delivery of DOX-SLNs showed significantly improved tumor
growth inhibition over 21 days compared to the water formulation of
doxorubicin and no treatment [40].
Photodynamic therapy involves the transdermal administration of
5-aminolevulinic acid (ALA), an amino acid necessary in the porphyrin
synthesis pathway that leads to the accumulation of Protoporphyrin IX
and, ultimately, tumor cell death. Transport of ALA significantly affects
the efficacy of this therapy. Iontophoresis was tested to improve penetration depth and quantity of ALA delivered, and it was found that
ALA was delivered at significantly higher concentrations using iontophoresis compared to passive diffusion [41]. The impact of ALA formulation composition, ionic strength, and ALA esters on iontophoresis
were subsequently tested. It was found that reducing the concentration
of sodium chloride in the ALA formulation improved ALA transport
[42]. Among the ALA esters, the methyl ester significantly improved
(~50-fold) ALA delivery compared to the ethyl, butyl, hexyl, and octyl
esters. Size and lipophilicity were directly related to transport [43].
ALA and the methyl ester formulated in a gel were also evaluated for
drug transport [44]. The quantity of ALA delivery by iontophoresis over
10 min was the same as passive diffusion over 6.5 h [45]. Lastly, permeation enhancers, including YAG laser, were evaluated in combination with the iontophoretic delivery of ALA. It was found that the use of
a YAG laser significantly enhanced the iontophoretic delivery of ALA by
up to 246-fold compared to skin permeation across intact skin [46].
In addition to chemotherapies and ALA, the iontophoresis of cancer
vaccines and immunotherapies have been explored. The iontophoresis
of nanogels containing gp-100 peptide KVPRNQDWL have been evaluated for potential use as a component of anti-cancer vaccines and were
found to improve transport of the nanogels into the superficial layer of
the skin, as well as accumulation of Langerhans cells. Efficacy of the
treatment was tested in immunocompetent mice with melanoma. After
Fig. 2. Patient with BCC of the face treated with cisplatin delivered iontophoretically. (A) Pre-treatment image of a 2.9 × 2.0 cm facial lesion. (B) Lesion
after 3 treatments. (C) Resolved lesion 10 months after completion of treatment.
Used with permission from references [32].
clinical and clinical studies for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) [10, 29–35]. The iontophoretic delivery of
5-FU has been evaluated for the treatment of SCC in situ in 26 patients.
Eight discrete treatments were performed over 4 weeks, with 25 of 26
patients having no clinical or histologic evidence of residual SCC in situ
3 months after the last treatment [30]. The use of transdermal iontophoresis of cisplatin was evaluated in patients with BCC and SCC; these
patients experienced improvement in pain and onset of healing. Fig. 2
shows the treatment response of BCC on the face of a patient after
cisplatin iontophoresis [32]. Another group used local iontophoretic
delivery of cisplatin for residual lesions on the eyelid and periorbital
region after systemic doxorubicin therapy, which resulted in partial
remission of the lesions [36, 37]. Additional clinical reports that
showcase the effectiveness of transdermal iontophoresis involve
147
Journal of Controlled Release 284 (2018) 144–151
J.D. Byrne et al.
3 treatments every 3 days, mice treated with the iontophoresis of the
nanogels experienced significant tumor growth inhibition compared to
no treatment [47]. The iontophoresis of CpG-oligodeoxynucleotides
(CpG-ODN) was tested in a mouse model of melanoma and was found to
result in significant tumor growth inhibition [48]. Others have evaluated the delivery of antisense oligonucleotide-dendrimer complexes
and oligonucleotides for gene silencing of skin cancers [49, 50].
3.2. Transpapillary
The concept of transpapillary administration of cancer therapeutics
was developed to treat ductal carcinoma in situ (DCIS) while limiting
systemic drug exposure [51]. Iontophoretic devices were generated for
the transpapillary delivery of the antiestrogen drug, miproxifen phosphate (TAT-59), and the dephosphorylated metabolite miproxifen (DPTAT-59). TAT-59 concentrations delivered by iontophoresis were found
to be significantly higher than passive diffusion in rat in vitro skin
studies. In a canine in vivo study, TAT-59 tissue concentrations were
compared after 5 daily iontophoretic treatments and 14 days after oral
delivery. Drug exposure as a function of area under the curve was found
to be 3-fold larger for iontophoresis compared to oral administration
[52]. Iontophoretic devices offer non-invasive routes for transpapillary
drug delivery that can lead to higher drug concentrations in the
mammary ducts for treatment of DCIS.
3.3. Intravesical
Fig. 3. Depiction of the iontophoretic foley catheter for intravesical delivery.
Used with permission from reference [63].
Non-muscle invasive bladder cancer (NMIBC) is primarily treated
with transurethral resection of the bladder tumor (TURBT). For patients
treated with a TURBT, the 2-year recurrence risk is slightly over 50%.
To reduce recurrences, patients may also undergo intravesical instillation of drugs, including mitomycin C (MMC), after TURBT.
Unfortunately, the penetration of MMC into the bladder mucosa is
somewhat limited. The iontophoretic delivery of MMC into the bladder
wall has been tested as a potential adjunct treatment to reduce recurrences [53–64].
The initial study using this technology evaluated the iontophoretic
delivery of methylene blue dye into canine bladder wall compared to
passive diffusion. A Foley catheter was designed with an electrode
(anode) distal to the balloon. Two skin electrodes (cathodes) were
placed on the abdomen of the dogs. The bladders were filled with
methylene blue solution, and current was applied (pulsed) for a total of
40 min. After treatment, the bladders were immediately removed and
frozen. Methylene blue was found deeper in the submucosa and the
muscularis after the application of a current compared to passive diffusion. This study established the potential for iontophoresis as a
treatment of bladder disorders [53].
Iontophoresis of MMC was subsequently compared to passive diffusion in ex vivo human bladder tissue. Using a diffusion cell, the iontophoretic transport of MMC was evaluated in human bladder tissue
and compared to passive diffusion over a treatment period of 15 min.
MMC delivered by iontophoresis was found to be 21.5 μg/g (mean),
which was significantly greater than passive diffusion (3.4 μg/g, mean)
[54]. Further studies by the same group evaluated duration of current
applied and depth of MMC transport compared to passive diffusion. The
concentration of drug delivered into bladder wall plateaued at 15 min
of applied current and was similar in quantity to 30, 45, and 60 min.
When current was applied at 30 min, there was at least 4-fold greater
concentration of drug transported into the different layers of bladder
wall compared to passive diffusion [55]. These studies showcased the
ability to deliver MMC deep into the bladder wall, which was an improvement above the standard drug instillation.
The utility of iontophoresis of MMC for NMIBC was next evaluated
in clinical trials [56–58]. Twenty-eight patients were administered 8
weekly treatments of either iontophoretically delivered mitomycin C
for 20 min or intravesical mitomycin C (passive diffusion) instilled for
approximately 2 h [56]. Fig. 3 demonstrates the device and device setup
used in clinical practice [63]. Of the patients treated with iontophoresis, 6 of 15 patients (40%) experienced a pathologic complete response
(pCR), which was similar to passive diffusion with 5 of 12 patients
(41.6%) demonstrating a pCR. Among patients that had a pCR, patients
treated with iontophoresis recurred at a rate of 33% versus 60% in
patients who received passive diffusion after 6 and 7.6 months, respectively [56]. In another study, patients with recurrent bladder carcinoma in situ were treated with photodynamic therapy after ALA was
driven into the bladder wall by iontophoresis. After administration of
the ALA, the bladder was treated with a laser at a wavelength of
632 nm. In follow-up, 5 of the 6 patients were disease-free at
10 months, and 1 patient developed a recurrence at 10 months [57].
Although the sample sizes of these studies were very small, the data
justified additional prospective study in superficial bladder cancer.
There were multiple prospective trials testing the iontophoresis of
MMC after a TURBT. In one of the initial prospective trials, the iontophoresis of MMC was compared to passive diffusion of MMC and BCG
therapy. The treatment regimen involved 6 weekly doses of intravesical
MMC therapy and then monthly maintenance doses up to 1 year. At
6 months, the percentage of patients with pCR was 58%, 31%, and 64%
for iontophoresis of MMC, passive diffusion of MMC, and BCG, respectively. The median time to recurrence was 35, 19.5, and 26 months
for iontophoresis of MMC, passive diffusion of MMC, and BCG, respectively [59]. Results of this study suggested that the iontophoresis of
MMC was a reasonable alternative in patients unable to receive BCG. In
a different prospective trial, an alternating regimen of iontophoresis of
MMC and intravesical BCG (3 cycles of 2 weekly treatments of BCG
followed by 1 treatment of the iontophoretic delivery of MMC) was
compared to BCG alone (6 weekly treatments). Both treatment groups
were given maintenance therapy for up to 1 year. In patients treated
with alternating iontophoresis of MMC and BCG experienced a diseasefree survival of 69 months compared to 21 months for BCG alone. In
addition, patients treated with alternating iontophoresis of MMC and
BCG had lower recurrence rates (41.9% versus 57.9%) and diseasespecific mortality (5.6% versus 16.2%) compared to BCG alone [60].
148
Journal of Controlled Release 284 (2018) 144–151
J.D. Byrne et al.
multiple agents simultaneously using a single device. Multiple groups
have evaluated the co-iontophoresis of drugs to improve management
of pancreatic cancer, chemotherapy-induced nausea, and head and neck
cancer [70, 71, 73, 74].
Taking advantage of the implanted device for pancreatic cancer, the
iontophoresis of the FOLFIRINOX regimen was tested in the orthotopic
PDX model as mentioned previously [70, 71]. The effect of drug formulation on the electro-transport of the FOLFIRINOX regimen was
tested prior to the evaluation of efficacy. Three different formulations
were tested with varying number of drugs per solution, and it was found
that a 2-drug cocktail enabled better delivery of the drugs compared to
a 4-drug cocktail or individual drugs [70]. It was concluded that electrolyte concentration in the formulation directly impacts drug transport.
Chemotherapy-induced nausea is a significant problem encountered
during administration of chemotherapy. The transdermal iontophoretic
delivery of multiple anti-emetics (granisetron, metoclopramide, and
dexamethasone) were tested to reduce chemotherapy-induced nausea.
They demonstrated that high concentrations of drug could be achieved
with delivery rates of 0.5, 3.3, and 2.0 μg*cm−2*min−1 for granisetron,
metoclopramide, and dexamethasone respectively, through the skin of
rats [73].
The co-iontophoresis of 5-FU and leucovorin was also evaluated for
head and neck cancers. Iontophoresis was tested in bovine mucosa and
was found to increase the delivery of 5-FU (8-fold increase) and leucovorin (3-fold increase) compared to passive diffusion [74]. In conclusion, co-iontophoresis can be successfully used to deliver multiple
drug simultaneously.
The utility of the iontophoresis of MMC has also been investigated
before TURBT. Patients treated with iontophoresis of MMC compared to
passive diffusion had lower recurrence rates (38% versus 59%) and
disease-free survival (52 months versus 16 months) [61]. Despite these
results, the adoption of the iontophoresis of MMC has been slow.
3.4. Transscleral
Systemic chemotherapy is one of the primary treatments for bilateral retinoblastoma. However, it is often not sufficient to induce a
complete response and is used in combination with cryoablation or
laser ablation if vision cannot be preserved [65]. There also exists the
concern for an increased risk of secondary tumors caused by chemotherapy in patients with RB1 mutations [66]. To reduce these effects,
multiple groups have compared local iontophoretic administration of
carboplatin to the eye to systemic administration in pre-clinical animal
models [65–67].
The transscleral iontophoresis of carboplatin was tested in mouse
models of retinoblastoma. Dose escalation of carboplatin concentration,
including 1.4, 7.0, 10.0, or 14.0 mg/mL, was evaluated using twice
weekly treatments over 3 weeks. These studies were compared to a no
current control, and inhibition of the tumor was found after multiple
iontophoretic treatments. There was minimal to no ocular toxicity up to
10 mg/mL carboplatin [67]. Furthermore, their team studied the
pharmacokinetics of the iontophoretic administration of carboplatin
after a single treatment in rabbits. Iontophoretic delivery of carboplatin
resulted in higher concentrations in ocular tissue and optic nerve
compared to IV delivery. Again, there was no evidence of ocular toxicity after iontophoretic delivery [68]. Additional evaluation of carboplatin delivery via a hydrogel-iontophoresis system did not result in
improved delivery compared to passive diffusion [69].
5. Challenges for clinical translation
There are many different challenges to the successful translation of
iontophoretic devices, including depth of drug transport, toxicity, location of tumor, and transport of large molecules. From our own data,
gemcitabine was found up to 1 cm away from the electrode in canine
pancreatic tissue. However, the quantity of drug at that distance away
may be subtherapeutic [11]. In addition, another group demonstrated
the distance of mitomycin C transport was greater than 4 mm into the
bladder wall [54]. Passive diffusion plays an additional role in drug
transport away from the device. Drug delivery in large, bulky tumors
may be a significant challenge that will need to be investigated.
Additional barriers to successful translation include toxicity to
normal tissue and location of tumor. Iontophoretic devices are able to
administer large concentrations of drugs to the local area around the
device and, thus, normal tissue nearby may be impacted. Toxicity
profiles will need to be evaluated, especially in sensitive or vital areas.
For example, the delivery of drugs directly into the pancreas raises the
concern for pancreatitis [75]. In addition, the location of the tumor
plays a role in accessibility. If the device is unable to be positioned for
optimal delivery, the full utility of the device may not be realized.
Lastly, the list of drug candidates for iontophoresis is limited by size
and potency. Antibodies, large molecules, and nanoparticles are particularly challenging to deliver [76]. The voltage required for delivery of
these agents is limited by normal tissue toxicity. In addition, compounds that require very high concentrations to be effective may not be
useful. Other strategies to increase drug concentration may be needed
to enhance efficacy [13].
3.5. Peri-pancreatic
Systemic chemotherapy has been minimally successful in controlling pancreatic tumor growth as a result of poor drug transport into
pancreatic tumors. Implantable iontophoretic devices were developed
for implantation directly onto pancreatic tumors. Initial device studies
involved single treatments performed in ex vivo patient-derived xenograft (PDX) tumors, showing a dose-dependent relationship between
concentration of gemcitabine in the device and gemcitabine delivered.
The efficacy of the iontophoretic devices was tested in an orthotopic
PDX mouse model. Devices were implanted directly on orthotopic tumors and resided on the tumors for up to 2 months, as seen in Fig. 4A
and B. Biweekly device treatments for 7 weeks with iontophoresis of
gemcitabine demonstrated significant tumor shrinkage (mean log2-fold
change in tumor volume of −0.8) compared to tumor growth in IV
gemcitabine, IV saline, and device saline groups (mean log2-fold change
in tumor volume of 1.1, 3.0, and 2.6, respectively) (Fig. 4C). The iontophoretic delivery of gemcitabine was subsequently tested in dogs
demonstrating a significantly higher local concentration of drug delivered (7-fold difference) and lower systemic drug level compared to drug
delivered by IV [11].
Furthermore, delivery of the drug regimen known as FOLFIRINOX
(folinic acid, fluorouracil, irinotecan, and oxaliplatin) was evaluated in
the same orthotopic PDX model [70, 71]. It was found that the iontophoresis of FOLFIRINOX resulted in tumor regression in 50% of the
mice treatment compared to 0% of mice treated with IV FOLFIRINOX
after 7 weeks of weekly treatment [71]. This iontophoretic device made
possible the local delivery of multiple agents to pancreatic tumors.
6. Conclusion
Iontophoresis can potentially offer a local drug delivery approach
resulting in high concentrations of anti-cancer drugs in the areas of
greatest need. Simultaneous delivery of multiple different drugs is also
feasible using iontophoresis. It may become a treatment option for
certain cancers, including retinoblastoma, skin, bladder, and pancreatic
cancers. The translation of iontophoretic devices is contingent on
4. Co-iontophoresis of chemotherapies
Current cancer therapy relies heavily on the delivery of multiple
agents for synergistic benefit to improve efficacy and reduce drug resistance [72]. Iontophoresis provides an opportunity for delivery of
149
Journal of Controlled Release 284 (2018) 144–151
J.D. Byrne et al.
Fig. 4. Iontophoretic delivery of gemcitabine through devices
implanted on orthotopic pancreatic tumors. (A) Images of the
device. (B) The setup for device delivery where the device
(anode) and the counter electrode (cathode) were connected
to an external power supply. (C) The efficacy of the iontophoretic device treatments were tested in orthotopic PDX
mice. Data are fold change in tumor volume (log2). Adapted
with permission from reference [11].
finding the right situation where the device can add benefit over current therapies.
[11] J.D. Byrne, M.R. Jajja, A.T. O'Neill, L.R. Bickford, A.W. Keeler, N. Hyder,
K. Wagner, A. Deal, R.E. Little, R.A. Moffitt, C. Stack, M. Nelson, C.R. Brooks,
W. Lee, J.C. Luft, M.E. Napier, D. Darr, C.K. Anders, R. Stack, J.E. Tepper,
A.Z. Wang, W.C. Zamboni, J.J. Yeh, J.M. Desimone, Local iontophoretic administration of cytotoxic therapies to solid tumors, Sci. Trans. Med. 7 (2015) 273ra14.
[12] Y.N. Kalia, A. Naik, J. Garrison, R.H. Guy, Iontophoretic drug delivery, Adv. Drug
Deliv. Rev. 27 (2004) 619–658.
[13] R.H. Guy, Interview with Richard H guy by Hannah Coaker, Ther. Deliv. 5 (2014)
123–128.
[14] A. Fanelli, M.C. Sorella, J.E. Chelly, Iontophoretic transdermal fentanyl for the
management of acute perioperative pain in hospitalized patients, Expert. Opin.
Pharmacother. 17 (2016) 571–577.
[15] M.C. Edmondson, R. Day, D. Wood, Vancomycin iontophoresis of allograft bone,
Bone Joint Res. 3 (2014) 101–107.
[16] L. Runeson, E. Haker, Iontophoresis with cortisone in the treatment of lateral epicondylalgia (tennis elbow)–a double-blind study, Scand. J. Med. Sci. Sports 12
(2002) 136–142.
[17] S. Baswan, G.B. Kasting, S.K. Li, R. Wickett, B. Adams, S. Eurich, R. Schamper,
Understanding the formidable nail barrier: a review of the nail microstructure,
composition and diseases, Mycoses 60 (2017) 284–295.
[18] J.A. Scott, A.K. Banga, Cosmetic devices based on active transdermal technologies,
Ther. Deliv. 6 (2015) 1089–1099.
[19] M. Yu, I.F. Tannock, Targeting tumor architecture to favor drug penetration: a new
weapon to combat chemoresistance in pancreatic cancer? Cancer Cell 21 (2012)
327–329.
[20] V.P. Chauhan, T. Stylianopoulos, Y. Boucher, R.K. Jain, Delivery of molecular and
nanoscale medicine to tumors: transport barriers and strategies, Annu. Rev. Chem.
Biomol. Eng. 2 (2011) 281–298.
[21] J.K. Saggar, M. Yu, Q. Tan, I.F. Tannock, The tumor microenvironment and strategies to improve drug distribution, Front. Oncol. 3 (2013) 154.
[22] J.Y. Fang, W.R. Lee, S.C. Shen, Y.P. Fang, C.H. Hu, Enhancement of topical 5-aminolaevulinic acid delivery by erbium:YAG laser and microdermabrasion: a comparison with
iontophoresis and electroporation, Br. J. Dermatol. 151 (2004) 132–140.
[23] M.S. Highley, A.T. van Oosterom, R.A. Maes, E.A. De Bruijn, Intravesical drug delivery. Pharmacokinetic and clinical considerations, Clin. Pharmacokinet. 37 (1999)
59–73.
[24] H. Zargar, J. Aning, J. Ischia, A. So, P. Black, Optimizing intravesical mitomycin C
therapy in non-muscle-invasive bladder cancer, Nat. Rev. Urol. 11 (2014) 220–230.
[25] R.H. Guy, Y.N. Kalia, M.B. Delgado-Charro, V. Merino, A. Lopez, D. Marro,
Iontophoresis: electrorepulsion and electroosmosis, J. Control. Release 64 (2000)
129–132.
[26] V. Merino, A. Lopez, Y.N. Kalia, R.H. Guy, Electrorepulsion versus electroosmosis:
effect of pH on the iontophoretic flux of 5-fluorouracil, Pharm. Res. 16 (1999)
758–761.
Acknowledgements and funding information
J.D.B. was supported by the UNC Medical Scientists Training
ProgramNIGMS-2-T32-GM008719, and PhRMA Foundation Fellowship.
Conflicts of interest
J.D.B., J.J.Y., and J.M.D. hold equity in the start-up company,
Advanced Chemotherapy Technologies L.L.C.
References
[1] R.L. Siegel, K.D. Miller, A. Jemal, Cancer statistics, 2018, CA-A Cancer J. Clin. 68
(2018) 7–30.
[2] C.R. Ferrone, M.F. Brennan, M. Gonen, D.G. Coit, Y. Fong, S. Chung, L. Tang,
D. Klimstra, P.J. Allen, Pancreatic adenocarcinoma: the actual 5-year survivors, J.
Gastrointest. Surg. 12 (2008) 701–706.
[3] S. Gillen, T. Schuster, C. Meyer Zum Büschenfelde, H. Friess, J. Kleeff,
Preoperative/neoadjuvant therapy in pancreatic cancer: A systematic review and
meta-analysis of response and resection percentages, PLOS Med. 7 (2010)
e1000267.
[4] M.F. Berry, Esophageal cancer: staging system and guidelines for staging and
treatment, J. Thorac. Dis. 6 (2014) S289–S297.
[5] S. Lin, K. Hoffmann, P. Schemmer, Treatment of hepatocellular carcinoma: A
systematic Review, Liver Cancer 1 (2012) 144–158.
[7] C. Laroche, F. Wells, R. Coulden, S. Stewart, M. Goddard, E. Lowry, A. Price, D. Gilligan,
Improving surgical resection rate in lung cancer, Thorax 53 (1998) 445–449.
[8] S. Msika, M.A. Tazi, A.M. Benhamiche, C. Couillault, M. Harb, J. Faivre,
Population-based study of diagnosis, treatment and prognosis of gastric cancer, Br.
J. Surg. 84 (1997) 1474–1478.
[9] H. Suit, S. Goldberg, A. Niemierko, M. Ancukiewicz, E. Hall, M. Goitein, W. Wong,
H. Paganetti, Secondary carcinogenesis in patients treated with radiation: a review
of data on radiation induced cancers in human, non-human primate, canine and
rodent subjects, Radiat. Res. 167 (2007) 12–42.
[10] J.B. Wolinsky, Y.L. Colson, M.W. Grinstaff, Local drug delivery strategies for
cancer treatment: gels, nanoparticles, polymeric films, rods, and wafers, J.
Control. Release 159 (2012) 14–26.
150
Journal of Controlled Release 284 (2018) 144–151
J.D. Byrne et al.
(1996) 1496–1501.
[54] S.M. Di Stasi, G. Vespasiani, A. Giannantoni, R. Massoud, S. Dolci, F. Micali,
Electromotive delivery of mitomycin C into human bladder wall, Cancer Res. 57
(1997) 875–880.
[55] S.M. Di Stasi, A. Giannantoni, R. Massoud, S. Dolci, P. Navarra, G. Vespasiani, R.L.,
Stephen, electromotive versus passive diffusion of mitomycin C into human bladder
wall: concentration-depth profiles studies, Cancer Res. 59 (1999) 4912–4918.
[56] M. Brausi, B. Campo, G. Pizzocaro, P. Rigatti, A. Parma, G. Mazza, A. Vicini,
R.L. Stephen, Intravesical electromotive administration of drugs for treatment of
superficial bladder cancer: a comparative phase II study, Urology 51 (1998)
506–509.
[57] A. Stenzl, I. Eder, H. Kostron, H. Klocker, G. Bartsch, Electromotive diffusion (EMD)
and photodynamic therapy with delta-aminolaevulinic acid (delta-ALA) for superficial bladder cancer, J. Photochem. Photobiol. B 36 (1996) 233–236.
[58] C.R. Riedl, M. Knoll, E. Plas, H. Pfluger, Intravesical electromotive drug administration technique: preliminary results and side effects, J. Urol. 159 (1998)
1851–1856.
[59] S.M. Di Stasi, A. Giannantoni, R.L. Stephen, G. Capelli, P. Navarra, R. Massoud,
G. Vespasiani, Intravesical electromotive mitomycin C versus passive transport
mitomycin C for high-risk superficial bladder cancer: a prospective randomized
study, J. Urol. 170 (2003) 777–782.
[60] S.M. Di Stasi, A. Giannantoni, G. Arcangelo, M. Valenti, G. Zampa, L. Storti,
F. Attisani, A. De Carolis, G. Capelli, G. Vespasiani, R.L. Stephen, Sequential BCG
and electromotive mitomycin versus BCG alone for high-risk superficial bladder
cancer: a randomized controlled trial, Lancet Oncol. 7 (2006) 43–51.
[61] S.M. Di Stasi, M. Valenti, C. Verri, E. Liberati, A. Giurioli, G. Leprini, F. Masedu,
A.R. Ricci, F. Micali, G. Vespasiani, Electromotive instillation of mitomycin immediately before transurethral resection for patients with primary urothelial nonmuscle invasive bladder cancer: a randomised controlled trial, Lancet Oncol. 12
(2011) 871–879.
[62] S.M. Di Stasi, L. Storti, A. Giurioli, G. Zampa, E. Liberati, M. Sciarra, B. Iorio,
R.L. Stephen, Carcinoma in situ of the bladder: long-term results of a randomized
prospective study comparing intravesical electromotive mitomycin-C, passive diffusion mitomycin-C and Bacillus Calmette-Guerin, Eur. Urol. Suppl. 7 (2008) 180.
[63] S.M. Di Stasi, C. Riedl, Updates in intravesical electromotive drug administration of
mitomycin-C for non-muscle invasive bladder cancer, World J. Urol. 27 (2009)
325–330.
[64] C. Gan, S. Amery, K. Chatterton, M.S. Khan, K. Thomas, T. O'Brien, Sequential
bacillus Calmette-Guérin/electromotive drug Administration of Mitomycin C as the
standard Intravesical regimen in high risk nonmuscle invasive bladder cancer: 2year outcomes, J. Urol. 195 (2016) 1697–1703.
[65] Y.A. Yousef, S.E. Soliman, P.P. Astudillo, P. Durairaj, H. Dimaras, H.S. Chan,
E. Héon, B.L. Gallie, F. Shaikh, Intra-arterial chemotherapy for retinoblastoma: a
systematic review, JAMA Ophthalmol. 134 (2016) 584–591.
[66] P. Temming, M. Arendt, A. Viehmann, L. Eisele, C.H. Le Guin, M.M. Schündeln,
E. Biewald, K. Astrahantseff, R. Wieland, N. Bornfeld, W. Sauerwein, A. Eggert,
K.H. Jöckel, D.R. Lohmann, Incidence of second cancers after radiotherapy and
systemic chemotherapy in heritable retinoblastoma survivors: a report from the
German reference center, Pediatr. Blood Cancer 64 (2017) 71–80.
[67] B. Hayden, M.E. Jockovich, T.G. Murray, M.T. Kralinger, M. Voigt, E. Hernandez,
W. Feuer, J.M. Parel, Iontophoretic delivery of carboplatin in a murine model of
retinoblastoma, Invest. Ophthalmol. Vis. Sci. 47 (2006) 3717–3721.
[68] B.C. Hayden, M.E. Jockovich, T.G. Murray, M. Voigt, P. Milne, M. Kralinger,
W.J. Feuer, E. Hernandez, J.M. Parel, Pharmacokinetics of systemic versus focal
carboplatin chemotherapy in the rabbit eye: possible implication in the treatment of
retinoblastoma, Invest. Ophthalmol. Vis. Sci. 45 (2004) 3644–3649.
[69] E. Eljarrat-Binstock, A.J. Domb, F. Orucov, A. Dagan, J. Frucht-Pery, J. Pe'Er, In
vitro and in vivo evaluation of carboplatin delivery to the eye using hydrogeliontophoresis, Curr. Eye Res. 33 (2008) 269–275.
[70] J.D. Byrne, M.R. Jajja, A.T. O'Neill, A.N. Schorzman, A.W. Keeler, J.C. Luft,
W.C. Zamboni, J.M. Desimone, J.J. Yeh, Impact of formulation on the iontophoretic
delivery of the FOLFIRINOX regimen for the treatment of pancreatic cancer, Cancer
Chemo. Pharm. 81 (2018) 991–998.
[71] J.D. Byrne, M.R. Jajja, A.N. Schorzman, A.W. Keeler, J.C. Luft, W.C. Zamboni,
J.M. DeSimone, J.J. Yeh, Iontophoretic device delivery for the localized treatment
of pancreatic ductal adenocarcinoma, Proc. Natl. Acad. Sci. U. S. A. 113 (2016)
2200–2205.
[72] J. Wheler, J.J. Lee, R. Kurzrock, Unique molecular landscapes in cancer: implications for individualized, curated drug combinations, Cancer Res. 74 (2014)
7181–7184.
[73] J. Cázares-Delgadillo, A. Ganem-Rondero, V. Merino, Y.N. Kalia, Controlled transdermal iontophoresis for poly-pharmacotherapy: simultaneous delivery of granisetron, metoclopramide and dexamethasone sodium phosphate in vitro and in vivo,
Eur. J. Pharm. Sci. 85 (2016) 31–38.
[74] T. Gratieri, Y.N. Kalia, Targeted local simultaneous iontophoresis of chemotherapeutics for topical therapy of head and neck cancers, Int. J. Pharm. 460 (2014)
24–27.
[75] M. Manohar, A.K. Verma, S.U. Venkateshaiah, N.L. Sanders, A. Mishra, Pathogenic
mechanisms of pancreatitis, World J Gastrointest Pharmacol Ther. 8 (2017) 10–25.
[76] R.H. Guy, Y.N. Kalia, M.B. Delgado-Charro, V. Merino, A. Lopez, D. Marro,
Iontophoresis: electrorepulsion and electroosmosis, J. Control. Release 64 (2000)
129–132.
[27] J. Hirvonen, Y.N. Kalia, R.H. Guy, Transdermal delivery of peptides by iontophoresis: structure, mechanism and feasibility, Nat. Biotechnol. 14 (1996)
1710–1713.
[28] M. Roustit, S. Blaise, J.L. Cracowski, Trials and tribulations of skin iontophoresis in
therapeutics, Br. J. Clin. Pharmacol. 77 (2014) 63–71.
[29] J.Y. Fang, C.F. Hung, Y.P. Fang, T.F. Chan, Transdermal iontophoresis of 5-fluorouracil combined with electroporation and laser treatment, Int. J. Pharm. 270
(2004) 241–249.
[30] M.L. Welch, W.J. Grabski, M.L. McCollough, H.G. Skelton, K.J. Smith, P.A. Menon,
L.L. Anderson, 5-fluorouracil iontophoretic therapy for Bowen's disease, J. Am.
Acad. Dermatol. 36 (1997) 956–958.
[31] N.S. Chandrashekar, R.H. Shobha Rani, Microprocessor-controlled iontophoretic
drug delivery of 5-fluorouracil: pharmacodynamic and pharmacokinetic study, J.
BUON 12 (2007) 529–534.
[32] B.K. Chang, T.H. Guthrie Jr., K. Hayakawa, L.P. Gangarosa Sr., A pilot study of
iontophoretic cisplatin chemotherapy of basal and squamous cell carcinomas of the
skin, Arch. Dermatol. 129 (1993) 425–427.
[33] T.R. Bacro, E.B. Holladay, M.J. Stith, J.C. Maize, C.M. Smith, Iontophoresis treatment of basal cell carcinoma with cisplatin: a case report, Cancer Detect. Prev. 24
(2000) 610–619.
[34] T. Tsuji, Bleomycin iontophoresis therapy for verrucous carcinoma, Arch. Dermatol.
127 (1991) 973–975.
[35] K.J. Smith, J.L. Konzelman, F.A. Lombardo, H.G. Skelton 3rd, T.T. Holland,
J. Yeager, K.F. Wagner, C.N. Oster, R. Chung, Iontophoresis of vinblastine into
normal skin and for treatment of Kaposi's sarcoma in human immunodeficiency
virus-positive patients. The Military Medical Consortium for Applied Retroviral
Research, Arch. Dermatol. 128 (1992) 1365–1370.
[36] M.N. Luxenberg, T.H. Guthrie Jr., Chemotherapy of eyelid and peritorbital tumors,
Trans. Am. Ophthalmol. Soc. 83 (1985) 162–180.
[37] M.N. Luxenberg, T.H. Guthrie Jr., Chemotherapy of basal cell and squamous cell
carcinoma of the eyelids and periorbital tissues, Ophthalmology 93 (1986)
504–510.
[38] S.F. Taveira, A. Nomizo, R.F. Lopez, Effect of the iontophoresis of a chitosan gel on
doxorubicin skin penetration and cytotoxicity, J. Control. Release 134 (2009)
35–40.
[39] S.F. Taveira, D.C. De Santana, L.M. Araújo, F. Marquele-Oliveira, A. Nomizo,
R.F. Lopez, Effect of iontophoresis on topical delivery of doxorubicin-loaded solid
lipid nanoparticles, J. Biomed. Nanotechnol. 10 (2014) 1382–1390.
[40] L.A. Huber, T.A. Pereira, D.N. Ramos, L.C. Rezende, F.S. Emery, L.M. Sobral,
A.M. Leopoldino, R.F. Lopez, Topical skin cancer therapy using doxorubicin-loaded
cationic lipid nanoparticles and iontophoresis, J. Biomed. Nanotechnol. 11 (2015)
1975–1988.
[41] R.F. Lopez, M.V. Bentley, M.B. Delgado-Charro, R.H. Guy, Iontophoretic delivery of
5-aminolevulinic acid (ALA): effect of pH, Pharm. Res. 18 (2001) 311–315.
[42] R.F. Lopez, M.V. Bentley, M. Begoña Delgado-Charro, R.H. Guy, Optimization of
aminolevulinic acid delivery by iontophoresis, J. Control. Release 88 (2003) 65–70.
[43] R.F. Lopez, M.V. Bentley, M.B. Delgado-Charro, D. Salomon, H. van den Bergh,
N. Lange, R.H. Guy, Enhanced delivery of 5-aminolevulinic acid esters by iontophoresis in vitro, Photochem. Photobiol. 77 (2003) 304–308.
[44] N. Merclin, T. Bramer, K. Edsman, Iontophoretic delivery of 5-aminolevulinic acid
and its methyl ester using a carbopol gel as vehicle, J. Control. Release 98 (2004)
57–65.
[45] H.E. Bodde, P.E.H. Roemele, W.M. Star, Quantification of topically delivered 5aminolevulinic acid by iontophoresis across ex vivo human stratum corneum,
Photochem. Photobiol. 75 (2002) 418–423.
[46] J.Y. Fang, W.R. Lee, S.C. Shen, Y.P. Fang, C.H. Hu, Enhancement of topical 5aminolaevulinic acid delivery by erbium:YAG laser and microdermabrasion: a
comparison with iontophoresis and electroporation, Br. J. Dermatol. 151 (2004)
132–140.
[47] M. Toyoda, S. Hama, Y. Ikeda, Y. Nagasaki, K. Kogure, Anti-cancer vaccination by
transdermal delivery of antigen peptide-loaded nanogels via iontophoresis, Int. J.
Pharm. 483 (2015) 110–114.
[48] K. Kigasawa, K. Kajimoto, T. Nakamura, S. Hama, K. Kanamura, H. Harashima,
K. Kogure, Noninvasive and efficient transdermal delivery of CpG-oligodeoxynucleotide for cancer immunotherapy, J. Control. Release 150 (2011) 256–265.
[49] V.V. Vlassov, M.V. Nechaeva, V.N. Karamyshev, L.A. Yakubov, Iontophoretic delivery of oligonucleotide derivatives into mouse tumor, Antisense Res. Dev. 4
(1994) 291–293.
[50] V.V. Venuganti, M. Saraswathy, C. Dwivedi, R.S. Kaushik, O.P. Perumal, Topical
gene silencing by iontophoretic delivery of an antisense oligonucleotide-dendrimer
nanocomplex: the proof of concept in a skin cancer mouse model, Nano 7 (2015)
3903–3914.
[51] V. Stearns, T. Mori, L.K. Jacobs, N.F. Khouri, E. Gabrielson, T. Yoshida,
S.L. Kominsky, D.L. Huso, S. Jeter, P. Powers, K. Tarpinian, R.J. Brown, J.R. Lange,
M.A. Rudek, Z. Zhang, T.N. Tsangaris, S. Sukumar, Preclinical and clinical evaluation of intraductally administered agents in early breast cancer, Sci Transl. Med.
26 (2011) 106ra108.
[52] M. Komuro, K. Suzuki, M. Kanebako, T. Kawahara, T. Otoi, K. Kitazato, T. Inagi,
K. Makino, M. Toi, H. Terada, Novel iontophoretic administration method for local
therapy of breast cancer, J. Control. Release 168 (2013) 298–306.
[53] T. Gürpinar, L.D. Truong, H.Y. Wong, D.P. Griffith, Electromotive drug administration to the urinary bladder: an animal model and preliminary results, J. Urol. 156
151