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Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx – xxx nanomedjournal.com
A novel topical nano-propranolol for treatment of infantile hemangiomas
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Zheng Gang Chen, PhD, MD a, c , Jia Wei Zheng, DDS, MD, FICD a,⁎, Ming Lu Yuan b , Ling Zhang, PhD, MD a , Wei En Yuan, MD b,⁎⁎
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Department of Oromaxillofacial Head and Neck Oncology, Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China b School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China c Department of Oral and Maxillofacial Surgery, Qingdao Municipal Hospital, Shandong, China Received 18 August 2014; accepted 17 February 2015
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Abstract
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Topical propranolol has been used for the therapy of superficial infantile hemangiomas (IH). A retrospective investigation was conducted in 50 patients to evaluate the clinical effect of a new type of topical nano-propranolol-dispersed hydrogel. Participants were treated 3 times per day for 2 weeks to 11 months. 68% of patients were female and 12% had received other treatments before therapy. The nano-propranolol 0.5% hydrogel was initiated at a mean age of 5.010 months and for a mean duration of 3.610 months. The response rate was 86%. No recurrence and rebound growth occurred after withdrawal of hydrogel. Slight side effects (application site itching, erosion and crusting) were observed in only 2 cases. All the local irritations were evaluated as mild and were tolerated without discontinuing the medication. We suggest that topical nano-propranolol hydrogel could be an alternative option for the treatment of uncomplicated superficial IH with satisfactory tolerability and optimal effectiveness. © 2015 Published by Elsevier Inc.
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Key words: Propranolol; Infantile hemangioma; Beta blocker; Topical therapy
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Background
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Infantile hemangiomas (IH) are the most common congenital vascular tumor of infancy with a reported incidence of 5%-10%. 1 The incidence is higher (20%-30%) in extreme low birth weight babies. 2 IH are most prevalent in Caucasian children and are three times more common in female infants than male. The head and neck region is the most frequently involved area (60%), followed by the trunk (25%) and the extremities (15%), and these tumors display a non-random distribution largely correlating with regions of embryological fusion. 3 The natural history of the hemangioma characteristically goes through a rapid proliferating phase in the
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Conflict of interest: None. ⁎ Correspondence to: J.-W. Zheng, Department of Oromaxillofacial Head and Neck Oncology, Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China. ⁎⁎ Correspondence to: W.-E. Yuan, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China. E-mail addresses: [email protected] (J.W. Zheng), [email protected] (W.E. Yuan).
first several months of life followed by a spontaneous involution stage, with slow resolution spanning years. These lesions are usually not present at birth but instead are noted within the first few weeks of life. Precursor lesions are common but often subtle; findings may include telangiectasias, pallor, a bruiselike appearance, and, rarely, ulceration. A residual fibrofatty mass often persists after spontaneous involution of IH. Because of the spontaneous regression and the majority of lesions produce no long-term scarring, most cases require no treatment. However, 10% of IH require treatment during the proliferating phase, 4 for the reason of life-threatening locations, local complications, or cosmetic/functional risks. 5 Since the serendipitous discovery of the efficacy of propranolol in the treatment of IH by Léauté-Labrèze et al, 6 the effectiveness of propranolol for IH of all types has been demonstrated in multiple publications. 7–10 Subsequently, the off-label use of this molecule became the first-line treatment for IH. Hemangeol (propranolol hydrochloride), an oral solution specially developed for safe and effective use in children, was FDA approved in the USA on March 17th, 2014 and marketed as the first and only FDA-approved treatment for proliferating IH requiring systemic therapy currently (http://www.pierre-fabre.com/en/fda-approvalmarket-hemangeoltm).
http://dx.doi.org/10.1016/j.nano.2015.02.015 1549-9634/© 2015 Published by Elsevier Inc. Please cite this article as: Chen Z.G., et al., A novel topical nano-propranolol for treatment of infantile hemangiomas. Nanomedicine: NBM 2015;xx:1-7, http://dx.doi.org/10.1016/j.nano.2015.02.015
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Table 1 Summary of baseline characteristics and treatment of IH.
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Patient characteristics and treatment
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Female-to-male ratio Type of hemangioma Superficial Deep Mixed Location of hemangioma Head and neck Limbs Trunk Periocular Mouth Indication for treatment Cosmetic risk Functional risk Life-threatening Local complication Previous treatment Laser treatment Radiation treatment Other invasive treatment (embolization, surgical excision) Other agents (corticosteroids, vincristine sulfate, cyclophosphamide, interferon) Other topical agents (imiquimod, timolol) Age at initiation of nano-propranolol treatment (months), median (range) Duration of nano-propranolol treatment (months), median (range) Age at end of nano-propranolol treatment (months), median (range)
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Subjects
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This study included patients with IH between January 2013 and February 2014, diagnosed according to the criteria established by the International Society for the Study of Vascular Anomalies (ISSVA). 15 A total of 50 outpatients with superficial IH at the Department of Oral & Maxillofacial Surgery in the Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, China, were enrolled. Those with deep IH were excluded and encouraged to take other treatment (oral
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Nano-propranolol hydrogel was produced by the Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, which contained 0.5% propranolol. Formulation: (1) 40 g glycerol, 16 g polyethylene glycol (Molecular Weight: 400 Da, PEG 400), 5 g sodium benzoate, and 20 g nanoparticles of colloidal silicon dioxide dispersed in 200 ml water, and then 5 g propranolol was added into the above suspension and made the propranolol sufficient for adsorption to nanoparticles of colloidal silicon dioxide; (2) 32 g polyvinyl alcohol (PVA, Molecular Weight: 100,000 Da) and 32 g PVA (Molecular Weight: 40,000 Da) dissolved in 650 ml water; (3) the suspension of 1) was added the solution of 2) and well dispersed. The treatment regimen involved the application of nanopropranolol hydrogel to the lesions 3 times per day for 2 weeks to 11 months. The hydrogel was evenly rubbed onto the surface for 2 ml/cm 2 each time. As a routine, cardiac examination (electrocardiographic and ultrasound echocolor Doppler examination) was performed before treatment. Blood pressure (BP) and heart rate (HR) were measured and recorded. Patients were examined 2 h after treatment and every 1 month during the treatment to monitor the skin response or other side effects of nano-propranolol hydrogel. Drug administration was discontinued when 90% of the lesion disappeared or the treatment duration was over 1 year. Posttreatment evaluations were performed every 3 months. The response was assessed by comparing the status at the start of treatment and at the last appointment. The lesions were photographed at baseline, during treatment, and at each follow-up.
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Clinical definition
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Hemangioma size was recorded using “hemispheric” measurement. 16 A soft tape measure was draped over the lesion, and the longest diameter and a measurement perpendicular to it were recorded, giving a measurement in cm 2. The response was classified as follows: clinical resolution—complete clearance of the lesion, scored 4; excellent—75% to 99% improvement, scored 3; moderate—50% to 74% improvement, scored 2; minimal—25% to 49% improvement, scored 1; failure—b25% improvement, scored 0. 17 The overall efficacy was calculated from the sum of cases that were scored above 2. Local skin responses were as follows: none—scored 0; mild—scored 1 (+, erythematous reaction); moderate—scored 2 (++, erosion or light crusting); severe—scored 3 (+++, ulceration, thick crusting or scarring).
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Results
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Clinical data
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A total of 50 cases were analyzed, 68% (34/50) of which were female and 32% (16/50) male, constituting a female/male ratio of
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Nanotechnology is the latest and fast emerging technology wherein dimension of particle of material is reduced nearly to that of individual molecule or their aggregates. 11 Recently, advances in nanotechnology have provided great opportunities for strategies in tumor treatment. 12–14 To improve the efficacy of drug delivery, nanotechnology-based drug-delivery systems are gaining considerable attention, as they have the potential to reduce side effects, minimize toxicity, and improve antitumor treatment efficacy. We retrospectively analyzed a group of children with IH to identify the therapeutic response and tolerability of a new type medicine, topical nano-propranolol hydrogel. The objective of this study was to assess the efficacy and safety of nano-propranolol hydrogel in the treatment of IH.
Methods
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propranolol). All patients received a physical examination and clinical data were recorded, including sex, age, size and location of the lesion, disease duration, previous history, current therapies, etc. The study was approved by the Ethics Committee of the hospital. Informed consent was obtained from the patients’ guardians prior to the study.
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Among the total 50 patients, an overall efficacy of 86% (43/ 50) was achieved, with a clinical complete clearance rate of 6% (3/50), excellent rate of 74% (37/50), and moderate rate of 6% (3/ 50). No obvious response to the treatment was noted in 7 patients (14%). There were significant fading of color and decrease in size of the IH during the follow-up period compared to the photographs at baseline for the 43 cases (Figures 1, 2, 3, 4). Blanching, softening, and early regression of the lesions started within the first 1 month of treatment. The earliest visible response to treatment varied from 2 weeks to 1 month after initiation of treatment. Even for the case that showed no response to oral propranolol in the involution stage, topical nano-propranolol was effective and devoid of local or systemic side effects (Figure 5). For the 43 patients who showed an effective result from nano-propranolol, the treatment duration varied between 1 and 11 months (3.546 ± 2.390 months).For the other 7 patients without response, the duration was from 0.5 to 11 months
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No severe adverse events were noted in our patients. No bradycardia, hypotension, hypoglycemia, bronchospasm, hyperkalemia, mood disturbances, somnolence, fever, nausea, and diarrhea occurred. Meanwhile, no erythema/edema, peeling, ulceration, and scarring were encountered. However, slight side effects were observed in 4% (2/50) of the IH, including application site itching, erosion and crusting. All the local irritations were evaluated as mild and were tolerated without discontinuing the medication.
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Discussion
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We report here for the first time to our knowledge the apparent efficacy of topical application of nano-propranolol hydrogel in the treatment of IH, and found that it was efficacious and tolerable for superficial IH. Meanwhile, no severe adverse effects were found in our patients. The non-selective β-adrenergic receptor antagonist, propranolol, was introduced as a treatment option for problematic IH in 2008 when distinct improvements in IH lesions in 2 individuals were observed after systemic propranolol was administered for cardiac indications. 6 Since then, numerous subsequent case reports and retrospective analyses have confirmed the beneficial effect of propranolol on IH. 7–10,18,19 Propranolol has become a new first-line treatment in clinic for IH children. Despite the lack of standardized guidelines for propranolol treatment for IH, oral propranolol has been popularly accepted by most clinicians. 20 Given the success of oral propranolol, many practitioners have used topical β-blockers for the management of superficial, localized IH although there are currently no commercially available forms of topical propranolol. Xu et al reported topical therapy with 1% propranolol ointment in 25 children with 28 IH, and among all the IH, 90% showed either good or partial responses to topical propranolol treatment. 21 Kunzi-Rapp treated 45 children with 65 hemangiomas with 1% propranolol in a hydrophilic ointment topically applied twice a day and induced
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(4.000 ± 3.428 months). No recurrence and rebound growth of the hemangioma occurred after withdrawal of nano-propranolol. No patients recommenced treatment after cessation.
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2.125 to 1. The age at the time of the patients’ first treatment ranged from 1 month to 18 months (5.010 ± 3.940 months). The surface area of the patients was 5.812 ± 3.128 cm 2 in average. A total of 47 patients (94%) started treatment at the age of less than one year, while 3 (6%) commenced after completing one year of age. The patients completed treatment at median age of 8.620 ± 4.327 months and after a median treatment duration of 3.610 ± 2.522 months. The relevant epidemiologic and clinic characteristics of the patients and details about the individual treatment indication and duration were shown in Table 1. All the hemangiomas were classified as superficial. With respect to the site of the lesions, 26 were located on the head and neck (52%), 5 on the trunk (10%), 9 on the limbs (18%), 8 on the periocular area (16%) and 2 on the lips (4%). Uncommonly, 4 hemangiomas (8%) extended into N 1 site (for example: shoulder and chest, frontal region and scalp, frontal and temporal region). Forty-four patients had not been treated previously, while 6 presented residual lesions and had been refractory to previous laser (4 IH) and isotope radiation (2 IH) therapy (in other hospitals). The detailed clinical characteristics of these hemangiomas were documented using topical nano-propranolol hydrogel 3 times per day, without oral propranolol intake or any other treatments. No patients had complications before enrollment.
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Figure 1. Case 1. A 5-month old girl presented with a flat hemangioma in the right labium major (A). The tumor regressed nearly completely after topical use of nano-propranolol-dispersed hydrogel for 3 months (B).
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and stratum corneum lipids. There is a requirement for efficient drug delivery systems past this barrier. In this study, propranolol was manufactured in the form of nano-hydrogel which means nanotechnology was used to modify the drug permeation/ penetration by controlling the release of active substances and increasing the period of permanence on the skin. 31 The nanoparticle of propranolol can also ensure a direct contact with the stratum corneum and skin appendages and protect the drug against chemical or physical instability. 32 Nanotechnology has developed a novel transdermal drug delivery method. 33,34 The nanoparticles may ensure close contact with the stratum corneum of skin and increases the adsorbed nanoparticles or encapsulated drug amount penetrating into the skin. The advantages of these kinds of nano-carriers are protection of unstable drugs from degradation and control of drug release rate from these nano-carriers. 32,34,35 Hydrogels have been applied to drug delivery system 36 and can control the release of the drugs in response to environmental stimuli, such as pH, temperature, and enzyme. 37 In this study, we selected polyethylene glycol (PEG) as hydrogel nanoparticle components to ensure its biocompatibilities with skin. The skin penetrations of hydrogel nanoparticles can be enhanced provided that the size of hydrogel nanoparticles is carefully regulated and they are dispersed in a proper medium. It is the most important issue for the hydrogel nanoparticles that the hydrogel nanoparticle should not increase much in their sizes during their delivery into a skin layer, especially when they are dispersed in water. As transdermal drug delivery carriers, our hydrogel nanoparticles are small enough (diameter of 5 to 10 nm) for the nanoparticles to sufficiently penetrate into skin layers. In addition, PEG is both biocompatible and highly water soluble, which can maximize the delivery efficiency of the nanoparticles into the skin.
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regression or stabilized growth in 85% of the hemangiomas within the first 6 months of therapy for the patients in the proliferative phase. 22 Mouhari-Toure et al reported rapid regression of infantile hemangioma with 2% propranolol ointment in a female infant aged 11 weeks. 23 Additionally, an in vivo study demonstrated that topical delivery of propranolol can provide higher drug concentrations in local tissues than oral and intravenous administration. 24 The drug in the tissues was slowly cleared, and significant amounts of the drug were still present at 24 h after topical application. However, intralesional propranolol injection seems safe but is not effective for the treatment of IH. 25 It is possibly because the vehicle of solution (1 mg/ml) was not appropriate for intralesional injection and the dose (0.2 ml/cm2) and number of injections were simply too low although the dose calculation depended on a previous clinical trial that reported successful results. 25 Moreover, intravenous administration of nanoparticles has been proved to be able to induce cardiovascular effects. 26,27 Therefore, topical agents are possible appropriate therapy in some situations (eg, small, thin lesions), and the risks of adverse effects are less with topical rather than systemic agents. Timolol, another β-blocker, was also administered topically and was documented to be effective for IH. 28,29 However, propranolol was proved to be approximately ten times more permeable than timolol across human epidermal membrane (HEM). 30 Furthermore, propranolol could be applied topically at lower concentration than timolol on the hemangioma skin to achieve the same drug concentration at the viable epidermal layer or hemangioma tissue. 30 This could be the possible theoretical basis for the preference of topical propranolol in clinic than topical timolol. The skin forms a barrier to the external environment and is impermeable to the drugs on account of epidermal cell cohesion
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Figure 2. Case 2. A 12-month-old girl presented with superficial cutaneous hemangioma on the left upper eyelid (A). The area of the lesion decreased significantly 10 days (B) and 16 days (C) after hydrogel was applied. 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272
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Figure 3. Case 3. A 2-month-old boy presented with a bulge in the left orbital area (A) and the tumor became flattened 2 months after hydrogel was applied (B).
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would have occurred as a result of spontaneous involution even without treatment; the mean age of 5.010 months at treatment initiation is far younger than when spontaneous involution typically happens, suggesting that the nano-propranolol treatment, not spontaneous involution, is the more relevant explanation. There are some reports on the first dramatic visible and measureable response to oral propranolol treatment on the size and volume of hemangiomas as early as 48 h. 39 In this follow-up study, the patients showed significant regression after 1 month of topical agent administration for the first revisit, suggesting a slower effect of nano-propranolol than oral propranolol. It is because of the function of controlled release of encapsulated active ingredients in nano-propranolol, which needs more time than oral propranolol to diffuse through the polymeric matrix to permeate the skin. On the other hand, the use of nanoscaled carriers in controlled drug delivery system reduced side effects and decreased the dose of administered propranolol simultaneously. The major advantages of topical nano-propranolol treatment are the convenient application, satisfactory tolerability, excellent cosmetic result, and low-recurrence. In patients with a positive response to nano-propranolol hydrogel, there were significant fading of color and significant decrease in size of the IH. Potential explanations include vasoconstriction, which is immediately visible as a change in color, associated with a palpable tissue softening. Other included suggestions are a down-regulation of angiogenetic factors such as VEGF (vascular endothelia growth factor) and bFGF (basic fibroblast growth factor) and an up-regulation of apoptosis of capillary endothelial cells. 6,40 There are also data published which indicate a beneficial effect of propranolol in inhibiting the expression of matrix metalloproteinase 9 (MMP-9). 41 The known side effects of propranolol include bradycardia, hypotension. 41,42 bronchospasm 43, hypoglycemia 41,44, mood disturbances, and somnolence. 45 However, there were no severe or obvious adverse reactions noted during follow-up. With more than 40 years of extensive clinical experience with infants and young children, there is no documented case of death or serious cardiovascular morbidity resulting directly from β-adrenergic receptor blocker exposure. 46 Bronchospasm is usually seen as a
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The female/male ratio was 2.125 to 1 in this patient series, which is in agreement with current literature in which the predominance of hemangiomas in females has been reported. Assessment of the site showed that 52% of the hemangiomas were located on the head and neck, 10% in the trunk, 18% in the limbs, 16% in the periocular area, and 4% in the lips, respectively. Meanwhile, some patients had multiple hemangiomas. The data in our investigation are in accordance with other reports. 38 From this standpoint, our patients could be considered representative for analyzing the effect of nano-propranolol hydrogel on IH. The principal finding of this follow-up study is that 86% of IH patients treated with nano-propranolol hydrogel were deemed to have a positive response to treatment. This kind of topical hydrogel showed high effectiveness in the present study as oral or other topical regular propranolol. 21,22 Although the efficacy of all these researches is similar, the concentration of topical propranolol in our study is 0.5%, half or a quarter of those in previous studies. 21,22 Meanwhile, the mean duration of 14.4 weeks (range, 4-44 weeks, 1 patient treated for 2 weeks was evaluated as failure because no changes occurred and the therapy was required to be ceased by the parents) in our study is far less than that of 21 weeks (range, 5-59 weeks) in a study of regular topical propranolol application. 21 In the group with effective results in our study, the duration was 3.547 ± 2.390 months (range, 1-11 months). The small size of the lesion or the individual sensitivity possibly explains the shorter duration in these patients. But for most cases, the duration is longer around 14 weeks. This suggests the sustained release of nanoparticles in the process of drug delivery with good or excellent efficacy. To the best of our knowledge, there are no data in the international literatures evaluating the effect of topical agent of nanoparticle on IH. During the follow-up period no complications, tumor regrowth, or general growth impairment were observed. Such a high response rate is noteworthy for most medical treatment, and is even more impressive when considering that the patients in this study varied in age at treatment initiation, duration, size, and anatomic site. Despite this it is possible that some improvement
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Figure 4. Case 4. A 12-month-old boy presented with superficial cutaneous hemangioma on the right temporal skin (A). The tumor contracted and flattened after 6 months of treatment (B).
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mild exacerbation in patients with underlying reactive airway diseases; before prescription of propranolol, parents should be questioned about previous atopic disease or episodes of wheezing. Bradycardia is also another side effect of propranolol which requires cardiac examination before the treatment initiation. In this follow-up, ultrasound echocolor Doppler examination is performed for evaluation of patients’ cardiac function as a routine. Our study has few important limitations. Deep or mixed IH were excluded and only superficial type was considered. The efficacy of topical nano-propranolol treatment on deep or mixed IH was unknown. Further investigation should be complemented. Furthermore, treatment response must account for color, surface area, and volume. Various methods to assess response, including serial photographs, visual analog scores, serial measurements, and, at times, ultrasound analysis, should be taken into account. This limitation highlights the requirement for more rigorous scoring tools with high interrater reliability to allow response to be monitored more systematically. To summarize, from the results of the present study, topical nano-propranolol hydrogel appears to be a valuable and effective therapy option for superficial IH as efficacious as oral propranolol. Topical nano-propranolol agent has a welldocumented long-term safety for IH. However, propranolol for hemangiomas is an off-label-indication and the parents have to be well informed and to assent. Our results may provide some insight into the mode of propranolol on IH and other potertial therapeutic applications.
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Figure 5. Case 5. A 17-month-old girl presented with superficial cutaneous hemangioma in the right suborbital region. Oral propranolol at a dose of 2 mg/kg/d in two divided doses was given until 1 year of age, but the lesion didn’t completely regress (A). Nano-propranolol hydrogel was topically administrated 3 times a day, improvement was noted 23 days after topical medication (B), and dramatic improvement was seen 2 months after topical nano-propranolol treatment (C). The patient is still under treatment currently.
Acknowledgments
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The study was supported by National Science Foundation of China (Project No. 81271163 and 81373366).
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Appendix A. Supplementary data
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Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.nano.2015.02.015.
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References
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on the cardiovascular function in healthy mice. Toxicol Appl Pharmacol 2013;266:276-88. Vlasova MA, Tarasova OS, Riikonen J, Raula J, Lobach AS, Borzykh AA, et al. Injected nanoparticles: the combination of experimental systems to assess cardiovascular adverse effects. Eur J Pharm Biopharm 2014;87:64-72. Semkova K, Kazandjieva J. Rapid complete regression of an early infantile hemangioma with topical timolol gel. Int J Dermatol 2014;53:241-2. Yu L, Li S, Su B, Liu Z, Fang J, Zhu L, et al. Treatment of superficial infantile hemangiomas with timolol: evaluation of short-term efficacy and safety in infants. Exp Ther Med 2013;6:388-90. Chantasart D, Hao J, Li SK. Evaluation of skin permeation of β-blockers for topical drug delivery. Pharm Res 2013;30:866-77. Hadgraft J. Skin, the final frontier. Int J Pharm 2001;224:1-18. Guterres SS, Alves MP, Pohlmann AR. Polymeric nanoparticles, nanospheres and nanocapsules, for cutaneous applications. Drug Target Insights 2007;2:147-57. Tomoda K, Terashima H, Suzuki K, Inagi T, Terada H, Makino K. Enhanced transdermal delivery of indomethacin-loaded PLGA nanoparticles by iontophoresis. Colloids Surf B Biointerfaces 2011;88:706-10. Tomoda K, Watanabe A, Suzuki K, Inagi T, Terada H, Makino K. Enhanced transdermal permeability of estradiol using combination of PLGA nanoparticles system and iontophoresis. Colloids Surf B 2012;97:84-9. Tomoda K, Terashima H, Suzuki K, Inagi T, Terada H, Makino K. Enhanced transdermal delivery of indomethacin using combination of PLGA nanoparticles and iontophoresis in vivo. Colloids Surf B 2012;92:50-4. Hamidi M, Azadi A, Rafiei P. Hydrogel nanoparticles in drug delivery. Adv Drug Deliv Rev 2008;60:1638-49. Kopecek J. Hydrogel biomaterials: a smart future? Biomaterials 2007;28:5185-92. Frieden IJ, Eichenfield LF, Esterly NB, Geronemus R, Mallory SB. Guidelines of care for hemangiomas of infancy. J Am Acad Dermatol 1997;37:631-7. Aletaha M, Salour H, Bagheri A, Raffati N, Amouhashemi N. Oral propranolol for treatment of pediatric capillary hemangiomas. J Ophthalmic Vis Res 2012;7:130-3. Léauté-Labrèze C, Taïeb A. Efficacy of beta-blockers in infantile haemangiomas: the physiopathological significance and therapeutic consequences. Ann Dermatol Venereol 2008;135:860-2. Lawley LP, Siegfried E, Todd JL. Propranolol treatment for hemangioma of infancy: risks and recommendations. Pediatr Dermatol 2009;26:610-4. Tan ST, Itinteang T, Leadbitter P. Low-dose propranolol for infantile haemangioma. J Plast Reconstr Aesthet Surg 2011;64:292-9. Sans V, de la Roque ED, Berge J, Grenier N, Boralevi F, MazereeuwHautier J, et al. Propranolol for severe of periocular capillary haemangiomas. Pediatrics 2009;124:e423-31. Holland KE, Frieden IJ, Frommelt PC, Mancini AJ, Wyatt D, Drolet BA. Hypoglycemia in children taking propranolol for the treatment of infantile haemangioma. Arch Dermatol 2010;146:775-8. Buckmiller LM, Richter GT, Suen JY. Diagnosis and management of haemangiomas and vascular malformations of the head and neck. Oral Dis 2010;16:405-18. Love JN, Sikka N. Are 1-2 tablets dangerous? Beta-blocker exposure in toddlers. J Emerg Med 2004;26:309-14.
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6. Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taïeb A. Propranolnol for severe hemangiomas of infancy. N Engl J Med 2008;358:2649-51. 7. Rosbe KW, Suh KY, Meyer AK, Maguiness SM, Frieden IJ. Propranolol in the management of airway infantile hemangiomas. Arch Otolaryngol Head Neck Surg 2010;136:658-65. 8. Mazereeuw-Hautier J, Hoeger PH, Benlahrech S, Ammour A, Broue P, Vial J, et al. Efficacy of propranolol in hepatic infantile hemangiomas with diffuse neonatal hemangiomatosis. J Pediatr 2010;157:340-2. 9. Solomon T, Ninnis J, Deming D, Merritt TA, Hopper A. Use of propranolol for treatment of hemangiomas in PHACE syndrome. J Perinatol 2011;31:739-41. 10. Sagi L, Zvulunov A, Lapidoth M, Ben Amitai D. Efficacy and safety of propranolol for the treatment of infantile hemangioma: a presentation of ninety-nine cases. Dermatology 2014;228:136-44. 11. Venugopal J, Prabhakaran MP, Low S, Choon AT, Zhang YZ, Deepika G, et al. Nanotechnology for nanomedicine and delivery of drugs. Curr Pharm Des 2008;14:2184-200. 12. Peer D, Karp JM, Hong S, Farokhzad OC, Margalit R, Langer R. Nanocarriers as an emerging platform for cancer therapy. Nat Nanotechnol 2007;2:751-60. 13. Ren Y, Wang R, Liu Y, Guo H, Zhou X, Yuan X, et al. A hematoporphyrin-based delivery system for drug resistance reversal and tumor ablation. Biomaterials 2014;35:2462-70. 14. Zhang X, Dong Y, Zeng X, Liang X, Li X, Tao W, et al. The effect of autophagy inhibitors on drug delivery using biodegradable polymer nanoparticles in cancer treatment. Biomaterials 2014;35:1932-43. 15. Werner JA, Dünne AA, Lippert BM, Folz BJ. Optimal treatment of vascular birthmarks. Am J Clin Dermatol 2003;4:745-56. 16. Tansg MW, Garzon MC, Freiden IJ. How to measure a growing hemangioma and assess response to therapy. Pediatr Dermatol 2006;23:187-90. 17. Welsh O, Olazarán Z, Gómez M, Salas J, Berman B. Treatment of infantile haemangiomas with short-term application of imiquimod 5% cream. J Am Acad Dermatol 2004;51:639-42. 18. Kim LH, Hogeling M, Wargon O, Jiwane A, Adams S. Propranolol: useful therapeutic agent for the treatment of ulcerated infantile hemangiomas. J Pediatr Surg 2011;46:759-63. 19. Buckmiller L, Dyamenahalli U, Richter GT. Propranolol for airway hemangiomas: case report of novel treatment. Laryngoscope 2009;119:2051-4. 20. Drolet BA, Frommelt PC, Chamlin SL, Haggstrom A, Bauman NM, Chiu YE, et al. Initiation and use of propranolol for infantile hemangioma: report of a consensus conference. Pediatrics 2013;131:128-40. 21. Xu G, Lv R, Zhao Z, Huo R. Topical propranolol for treatment of superficial infantile hemangiomas. J Am Acad Dermatol 2012;67:1210-3. 22. Kunzi-Rapp K. Topical propranolol therapy for infantile hemangiomas. Pediatr Dermatol 2012;29:154-9. 23. Mouhari-Toure A, Azoumah KD, Tchamdja K, Saka B, Kombate K, Tchangai-Walla K, et al. Rapid regression of infantile haemangioma with 2% propranolol ointment. Ann Dermatol Venereol 2013;140:462-4. 24. Hao J, Yang MB, Liu H, Li SK. Distribution of propranolol in periocular tissues: a comparison of topical and systemic administration. J Ocul Pharmacol Ther 2011;27:453-9. 25. Torres-Pradilla M, Baselga E. Failure of intralesional propranolol in infantile hemangiomas. Pediatr Dermatol 2014;31:156-8. 26. Iversen NK, Frische S, Thomsen K, Laustsen C, Pedersen M, Hansen PB, et al. Superparamagnetic iron oxide polyacrylic acid coated gammaFe2O3 nanoparticles do not affect kidney function but cause acute effect
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Graphical Abstract
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A novel topical nano-propranolol for treatment of infantile hemangiomas
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Zheng Gang Chen, PhD, MD a,c, Jia Wei Zheng, DDS, MD, FICD a,⁎, Ming Lu Yuan b, Ling Zhang, PhD, MD a, Wei En Yuan, MD b,⁎⁎
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Department of Oromaxillofacial Head and Neck Oncology, Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China b School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China c Department of Oral and Maxillofacial Surgery, Qingdao Municipal Hospital, Shandong, China
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All the local irritations were evaluated as mild and were tolerated without discontinuing the medication. We suggest that topical nano-propranolol hydrogel could be an alternative option for the treatment of uncomplicated superficial IH with satisfactory tolerability and optimal effectiveness.
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Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx – xxx nanomedjournal.com
A novel topical nano-propranolol for treatment of infantile hemangiomas
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Zheng Gang Chen, PhD, MD a, c , Jia Wei Zheng, DDS, MD, FICD a,⁎, Ming Lu Yuan b , Ling Zhang, PhD, MD a , Wei En Yuan, MD b,⁎⁎
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Department of Oromaxillofacial Head and Neck Oncology, Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China b School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China c Department of Oral and Maxillofacial Surgery, Qingdao Municipal Hospital, Shandong, China Received 18 August 2014; accepted 17 February 2015
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Topical propranolol has been used for the therapy of superficial infantile hemangiomas (IH). A retrospective investigation was conducted in 50 patients to evaluate the clinical effect of a new type of topical nano-propranolol-dispersed hydrogel. Participants were treated 3 times per day for 2 weeks to 11 months. 68% of patients were female and 12% had received other treatments before therapy. The nano-propranolol 0.5% hydrogel was initiated at a mean age of 5.010 months and for a mean duration of 3.610 months. The response rate was 86%. No recurrence and rebound growth occurred after withdrawal of hydrogel. Slight side effects (application site itching, erosion and crusting) were observed in only 2 cases. All the local irritations were evaluated as mild and were tolerated without discontinuing the medication. We suggest that topical nano-propranolol hydrogel could be an alternative option for the treatment of uncomplicated superficial IH with satisfactory tolerability and optimal effectiveness. © 2015 Published by Elsevier Inc.
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Key words: Propranolol; Infantile hemangioma; Beta blocker; Topical therapy
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Background
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Infantile hemangiomas (IH) are the most common congenital vascular tumor of infancy with a reported incidence of 5%-10%. 1 The incidence is higher (20%-30%) in extreme low birth weight babies. 2 IH are most prevalent in Caucasian children and are three times more common in female infants than male. The head and neck region is the most frequently involved area (60%), followed by the trunk (25%) and the extremities (15%), and these tumors display a non-random distribution largely correlating with regions of embryological fusion. 3 The natural history of the hemangioma characteristically goes through a rapid proliferating phase in the
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Conflict of interest: None. ⁎ Correspondence to: J.-W. Zheng, Department of Oromaxillofacial Head and Neck Oncology, Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China. ⁎⁎ Correspondence to: W.-E. Yuan, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China. E-mail addresses: [email protected] (J.W. Zheng), [email protected] (W.E. Yuan).
first several months of life followed by a spontaneous involution stage, with slow resolution spanning years. These lesions are usually not present at birth but instead are noted within the first few weeks of life. Precursor lesions are common but often subtle; findings may include telangiectasias, pallor, a bruiselike appearance, and, rarely, ulceration. A residual fibrofatty mass often persists after spontaneous involution of IH. Because of the spontaneous regression and the majority of lesions produce no long-term scarring, most cases require no treatment. However, 10% of IH require treatment during the proliferating phase, 4 for the reason of life-threatening locations, local complications, or cosmetic/functional risks. 5 Since the serendipitous discovery of the efficacy of propranolol in the treatment of IH by Léauté-Labrèze et al, 6 the effectiveness of propranolol for IH of all types has been demonstrated in multiple publications. 7–10 Subsequently, the off-label use of this molecule became the first-line treatment for IH. Hemangeol (propranolol hydrochloride), an oral solution specially developed for safe and effective use in children, was FDA approved in the USA on March 17th, 2014 and marketed as the first and only FDA-approved treatment for proliferating IH requiring systemic therapy currently (http://www.pierre-fabre.com/en/fda-approvalmarket-hemangeoltm).
http://dx.doi.org/10.1016/j.nano.2015.02.015 1549-9634/© 2015 Published by Elsevier Inc. Please cite this article as: Chen Z.G., et al., A novel topical nano-propranolol for treatment of infantile hemangiomas. Nanomedicine: NBM 2015;xx:1-7, http://dx.doi.org/10.1016/j.nano.2015.02.015
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Table 1 Summary of baseline characteristics and treatment of IH.
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Patient characteristics and treatment
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Female-to-male ratio Type of hemangioma Superficial Deep Mixed Location of hemangioma Head and neck Limbs Trunk Periocular Mouth Indication for treatment Cosmetic risk Functional risk Life-threatening Local complication Previous treatment Laser treatment Radiation treatment Other invasive treatment (embolization, surgical excision) Other agents (corticosteroids, vincristine sulfate, cyclophosphamide, interferon) Other topical agents (imiquimod, timolol) Age at initiation of nano-propranolol treatment (months), median (range) Duration of nano-propranolol treatment (months), median (range) Age at end of nano-propranolol treatment (months), median (range)
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Subjects
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This study included patients with IH between January 2013 and February 2014, diagnosed according to the criteria established by the International Society for the Study of Vascular Anomalies (ISSVA). 15 A total of 50 outpatients with superficial IH at the Department of Oral & Maxillofacial Surgery in the Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, China, were enrolled. Those with deep IH were excluded and encouraged to take other treatment (oral
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Nano-propranolol hydrogel was produced by the Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, which contained 0.5% propranolol. Formulation: (1) 40 g glycerol, 16 g polyethylene glycol (Molecular Weight: 400 Da, PEG 400), 5 g sodium benzoate, and 20 g nanoparticles of colloidal silicon dioxide dispersed in 200 ml water, and then 5 g propranolol was added into the above suspension and made the propranolol sufficient for adsorption to nanoparticles of colloidal silicon dioxide; (2) 32 g polyvinyl alcohol (PVA, Molecular Weight: 100,000 Da) and 32 g PVA (Molecular Weight: 40,000 Da) dissolved in 650 ml water; (3) the suspension of 1) was added the solution of 2) and well dispersed. The treatment regimen involved the application of nanopropranolol hydrogel to the lesions 3 times per day for 2 weeks to 11 months. The hydrogel was evenly rubbed onto the surface for 2 ml/cm 2 each time. As a routine, cardiac examination (electrocardiographic and ultrasound echocolor Doppler examination) was performed before treatment. Blood pressure (BP) and heart rate (HR) were measured and recorded. Patients were examined 2 h after treatment and every 1 month during the treatment to monitor the skin response or other side effects of nano-propranolol hydrogel. Drug administration was discontinued when 90% of the lesion disappeared or the treatment duration was over 1 year. Posttreatment evaluations were performed every 3 months. The response was assessed by comparing the status at the start of treatment and at the last appointment. The lesions were photographed at baseline, during treatment, and at each follow-up.
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Hemangioma size was recorded using “hemispheric” measurement. 16 A soft tape measure was draped over the lesion, and the longest diameter and a measurement perpendicular to it were recorded, giving a measurement in cm 2. The response was classified as follows: clinical resolution—complete clearance of the lesion, scored 4; excellent—75% to 99% improvement, scored 3; moderate—50% to 74% improvement, scored 2; minimal—25% to 49% improvement, scored 1; failure—b25% improvement, scored 0. 17 The overall efficacy was calculated from the sum of cases that were scored above 2. Local skin responses were as follows: none—scored 0; mild—scored 1 (+, erythematous reaction); moderate—scored 2 (++, erosion or light crusting); severe—scored 3 (+++, ulceration, thick crusting or scarring).
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A total of 50 cases were analyzed, 68% (34/50) of which were female and 32% (16/50) male, constituting a female/male ratio of
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Nanotechnology is the latest and fast emerging technology wherein dimension of particle of material is reduced nearly to that of individual molecule or their aggregates. 11 Recently, advances in nanotechnology have provided great opportunities for strategies in tumor treatment. 12–14 To improve the efficacy of drug delivery, nanotechnology-based drug-delivery systems are gaining considerable attention, as they have the potential to reduce side effects, minimize toxicity, and improve antitumor treatment efficacy. We retrospectively analyzed a group of children with IH to identify the therapeutic response and tolerability of a new type medicine, topical nano-propranolol hydrogel. The objective of this study was to assess the efficacy and safety of nano-propranolol hydrogel in the treatment of IH.
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propranolol). All patients received a physical examination and clinical data were recorded, including sex, age, size and location of the lesion, disease duration, previous history, current therapies, etc. The study was approved by the Ethics Committee of the hospital. Informed consent was obtained from the patients’ guardians prior to the study.
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Among the total 50 patients, an overall efficacy of 86% (43/ 50) was achieved, with a clinical complete clearance rate of 6% (3/50), excellent rate of 74% (37/50), and moderate rate of 6% (3/ 50). No obvious response to the treatment was noted in 7 patients (14%). There were significant fading of color and decrease in size of the IH during the follow-up period compared to the photographs at baseline for the 43 cases (Figures 1, 2, 3, 4). Blanching, softening, and early regression of the lesions started within the first 1 month of treatment. The earliest visible response to treatment varied from 2 weeks to 1 month after initiation of treatment. Even for the case that showed no response to oral propranolol in the involution stage, topical nano-propranolol was effective and devoid of local or systemic side effects (Figure 5). For the 43 patients who showed an effective result from nano-propranolol, the treatment duration varied between 1 and 11 months (3.546 ± 2.390 months).For the other 7 patients without response, the duration was from 0.5 to 11 months
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No severe adverse events were noted in our patients. No bradycardia, hypotension, hypoglycemia, bronchospasm, hyperkalemia, mood disturbances, somnolence, fever, nausea, and diarrhea occurred. Meanwhile, no erythema/edema, peeling, ulceration, and scarring were encountered. However, slight side effects were observed in 4% (2/50) of the IH, including application site itching, erosion and crusting. All the local irritations were evaluated as mild and were tolerated without discontinuing the medication.
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We report here for the first time to our knowledge the apparent efficacy of topical application of nano-propranolol hydrogel in the treatment of IH, and found that it was efficacious and tolerable for superficial IH. Meanwhile, no severe adverse effects were found in our patients. The non-selective β-adrenergic receptor antagonist, propranolol, was introduced as a treatment option for problematic IH in 2008 when distinct improvements in IH lesions in 2 individuals were observed after systemic propranolol was administered for cardiac indications. 6 Since then, numerous subsequent case reports and retrospective analyses have confirmed the beneficial effect of propranolol on IH. 7–10,18,19 Propranolol has become a new first-line treatment in clinic for IH children. Despite the lack of standardized guidelines for propranolol treatment for IH, oral propranolol has been popularly accepted by most clinicians. 20 Given the success of oral propranolol, many practitioners have used topical β-blockers for the management of superficial, localized IH although there are currently no commercially available forms of topical propranolol. Xu et al reported topical therapy with 1% propranolol ointment in 25 children with 28 IH, and among all the IH, 90% showed either good or partial responses to topical propranolol treatment. 21 Kunzi-Rapp treated 45 children with 65 hemangiomas with 1% propranolol in a hydrophilic ointment topically applied twice a day and induced
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(4.000 ± 3.428 months). No recurrence and rebound growth of the hemangioma occurred after withdrawal of nano-propranolol. No patients recommenced treatment after cessation.
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2.125 to 1. The age at the time of the patients’ first treatment ranged from 1 month to 18 months (5.010 ± 3.940 months). The surface area of the patients was 5.812 ± 3.128 cm 2 in average. A total of 47 patients (94%) started treatment at the age of less than one year, while 3 (6%) commenced after completing one year of age. The patients completed treatment at median age of 8.620 ± 4.327 months and after a median treatment duration of 3.610 ± 2.522 months. The relevant epidemiologic and clinic characteristics of the patients and details about the individual treatment indication and duration were shown in Table 1. All the hemangiomas were classified as superficial. With respect to the site of the lesions, 26 were located on the head and neck (52%), 5 on the trunk (10%), 9 on the limbs (18%), 8 on the periocular area (16%) and 2 on the lips (4%). Uncommonly, 4 hemangiomas (8%) extended into N 1 site (for example: shoulder and chest, frontal region and scalp, frontal and temporal region). Forty-four patients had not been treated previously, while 6 presented residual lesions and had been refractory to previous laser (4 IH) and isotope radiation (2 IH) therapy (in other hospitals). The detailed clinical characteristics of these hemangiomas were documented using topical nano-propranolol hydrogel 3 times per day, without oral propranolol intake or any other treatments. No patients had complications before enrollment.
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Figure 1. Case 1. A 5-month old girl presented with a flat hemangioma in the right labium major (A). The tumor regressed nearly completely after topical use of nano-propranolol-dispersed hydrogel for 3 months (B).
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and stratum corneum lipids. There is a requirement for efficient drug delivery systems past this barrier. In this study, propranolol was manufactured in the form of nano-hydrogel which means nanotechnology was used to modify the drug permeation/ penetration by controlling the release of active substances and increasing the period of permanence on the skin. 31 The nanoparticle of propranolol can also ensure a direct contact with the stratum corneum and skin appendages and protect the drug against chemical or physical instability. 32 Nanotechnology has developed a novel transdermal drug delivery method. 33,34 The nanoparticles may ensure close contact with the stratum corneum of skin and increases the adsorbed nanoparticles or encapsulated drug amount penetrating into the skin. The advantages of these kinds of nano-carriers are protection of unstable drugs from degradation and control of drug release rate from these nano-carriers. 32,34,35 Hydrogels have been applied to drug delivery system 36 and can control the release of the drugs in response to environmental stimuli, such as pH, temperature, and enzyme. 37 In this study, we selected polyethylene glycol (PEG) as hydrogel nanoparticle components to ensure its biocompatibilities with skin. The skin penetrations of hydrogel nanoparticles can be enhanced provided that the size of hydrogel nanoparticles is carefully regulated and they are dispersed in a proper medium. It is the most important issue for the hydrogel nanoparticles that the hydrogel nanoparticle should not increase much in their sizes during their delivery into a skin layer, especially when they are dispersed in water. As transdermal drug delivery carriers, our hydrogel nanoparticles are small enough (diameter of 5 to 10 nm) for the nanoparticles to sufficiently penetrate into skin layers. In addition, PEG is both biocompatible and highly water soluble, which can maximize the delivery efficiency of the nanoparticles into the skin.
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regression or stabilized growth in 85% of the hemangiomas within the first 6 months of therapy for the patients in the proliferative phase. 22 Mouhari-Toure et al reported rapid regression of infantile hemangioma with 2% propranolol ointment in a female infant aged 11 weeks. 23 Additionally, an in vivo study demonstrated that topical delivery of propranolol can provide higher drug concentrations in local tissues than oral and intravenous administration. 24 The drug in the tissues was slowly cleared, and significant amounts of the drug were still present at 24 h after topical application. However, intralesional propranolol injection seems safe but is not effective for the treatment of IH. 25 It is possibly because the vehicle of solution (1 mg/ml) was not appropriate for intralesional injection and the dose (0.2 ml/cm2) and number of injections were simply too low although the dose calculation depended on a previous clinical trial that reported successful results. 25 Moreover, intravenous administration of nanoparticles has been proved to be able to induce cardiovascular effects. 26,27 Therefore, topical agents are possible appropriate therapy in some situations (eg, small, thin lesions), and the risks of adverse effects are less with topical rather than systemic agents. Timolol, another β-blocker, was also administered topically and was documented to be effective for IH. 28,29 However, propranolol was proved to be approximately ten times more permeable than timolol across human epidermal membrane (HEM). 30 Furthermore, propranolol could be applied topically at lower concentration than timolol on the hemangioma skin to achieve the same drug concentration at the viable epidermal layer or hemangioma tissue. 30 This could be the possible theoretical basis for the preference of topical propranolol in clinic than topical timolol. The skin forms a barrier to the external environment and is impermeable to the drugs on account of epidermal cell cohesion
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Figure 2. Case 2. A 12-month-old girl presented with superficial cutaneous hemangioma on the left upper eyelid (A). The area of the lesion decreased significantly 10 days (B) and 16 days (C) after hydrogel was applied. 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272
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Figure 3. Case 3. A 2-month-old boy presented with a bulge in the left orbital area (A) and the tumor became flattened 2 months after hydrogel was applied (B).
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would have occurred as a result of spontaneous involution even without treatment; the mean age of 5.010 months at treatment initiation is far younger than when spontaneous involution typically happens, suggesting that the nano-propranolol treatment, not spontaneous involution, is the more relevant explanation. There are some reports on the first dramatic visible and measureable response to oral propranolol treatment on the size and volume of hemangiomas as early as 48 h. 39 In this follow-up study, the patients showed significant regression after 1 month of topical agent administration for the first revisit, suggesting a slower effect of nano-propranolol than oral propranolol. It is because of the function of controlled release of encapsulated active ingredients in nano-propranolol, which needs more time than oral propranolol to diffuse through the polymeric matrix to permeate the skin. On the other hand, the use of nanoscaled carriers in controlled drug delivery system reduced side effects and decreased the dose of administered propranolol simultaneously. The major advantages of topical nano-propranolol treatment are the convenient application, satisfactory tolerability, excellent cosmetic result, and low-recurrence. In patients with a positive response to nano-propranolol hydrogel, there were significant fading of color and significant decrease in size of the IH. Potential explanations include vasoconstriction, which is immediately visible as a change in color, associated with a palpable tissue softening. Other included suggestions are a down-regulation of angiogenetic factors such as VEGF (vascular endothelia growth factor) and bFGF (basic fibroblast growth factor) and an up-regulation of apoptosis of capillary endothelial cells. 6,40 There are also data published which indicate a beneficial effect of propranolol in inhibiting the expression of matrix metalloproteinase 9 (MMP-9). 41 The known side effects of propranolol include bradycardia, hypotension. 41,42 bronchospasm 43, hypoglycemia 41,44, mood disturbances, and somnolence. 45 However, there were no severe or obvious adverse reactions noted during follow-up. With more than 40 years of extensive clinical experience with infants and young children, there is no documented case of death or serious cardiovascular morbidity resulting directly from β-adrenergic receptor blocker exposure. 46 Bronchospasm is usually seen as a
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The female/male ratio was 2.125 to 1 in this patient series, which is in agreement with current literature in which the predominance of hemangiomas in females has been reported. Assessment of the site showed that 52% of the hemangiomas were located on the head and neck, 10% in the trunk, 18% in the limbs, 16% in the periocular area, and 4% in the lips, respectively. Meanwhile, some patients had multiple hemangiomas. The data in our investigation are in accordance with other reports. 38 From this standpoint, our patients could be considered representative for analyzing the effect of nano-propranolol hydrogel on IH. The principal finding of this follow-up study is that 86% of IH patients treated with nano-propranolol hydrogel were deemed to have a positive response to treatment. This kind of topical hydrogel showed high effectiveness in the present study as oral or other topical regular propranolol. 21,22 Although the efficacy of all these researches is similar, the concentration of topical propranolol in our study is 0.5%, half or a quarter of those in previous studies. 21,22 Meanwhile, the mean duration of 14.4 weeks (range, 4-44 weeks, 1 patient treated for 2 weeks was evaluated as failure because no changes occurred and the therapy was required to be ceased by the parents) in our study is far less than that of 21 weeks (range, 5-59 weeks) in a study of regular topical propranolol application. 21 In the group with effective results in our study, the duration was 3.547 ± 2.390 months (range, 1-11 months). The small size of the lesion or the individual sensitivity possibly explains the shorter duration in these patients. But for most cases, the duration is longer around 14 weeks. This suggests the sustained release of nanoparticles in the process of drug delivery with good or excellent efficacy. To the best of our knowledge, there are no data in the international literatures evaluating the effect of topical agent of nanoparticle on IH. During the follow-up period no complications, tumor regrowth, or general growth impairment were observed. Such a high response rate is noteworthy for most medical treatment, and is even more impressive when considering that the patients in this study varied in age at treatment initiation, duration, size, and anatomic site. Despite this it is possible that some improvement
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Figure 4. Case 4. A 12-month-old boy presented with superficial cutaneous hemangioma on the right temporal skin (A). The tumor contracted and flattened after 6 months of treatment (B).
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mild exacerbation in patients with underlying reactive airway diseases; before prescription of propranolol, parents should be questioned about previous atopic disease or episodes of wheezing. Bradycardia is also another side effect of propranolol which requires cardiac examination before the treatment initiation. In this follow-up, ultrasound echocolor Doppler examination is performed for evaluation of patients’ cardiac function as a routine. Our study has few important limitations. Deep or mixed IH were excluded and only superficial type was considered. The efficacy of topical nano-propranolol treatment on deep or mixed IH was unknown. Further investigation should be complemented. Furthermore, treatment response must account for color, surface area, and volume. Various methods to assess response, including serial photographs, visual analog scores, serial measurements, and, at times, ultrasound analysis, should be taken into account. This limitation highlights the requirement for more rigorous scoring tools with high interrater reliability to allow response to be monitored more systematically. To summarize, from the results of the present study, topical nano-propranolol hydrogel appears to be a valuable and effective therapy option for superficial IH as efficacious as oral propranolol. Topical nano-propranolol agent has a welldocumented long-term safety for IH. However, propranolol for hemangiomas is an off-label-indication and the parents have to be well informed and to assent. Our results may provide some insight into the mode of propranolol on IH and other potertial therapeutic applications.
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Figure 5. Case 5. A 17-month-old girl presented with superficial cutaneous hemangioma in the right suborbital region. Oral propranolol at a dose of 2 mg/kg/d in two divided doses was given until 1 year of age, but the lesion didn’t completely regress (A). Nano-propranolol hydrogel was topically administrated 3 times a day, improvement was noted 23 days after topical medication (B), and dramatic improvement was seen 2 months after topical nano-propranolol treatment (C). The patient is still under treatment currently.
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The study was supported by National Science Foundation of China (Project No. 81271163 and 81373366).
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Appendix A. Supplementary data
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Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.nano.2015.02.015.
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Graphical Abstract
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A novel topical nano-propranolol for treatment of infantile hemangiomas
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Zheng Gang Chen, PhD, MD a,c, Jia Wei Zheng, DDS, MD, FICD a,⁎, Ming Lu Yuan b, Ling Zhang, PhD, MD a, Wei En Yuan, MD b,⁎⁎
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Department of Oromaxillofacial Head and Neck Oncology, Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China b School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China c Department of Oral and Maxillofacial Surgery, Qingdao Municipal Hospital, Shandong, China
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All the local irritations were evaluated as mild and were tolerated without discontinuing the medication. We suggest that topical nano-propranolol hydrogel could be an alternative option for the treatment of uncomplicated superficial IH with satisfactory tolerability and optimal effectiveness.
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