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Experimental procedure. (a) Intradermal administration of ALA with a MadaJet medical injector; (b) lesion immediately post-Madajet and prior to the PDT procedure; (c) lesion after the PDT procedure.
Source publication
Photodynamic therapy (PDT) with aminolevulinic acid (ALA) to treat nodular basal cell carcinoma (BCC) has been shown to be beneficial. The success rate of ALA-PDT in the treatment of nodular BCC is dependent on optimal penetration of the photosensitizing agent and subsequent PpIX production. To enhance topical delivery of drugs intradermally, a nee...
Similar publications
Prolonged follow-up data on topical photodynamic therapy (PDT) in basal cell carcinoma (BCC) are necessary for a full evaluation of its effect and for comparison with conventional treatment methods.
To assess 10-year long-term PDT efficacy in primary and recurrent BCC and to evaluate clinical and histopathological factors which may be associated wi...
Objective:
This article presents long-term follow-up after use of topical photodynamic therapy (PDT) for basal cell carcinoma. PDT is treatment option for different tumors, involving use of specific agent which is activated by visible light and results in tissue destruction.
Materials and methods:
Overall 20 patients with 29 tumors were treated...
Photodynamic therapy (PDT) exploits light interactions and photosensitizers to induce cytotoxic reactive oxygen species. Photodynamic diagnosis (PDD) uses the phenomenon of photosensitizer emitting fluorescence to distinguish some tumors from normal tissue. The standard photosensitizer used for PDD is 5-aminolevulinic acid (5-ALA), although it is n...
We evaluated the potential utility of hydrogels for delivery of the photosensitizing agents 5-Aminolevulinic acid (ALA) and hematoporphyrin monomethyl ether (HMME) to rectal tumors. Hydrogel suppositories containing ALA or HMME were administered to the rectal cavity of BALB/c mice bearing subcutaneous tumors of SW837 rectal carcinoma cells. For com...
Optoelectronics techniques to induce protoporphyrin IX fluorescence with topically applied 5-aminolevulinic acid on the oral mucosa have been developed to noninvasively detect oral cancer. Fluorescence imaging enables wide-area screening for oral premalignancy, but the lack of an adequate fluorescence enhancement method restricts the clinical imagi...
Citations
... Other, more specialized indications are the delivery of bleomycin in common warts, anaesthetics for local pain management, botulinum toxin for hyperhidrosis, and 5-aminolevulinic acid for photodynamic therapy. [10][11][12][13][14][15] Jet injectors can also be directed to target the subcutaneous tissue, for example, for administration of biologicals, vaccines, insulin, and nicotine. [16][17][18][19] The parameters of the currently available jet injector systems, however, needs to be optimized to adequately deliver larger volumes. ...
Objectives:
Needle-free jet injectors have been used in dermatological practice for many years. However, predefined clinical endpoints that guide physicians to choose optimal device settings have not been clearly defined. Here, we evaluate immediate skin responses as clinical endpoints for needle-free jet injector treatments.
Methods:
We injected methylene blue in ex vivo human skin using an electronically-controllable pneumatic injector (EPI; 3-6 bar, 50-130 µl; n = 63), and a spring-loaded jet injector (SLI) with fixed settings (100 µl; n = 9). We measured the immediate skin papule (3D-camera), residual surface fluid (pipette), dermal dye distribution by estimating depth and width, and subcutaneous dye deposition.
Results:
EPI with 4 bar and 100 µl resulted in the largest skin papule of 48.7 mm3 (35.4-62.6 mm3 ) and widest dermal distribution of 8.0 mm (5.5-9.0 mm) compared to EPI with 6 bar and 100 µl (p < 0.001, p = 0.018, respectively). The skin papule volume showed a significant moderate to high positive correlation with the width and depth of dye distribution in the dermis (rs = 0.63, rs = 0.58, respectively; p < 0.001 for both correlations). SLI showed high variability for all outcome measures. Finally, a trend was observed that a small skin papule (≤7 mm) and little residual surface fluid (≤10% of injection volume) were warning signs for subcutaneous deposition.
Conclusions:
The immediate skin papule and residual surface fluid correspond with dermal drug deposition and are relevant clinical endpoints for needle-free jet injector treatments in dermatological practice.
... EPI has previously been used for the treatment of acne scars [24] and palmar hyperhidrosis [25]. There are only a few studies, mainly case reports, on EPI for the treatment of keratinocyte cancers [23,26]. ...
... Thus, these studies confirm the rationale for local, topical LADD of immunotherapeutic antibodies when treating keratinocyte cancers. EPI-assisted drug delivery is less welldescribed, but two studies report promising results on improving photodynamic therapy with aminolevulinic acid for treatments of keratinocyte cancer [23,26]. Compared with intradermal needle injection, EPI provides a less painful and less operator-dependent injection [23] and could offer a more controllable and consistent delivery. ...
Background and objectives:
PD-L1 is a tumor ligand that binds to the PD-1 receptor on immune cells, thereby inhibiting the antitumor immune response. The antibody nivolumab is a PD-1 inhibitor, Food and Drug Administration approved for systemic treatment of several aggressive cancer types. Topically applied nivolumab may hold potential as a future strategy to treat keratinocyte cancer, but its molecular properties preclude unassisted topical uptake. The aim of this study was to investigate uptake and biodistribution of topically delivered nivolumab, assisted by two physical enhancement techniques with different delivery kinetics; ablative fractional laser (AFL) and electronically controlled pneumatic injection (EPI).
Study design/materials and methods:
In vitro porcine skin was exposed to CO2 AFL (20 mJ/mb, 5% density), followed by passive diffusion of nivolumab in a Franz cell (1 mg/ml, 18 hours, n = 6) or treated with EPI (4 bar) for immediate delivery of nivolumab (1 mg/ml, 10 minutes, n = 6). The resulting nivolumab skin concentrations were quantified by enzyme-linked immunosorbent assay (ELISA) at three skin depths (100, 500, and 1500 µm), comparing the uptake from assisted delivery with intact skin. Biodistribution of nivolumab in the skin for all interventions was visualized by laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) and fluorescence microscopy.
Results:
Delivery of nivolumab by AFL-assisted passive diffusion and immediate EPI both resulted in significantly enhanced uptake of nivolumab in all skin depths compared with intact skin (P < 0.05). With AFL, nivolumab concentrations reached 86.3 µg/cm3 (100 µm), 105.8 µg/cm3 (500 µm), and 19.3 µg/cm3 (1500 µm), corresponding to 2-10% of the applied concentration, with the highest deposition in the mid dermis. Immediate EPI delivered 429.4 µg/cm3 (100 µm), 584.9 µg/cm3 (500 µm), and 295.9 µg/cm3 (1500 µm) into the skin, corresponding to 29-58% of the applied nivolumab concentration. From qualitative visualization of the biodistribution, it appeared that nivolumab distributed in a horizontal and continuous homogenous band in the upper and mid dermis through AFL-exposed skin, whereas EPI-delivery showed a deep focal deposition extending into the deep dermis.
Conclusions:
AFL-assisted passive diffusion and immediate EPI-assisted delivery show the potential to deliver therapeutic antibodies locally. Future in vivo and pharmacokinetic studies would reveal the full potential for topical antibody delivery by energy-based devices. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.
... With a needle-free injection, the drug can be delivered in a controlled and standardized way that secures an instant and a far-reaching allocation. In accordance, a recent case report described a patient with a high-risk nodular BCC on the nose that was treated with needle-free injection assisted PDT after two failed excisional surgeries [25]. The nodular BCC was successfully treated, and no recurrence was seen at 2 years follow up. ...
Background and objectives:
Many cutaneous drug-delivery techniques rely on passive diffusion to deliver topical compounds to the skin. When attempting to deliver drugs to thicker lesions, such as skin tumors, modalities that do not rely on diffusion may serve as a better drug-delivery method. In this histological study, we aim to investigate the cutaneous delivery patterns of an electronic pneumatic needle-free injection device.
Study design/materials and methods:
Needle-free-injection was investigated in 24 ex vivo porcine skin samples and one basal cell carcinoma (BCC) tissue sample. A needle-free injection device with a nozzle size of 200 μm delivered 80 μl compound ink (0.1 cc black ink: 5.0 cc saline) at low (30%/3.1 bar; n = 6 porcine skin; n = 1 BCC tissue), medium (50%/3.9 bar; n = 6 porcine skin), high (65%/4.6 bar; n = 6 porcine skin), and stacked (30 + 50%/3.1 + 3.9 bar; n = 6 porcine skin) pressures. Depth, width, and depth of maximum width of ink deposition were evaluated on histological slides.
Results:
Depositions with small ink-lined vacuoles were seen intra-dermally in all samples, including the BCC tissue. Deposition depth was similar at low and medium pressures (924 vs. 994 μm; P = 0.873) but increased significantly with high pressure (1,564 μm; P = 0.010). When injections were stacked (3.1 + 3.9 bar), the depth remained similar to that of a single injection (931 μm; P = 1.000). The width of the deposition stayed comparable for low, medium, and high pressures when a single needle-free injection was performed (30% = 2,394 μm; 50% = 2,226 μm; and 65% = 2,757 μm; P = 0.09), but increased significantly with stacking (2,979 μm; P = 0.037). The depth of maximal width was superficially located in the papillary dermis at low and medium pressures (321 and 305 μm; P = 0.748) but shifted to the deeper reticular dermis with high pressure (950 μm; P = 0.004) and with stacking (734 μm; P = 0.004).
Conclusions:
In conclusion, with an electronically controlled, pneumatic needle-free injector, depth and width of a cutaneous deposition can be influenced by pressure and stacking, respectively. The pneumatic needle-free injection can potentially serve as a viable drug-delivery technique for cutaneous pathologies where dermal deposition is essential. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.
... High-pressure, needle-free injection systems are also able to decrease the DLI for aminolevulinic acid (ALA) vehicled as a solution, with the advantage of carrying the precursor to deeper layers compared to the topical application [24]. A case report published satisfactory results of BCC treatment using PDT with the PpIX precursor delivered by a needle-free injection system [25]. Li et al. compared the PDT treatment of condyloma acuminatum by both topical and intradermal application of ALA, showing that needle-free injection allowed significant improvement in delivery, including faster treatment time, as the DLI successfully used was 90 min [26]. ...
In order to purposely decrease the time of the photodynamic therapy (PDT) sessions, this study evaluated the effects of PDT using topical and intradermal delivery of two protoporphyrin (PpIX) precursors with intense pulsed light (IPL) as irradiation source. This study was performed on porcine skin model, using an IPL commercial device (Intense Pulse Light, HKS801). IPL effect on different administration methods of two PpIX precursors (ALA and MAL) was investigated: a topical cream application and an intradermal application using a needle-free, high-pressure injection system. Fluorescence investigation showed that PpIX distribution by needle-free injection was more homogeneous than that by cream, suggesting that a shorter drug-light interval in PDT protocols is possible. The damage induced by IPL-PDT assessed by histological analysis mostly shows modifications in collagens fibers and inflammation signals, both expected for PDT. This study suggested an alternative protocol for the PDT treatment, possibility half of the incubation time and with just 3 min of irradiation, making the IPL-PDT, even more, promising for the clinical treatment.
... Approaching this cancer with photodynamic therapy offers significant cosmetic advantages over the gold-standard surgery, which may leave scars in sensitive areas such as the face, but its success is dependent on the penetration of ALA in the tissue. To address this issue, ALA was administered by a needle-free injector to the dermis of a patient bearing basal cell carcinoma of the nose, who then undergone photodynamic therapy [48]. In the case reported, the authors obtained an excellent cosmetic outcome with complete remission of the cancer and no recurrent lesions in the follow-up period of two years. ...
Needle‐free jet injectors are medical devices used for the delivery of liquid medications across the skin as a high‐speed stream of fluid, without the use of a needle. The absence of a needle abolishes the risk of needle‐stick injuries, frequent among healthcare providers, and increases the compliance to injections in needle‐phobic patients. Through the modulation of several parameters of the jet injectors, the liquid medication can be delivered to different sites within or below the skin, thus allowing the use of such devices for both local and systemic therapies in a multitude of disorders. In the present chapter, after a brief historical overview, the functioning principles and the rationale behind the use of needle‐free jet injectors are presented. Moreover, preclinical and clinical studies where jet injectors have been employed for the systemic or local delivery of therapeutics are reviewed. Finally, in the last section, the potential of such devices for the administration of nano‐ and micro‐particulate drug delivery systems is discussed.
... BCC is a malignant tumor localized in follicular germinative cells, which grows rapidly, causes destruction or damage of the surrounding tissue (in the area of the nose and ear) and can rarely cause metastasis to the lymph nodes, lung, bone, and liver [4]. Focused intervention, including cryotherapy, surgical excision, radiation therapy, photodynamic therapy, and chemotherapy (using antiproliferation drugs such as 5-aminolevulinic acid (5-ALA), 5-fluorouracil (5-FU), paclitaxel, resveratrol, imiquimod, temoporfin, and vismodegib) are usually used to combat the tumors [5][6][7][8][9]. Unfortunately, conventional chemotherapy applied to these conditions shows non-specific targeting, and high doses of anticancer drugs affect both normal and tumor cells, purchased from Alfa Aeser (Kandel, Germany); DSPE-PEG-Maleimide (DSPE-PEG-MAL) from Iris Biotech GmbH (Marktredwitz, Germany); DNA aptamer (AS1411-SH) was purchased from Integrated DNA Technologies, Inc. (Leuven, Belgium); chloroform was obtained from VWR Chemicals (Fontenay-sous-Bois, France). ...
More than one out of every three new cancers is a skin cancer, and the large majority are basal cell carcinomas (BCC). Targeted therapy targets the cancer’s specific genes, proteins, or tissue environment that contributes to cancer growth and survival and blocks the growth as well as the spread of cancer cells while limiting damage to healthy cells. Therefore, in the present study AS1411 aptamer-functionalized liposomes for the treatment of BCC were obtained and characterized. Aptamer conjugation increased liposome size, suggesting that the presence of an additional hydrophilic molecule on the liposomal surface increased the hydrodynamic diameter. As expected, the negatively charged DNA aptamer reduced the surface potential of the liposomes. Vertical Franz diffusion cells with artificial membranes were used to evaluate the in vitro release of 5-fluorouracil (5-FU). The aptamer moieties increase the stability of the liposomes and act as a supplementary steric barrier leading to a lower cumulative amount of the released 5-FU. The in vitro cell viability, targeting capability and apoptotic effects of liposomes on the human dermal fibroblasts and on the basal cell carcinoma TE 354.T cell lines were also evaluated. The results indicate that the functionalized liposomes are more efficient as nanocarriers than the non-functionalized ones.
... In Definition NFII can be defined as a needle-free drug delivery method in which a high-speed stream of fluid impacts the skin and delivers a drug 13 excluding vaccines and systemically absorbed medications like insulin. The fluid can contain a corticosteroid, 14 an anesthetic agent, 14 onabotulinum toxin A (BoNT-ONA), 15,16 bleomycin, 17 5-aminolevulinic acid (ALA), 18 or any injectable substance. ...
... 61 Using NFII to inject nodular basal cell carcinomas (BCCs) with intralesional 5-ALA 20% before PDT (photoactivation) led to complete, years-long remissions and few side effects. 18 This approach represents an interesting alternative to Mohs micrographic surgery that remains the standard of care for BCC in high-risk sites at least in North America. 62 However, the later can cause noticeable scarring. ...
Background
Jet injection can be defined as a needle-free drug delivery method in which a high-speed stream of fluid impacts the skin and delivers a drug. Despite 75 years of existence, it never reached its full potential as a strategic tool to deliver medications through the skin.
Objective
The aim of this review was to evaluate and summarize the evolution of jet injection intradermal drug delivery method including technological advancements and new indications for use.
Methods
A review of the literature was performed with no limits placed on publication date.
Results
Needleless injectors not only reduce pain during drug delivery but also confine the drug more evenly in the dermis. Understanding skin properties of the injection site is a key factor to obtain optimal results as well as setting the right parameters of the jet injector. Until the advent of disposable jet injectors/cartridges, autoclaving of the injector remains the only reliable method to eliminate the risk of infection. Needle-free intradermal injection using corticosteroids and/or local anesthetics is well documented with promising indications being developed.
Limitations
Limitations of the review include low-quality evidence, small sample sizes, varying treatment parameters, and publication bias.
Conclusion
New developments may help reconsider the use of jet injection technology. Future studies should focus on measurable optimized parameters to insure a safe and effective outcome.
... To deal with this, an intradermal application with a needle-free injection system 5 was already explored for PS precursors delivery. 6,7 In this study, we use needle-free injection for delivery of Photodithazine and Indocyanine green (ICG) into the skin to be used as phototosentizers. Regarding the light source, PDT can be performed with laser or LED, depending on the application. ...
... Specially, in clinical experience we acknowledged that in patients with thick and extensive tumors, a single intralesional ALA-PDT treatment does not completely eliminate the tumors and the use of traditional needles, however, may lead to profound vascular compromise with possible vasoconstriction, deep purpura, necrosis, and infection and cause pain (12). Besides, it has been reported by Annie Boucher in 2012 that the results of no-needle Jet intradermal ALA photodynamic therapy for a patient of nodular BCC was encouraging (13). So with the aim of improving the treatment efficacy as well as alleviating the suffering of patients, we experimented the new method of applying ALA to the cutaneous lesions using needle-free injection. ...
Background:
Photodynamic therapy (PDT) has been widely used in treatment for skin cancer. However, topical 5-aminolevulinic acid (ALA) in PDT demonstrates poor therapeutic effect due to its shallow penetration. And intralesional ALA-PDT can bring great pain. The purpose of this study was to evaluate the efficacy of PDT with needle-free injection of ALA in the treatment of nonmalignant skin tumors.
Methods:
54 non-melanocytic malignant lesions of 54 subjects were treated with needle-free injection of 20% 5-ALA under occlusion for 1.5 hours, and irradiated with light dose of 100 J/cm(2) at 100 mW for 20 minutes. Evaluation of treatment efficacy was conducted at 2 week after treatment.
Results:
44 cases showed complete response with six cycles of PDT, three cases with seven cycles, and three cases with nine cycles. The remaining four cases failed to show complete response even with nine cycle of PDT. No case was reported to have recurrence in 6 months posttreatment. Only four cases experienced disease recurrence in 1 year posttreatment.
Conclusions:
The treatment with PDT using needle-free injection of 5-ALA appears to be effective and well tolerated with milder therapeutic pain and low recurrence rate. It can be proposed as an effective treatment alternative for non-melanoma skin cancer.
... This modification showed results more pronounced than those observed with only the topical use, besides the possibility to decrease DLI to about 120 minutes [16]. A study performing PDT with ALA solution delivered by a needle-free injection for the treatment of condyloma acuminatum, showed that it is possible to decrease the DLI to 90 minutes [17], while another application through a similar equipment in the treatment of BCC with ALA solution indicated a good response with only 60 minutes for the DLI [18]. ...
Photodynamic Therapy (PDT) requires the interaction of light with a specific wavelength, photosensitizer (PS) and the molecular oxygen, which resulting in the production of reactive species of oxygen (ROS) able to induce cell death. As PS is one of the elements necessary for the success of PDT, is expected that it reaches the target cells to get an effective treatment. Furthermore, delivery of the compounds related to a clinical procedure a more acceptable both for medical community and by patients undergoing PDT. The first clinical applications of PDT occurred with systemic application of PS, which ensures that the FS reaches deeper layers of the treated tissue. However, this way of administration has several side effects, as well as, photosensitivity and hepatotoxicity and, in this context, the topic application has become increasingly visibility in disease treatment, especially in non-melanoma skin cancer, skin infections, cervical intraepithelial neoplasia and condyloma by HPV (Human papillomavirus) and venous ulcers. Among the used PS, there is the Protoporphyrin IX (PpIX) generated from the prodrug aminolevulinic acid (ALA) or its methylated form (MAL). The topical application still has many challenges to be overcome, such as the Drug Light Interval (DLI). One possibility to improve the delivery of the desired compound is facilitating the disruption of tissue barriers. Techniques as curettage, microneedle application that enables the cream or solution permeation or the use of needle-free injection are examples of procedures to optimize this process. Besides, reduce incubation time, they can help in the homogeneity of delivery of FS or in its production. It is still possible to change the composition of formulation and, actually, cream, solution or gels are the most common form that PS or prodrugs are available. For the treatment of large areas, there is the biofilm with the photosensitizer, such as the curcumin biofilm, which has been used both for the treatment of ulcers and for disinfection of medical tubes. One way to increase the efficiency of these PS for treatment of tumors and for inactivation of microorganisms is nanoencapsulation of photosensitive agents, such as curcumin and PpIX. These nanoformulations have advantages in terms of protection against premature degradation and promotion of a controlled release of the drug, ensuring greater bioavailability with lower side effects. Therefore, among the current challenges for PDT are decreasing of incubation time without loss of efficiency and homogeneity and production of drugs to make PDT a more attractive option in the clinical application.
