Application of biomacromolecule-based passive penetration enhancement technique in superficial tumor therapy: A review.

Transdermal drug delivery (TDD) has shown great promise in superficial tumor therapy due to its noninvasive and avoidance of the first-pass effect. Especially, passive penetration enhancement technique (PPET) provides the technical basis for TDD by temporarily altering the skin surface structure without requiring external energy. Biomacromolecules and their derived nanocarriers offer a wide range of options for PPET development, with outstanding biocompatibility and biodegradability. Furthermore, the abundant functional groups on biomacromolecule surfaces can be modified to yield functional materials capable of targeting specific sites and responding to stimuli. This enables precise drug delivery to the tumor site and controlled drug release, with the potential to replace traditional drug delivery methods and make PPET-related personalized medicine a reality. This review focuses on the mechanism of biomacromolecules and nanocarriers with skin, and the impact of nanocarriers' surface properties of nanocarriers on PPET efficiency. The applications of biomacromolecule-based PPET in superficial tumor therapy are also summarized. In addition, the advantages and limitations are discussed, and their future trends are projected based on the existing work of biomacromolecule-based PPET.

Double enhancement effect of a surface dose with tungsten rubber bolus in photon radiotherapy for keloids and superficial tumors.

To clarify the dosimetric characteristics of a real-time variable shape rubber-containing tungsten (STR) bolus in a clinical plan and investigate the efficacy of the STR bolus in photon radiotherapy for keloids and other superficial tumors. A 5 mm gel bolus or 1 mm STR bolus was placed on a solid water phantom. Tangential irradiation was performed using a TomoTherapy Radixact-X9 and 6 MV X-ray flattening-filter-free beam, and the surface dose was measured with radiochromic film. Clinical-like plans (TomoDirect; TD and TomoHelical; TH) were applied with the same geometry and the dose distributions were measured. The increase in surface dose by the build-up effect and backscatter was 37.7% and 8.0% for the gel bolus, and 40.5% and 26.4% for the STR bolus, respectively. In the TD and TH plans, the increase in surface dose was 27.4% and 48.3% for the gel bolus, and 39.0% and 63.2% for the STR bolus. Similary, changes in the sagittal plane dose were - 3.9% and 6.1% for the gel bolus, and - 6.3% and 6.9% for the STR bolus. The STR bolus effectively increased the surface dose by the build-up effect and backscatter in photon radiotherapy for keloids and other superficial tumors.

Microneedle-mediated transdermal drug delivery for treating diverse skin diseases.

Transdermal drug delivery is an attractive route for dermatological disease therapy because it can directly target the lesion site on the skin, reduce adverse reactions associated with systemic administration, and improve patient compliance. However, the stratum corneum, as the main skin barrier, severely limits transdermal drug penetration, with compromised bioavailability. Microneedles (MNs), which are leveraged to markedly improve the penetration of therapeutic agents by piercing the stratum corneum and creating hundreds of reversible microchannels in a minimally invasive manner, have been envisioned as a milestone for effective transdermal drug delivery, especially for superficial disease therapy. Here, the emergence of versatile MNs for the transdermal delivery of various drugs is reviewed, particularly focusing on the application of MNs for the treatment of diverse skin diseases, including superficial tumors, scars, psoriasis, herpes, acne, and alopecia. Additionally, the promises and challenges of the widespread translation of MN-mediated transdermal drug delivery in the dermatology field are summarized.

Intelligent and spatiotemporal drug release based on multifunctional nanoparticle-integrated dissolving microneedle system for synergetic chemo-photothermal therapy to eradicate melanoma.

Cutaneous melanoma is one of the most common malignant skin cancer with high lethality. Chemotherapy and photothermal therapy are important and extensively studied treatment modalities for melanoma. However, these therapies still face some challenges, which severely restrict their further applications, such as unsatisfactory efficacy of monotherapy, nonspecific uptake and release during drug delivery, and unexpected adverse effects from system administration. Recently, the strategies of collaboration, functional modification, stimuli-responsive design, and topical administration all show great prospect for solving above problems. In this research, a multifunctional nanoparticle-integrated dissolving microneedle drug delivery system was constructed, in which the nanoparticles were prepared based on the framework with the incorporation of photothermal agent (CuS) into Zeolitic imidazolate framework-8 and functionalized by hyaluronic acid. This system can co-load multi-modal drugs, improve specific uptake and distribution of targeted tumor, deliver drug locally, and release drug intelligently and spatiotemporally, thereby promising a low-dose administration with high efficiency. The high inhibiting tumor performance and excellent systematic safety were verified both in vitro and in vivo. Together, this smart design overcame the drawbacks of monotherapy and conventional system administration. We believe the nanoparticle-integrated dissolving microneedles will be in prospect of clinical application for more superficial tumors with further delicate optimization. STATEMENT OF SIGNIFICANCE: Melanoma is one of the most common skin cancers with high lethality. Extensively studied chemotherapy and photothermal therapy still face some challenges, such as the limited therapeutic efficacy and the severe system adverse effects. In order to overcome these drawbacks, the multifunctional nanoparticle-integrated dissolving microneedles (DMNs) were designed. Especially, the nanoparticles could co-load multi-modal drugs, improve specific uptake, and release drug intelligently and spatiotemporally. The microneedles could increase the drug accumulation in tumor, thus achieving excellent therapeutic efficacy and reducing side effects. This system paved the way to a less invasive, more focused and efficient therapeutic strategy for melanoma therapy.

The Clinical Application of 3D-Printed Boluses in Superficial Tumor Radiotherapy.

During the procedure of radiotherapy for superficial tumors, the key to treatment is to ensure that the skin surface receives an adequate radiation dose. However, due to the presence of the built-up effect of high-energy rays, equivalent tissue compensators (boluses) with appropriate thickness should be placed on the skin surface to increase the target radiation dose. Traditional boluses do not usually fit the skin perfectly. Wet gauze is variable in thickness day to day which results in air gaps between the skin and the bolus. These unwanted but avoidable air gaps lead to a decrease of the radiation dose in the target area and can have a poor effect on the outcome. Three-dimensional (3D) printing, a new rising technology named "additive manufacturing" (AM), could create physical models with specific shapes from digital information by using special materials. It has been favored in many fields because of its advantages, including less waste, low-cost, and individualized design. It is not an exception in the field of radiotherapy, personalized boluses made through 3D printing technology also make up for a number of shortcomings of the traditional commercial bolus. Therefore, an increasing number of researchers have tried to use 3D-printed boluses for clinical applications rather than commercial boluses. Here, we review the 3D-printed bolus's material selection and production process, its clinical applications, and potential radioactive dermatitis. Finally, we discuss some of the challenges that still need to be addressed with the 3D-printed boluses.

TPGS/hyaluronic acid dual-functionalized PLGA nanoparticles delivered through dissolving microneedles for markedly improved chemo-photothermal combined therapy of superficial tumor.

Nanoparticles (NPs) have shown potential in cancer therapy, while a single administration conferring a satisfactory outcome is still unavailable. To address this issue, the dissolving microneedles (DMNs) were developed to locally deliver functionalized NPs with combined chemotherapy and photothermal therapy (PTT). α-Tocopheryl polyethylene glycol succinate (TPGS)/hyaluronic acid (HA) dual-functionalized PLGA NPs (HD10 NPs) were fabricated to co-load paclitaxel and indocyanine green. HD10 NPs significantly enhanced the cytotoxicity of low-dose paclitaxel because of active and mitochondrial targeting by HA and TPGS, respectively. PTT could further sensitize tumor cells toward chemotherapy by promoting apoptosis into the advanced period, highly activating caspase 3 enzyme, and significantly reducing the expression of survivin and MMP-9 proteins. Further, the anti-tumor effects of HD10 NPs delivered through different administration routes were conducted on the 4T1 tumor-bearing mice. After a single administration, HD10 NPs delivered with DMNs showed the best anti-tumor effect when giving chemotherapy alone. As expected, the anti-tumor effect was profoundly enhanced after combined therapy, and complete tumor ablation was achieved in the mice treated with DMNs and intra-tumor injection. Moreover, DMNs showed better safety due to moderate hyperthermia. Therefore, the DMNs along with combined chemo-photothermal therapy provide a viable treatment option for superficial tumors.

Feasibility of a Tungsten Rubber Grid Collimator for Electron Grid Therapy.

BACKGROUND/AIM: Spatially fractionated radiotherapy (grid therapy) can control some bulky tumors which is challenging for conventional radiotherapy. This study aimed to investigate whether a novel tungsten contained rubber (TCR) grid collimator can be employed in electron grid therapy. MATERIALS AND METHODS: The TCR grid collimator placed on a solid water phantom, and percentage depth doses (PDDs) and lateral dose profiles were measured for 9 MeV electron beam with Gafchromic EBT3 films. At the lateral dose profile, the ratios of the dose in the areas with and without shielding (valley-to-peak ratios) were evaluated. RESULTS: The dmax values with the 1, 2 and 3 mm TCR grid collimators were 1.2, 1.1 and 0.7 cm, respectively, while the valley-to-peak ratios at each dmax were 0.566, 0.412 and 0.293, respectively. CONCLUSION: Only the 2 mm TCR grid collimator had adequate dosimetric features compared to the conventional grid collimator and could be substituted.

Assessment of 3D-printed tissue compensators for superficial tumor X-ray radiation compensation / 中华放射医学与防护杂志

Objective:To investigate the advantage of three dimensional(3D)-printed tissue compensators in radiotherapy for superficial tumors at irregular sites.Methods:A subcutaneous xenograft model of prostate cancer in nude mice was established. Mice were randomly divided into no tissue compensator group( n=6), common tissue compensator group( n=6), and 3D-printed tissue compensator group( n=6). Computed tomography (CT) images of nude mice in the 3D-printed tissue compensator group were acquired. Compensator models were made using polylactic acid, and material properties were evaluated by measuring electron density. CT positioning images of the three groups after covering the corresponding tissue compensators were acquired to delineate the gross tumor volume (GTV). Nude mice in the three groups were irradiated with 6 MV X-rays at the prescribed dose. The prescribed dose for the three groups was 1 500 cGy. The dose distribution in the GTV of the three groups was calculated and compared using the analytical anisotropic algorithm in the Eclipse 13.5 treatment planning system. The metal-oxide-semiconductor field-effect transistor was used to verify the actual dose received on the skin surface of nude mice. Results:The air gap in the 3D-printed tissue compensator group and the common tissue compensator group was 0.20±0.07 and 0.37±0.07 cm 3, respectively ( t=4.02, P<0.01). For the no tissue compensator group, common tissue compensator group, and 3D-printed tissue compensator group, the D95% in the target volume was (1 188.58±92.21), (1 369.90±146.23), and (1 440.29±45.78) cGy, respectively ( F=9.49, P<0.01). D98% was (1 080.13±88.30), (1 302.76±158.43), and (1 360.23±48.71) cGy, respectively ( F=11.17, P<0.01). Dmean was (1 549.08±44.22), (1 593.05±65.40), and (1 638.87±40.83) cGy, respectively ( F=4.59, P<0.05). The measured superficial dose was (626.03±26.75), (1 259.83±71.94), and (1 435.30±67.22) cGy, respectively ( F=263.20, P<0.001). The percentage variation in tumor volume growth after radiation was not significantly different between the common tissue compensator group and the 3D-printed tissue compensator group ( P>0.05). Conclusions:3D-printed tissue compensators fit well to the body surface, which reduces air gaps, effectively increases the dose on the body surface near the target volume, and provides ideas for radiotherapy for superficial tumors at some irregular sites.

Nanocomposite plasters for the treatment of superficial tumors by chemo-photothermal combination therapy.

INTRODUCTION: Novel nanomedical systems are being developed as multiple therapeutic modalities because the combinational therapies for cancer on a single platform can have larger chance to address tumor heterogeneity and drug resistance than any mono-therapeutic modality. METHODS: In this study, photothermal therapy (PTT) and chemotherapy (CT) were combined to treat squamous cell carcinoma by using a novel type of noninvasive plaster composed of carboxylated-reduced graphene oxide (rGO-COOH), gold nanorods (Au NRs), and doxorubicin (DOX). Firstly, DOX was loaded onto rGO-COOH to form DOX_rGO-COOH. Then, the obtained DOX_rGO-COOH and Au NRs were co-assembled to obtain nanocomposite multilayer. rGO-COOH and Au NRs were combined together to obtain high light-to-heat conversion efficiency. Using them as photothermal agents for PTT and using DOX in rGO-COOH as an anticancer drug for CT, their synergistic combination therapy could be applicable practically. RESULTS: As a result, DOX_rGO-COOH/Au NRs showed higher photothermal effects than that showed by rGO-COOH or Au NRs alone. It also showed higher therapeutic effects than DOX_rGO-COOH (for CT) or Au nr (for PTT) alone. Moreover, the system can repeatedly produce heat and simultaneously stimulate the release of the encapsulated anticancer drug into the tumor upon being irradiated by near-infrared laser. In vivo experiments demonstrated that the squamous cell carcinoma-bearing mice treated with DOX_rGO-COOH/Au NRs were healthy for more than 60 days without tumor recurrence. CONCLUSION: The as-developed DOX_rGO-COOH/Au NRs plaster could be an effective, convenient, and noninvasive treatment option for treating superficial tumors.

Experimental analysis of clinical applicability of individualized customized materials / 中国辐射卫生

@#<b>Objective</b> To study the feasibility of clinical application of an individualized customized material. <b>Methods</b> Five batches of individualized customized materials were randomly selected, from which 10 cm × 11 cm samples were intercepted for experimental analysis. Among them, 10 cm × 10 cm materials were selected to perform dosimetric analysis and HU change analysis before and after irradiation with a radiotherapy dose for breast cancer of 50 Gy as the irradiation basis. The center Point 1 on the lower surface of the individualized material and the center Point 2 of the solid water volume were selected for dosimetric analysis before and after the sample is irradiated. After reaching a sufficient amount of irradiation, the 1 cm × 10 cm materials intercepted in the center position and the remaining 1 cm × 10 cm materials after the first sampling were sent to the material science laboratory for analysis of physical properties of density, viscosity, hardness, and tear strength. <b>Results</b> In the comparative analysis of HU values before and after exposure, after receiving 50 Gy dose irradiation, the difference rate of HU value was 5.252%, which was close to the expected 5% difference rate in clinical medicine. In the dosimetric analysis of Point 1 and Point 2, the dose in the irradiated samples was significantly higher than that in the unirradiated samples; the dose in Point 1 increased by 3.742%, and the dose in Point 2 increased by 2.039%. Before and after irradiation, except for the physical density which showed a significant difference, there was no significant difference in viscosity, hardness, and tear strength. <b>Conclusion</b> The individualized customized material can meet the requirements of routine clinical medicine.

Usefulness and feasibility of endoscopic submucosal dissection for colorectal tumor: a nationwide multicenter retrospective study in Korea.

BACKGROUND: Detection rate of precursor lesion of colorectal cancer and early colon cancer have recently been rising because of increased screening endoscopy and increased incidence of colorectal cancer. Endoscopic submucosal dissection (ESD) technique has been reported to be useful in the treatment of such superficial lesions in colon. However, nationwide multicenter study for usefulness and feasibility of colorectal ESD is still limited. METHODS: From January 2009 to February 2014, colorectal ESD data performed at nationwide university hospitals were enrolled in retrospective design. Demographic, clinical, technical data, and data of complications were reviewed. RESULTS: A total of 189 patients were included with 191 lesions resected by colorectal ESD. The indications were epithelial lesions (n=120), neuroendocrine tumor (n=25), cancer (n=46). The lesion locations were right colon (n=45), transverse colon (n=17), descending colon (n=8), sigmoid colon (n=33), rectum (n=88). The median size of the lesions was 21.1 mm. En bloc resection rate of the lesion was 83.3%, with complete R0 resection in 73.3%. The median duration of ESD was 53.7 minutes. Factor related to En bloc resection was tumor location (right colon/transverse colon 72.6% vs. other location 89.2%, P=0.004). Factors related complication were tumor location (right colon/transverse colon 12.9% vs. Other location 10.13%, P=0.044) and tumor size (without complication 20.5±10.2 mm vs. with complication 25.9±11.7 mm, P=0.027). The short term morbidity rate was 11.0% including 5 hemorrhages (2.6%) and 16 perforations (8.4%). CONCLUSIONS: In this study, ESD shows promise as a useful, potentially feasible procedure in colorectal superficial tumor because of high en bloc resection rate and low morbidity rate, especially in small lesions located from descending colon to rectum.

TPGS/hyaluronic acid dual-functionalized PLGA nanoparticles delivered through dissolving microneedles for markedly improved chemo-photothermal combined therapy of superficial tumor

Nanoparticles (NPs) have shown potential in cancer therapy, while a single administration conferring a satisfactory outcome is still unavailable. To address this issue, the dissolving microneedles (DMNs) were developed to locally deliver functionalized NPs with combined chemotherapy and photothermal therapy (PTT).

Near-Infrared Light-Activatable Microneedle System for Treating Superficial Tumors by Combination of Chemotherapy and Photothermal Therapy.

Because of the aggressive and recurrent nature of cancers, repeated and multimodal treatments are often necessary. Traditional cancer therapies have a risk of serious toxicity and side effects. Hence, it is crucial to develop an alternative treatment modality that is minimally invasive, effectively treats cancers with low toxicity, and can be repeated as required. We developed a light-activatable microneedle (MN) system that can repeatedly and simultaneously provide photothermal therapy and chemotherapy to superficial tumors and exert synergistic anticancer effects. This system consists of embeddable polycaprolactone MNs containing a photosensitive nanomaterial (lanthanum hexaboride) and an anticancer drug (doxorubicin; DOX), and a dissolvable poly(vinyl alcohol)/polyvinylpyrrolidone supporting array patch. Because of this supporting array, the MNs can be completely inserted into the skin and embedded within the target tissue for locoregional cancer treatment. When exposed to near-infrared light, the embedded MN array uniformly heats the target tissue to induce a large thermal ablation area and then melts at 50 °C to release DOX in a broad area, thus destroying tumors. This light-activated heating and releasing behavior can be precisely controlled and switched on and off on demand for several cycles. We demonstrated that the MN-mediated synergistic therapy completely eradicated 4T1 tumors within 1 week after a single application of the MN and three cycles of laser treatment. No tumor recurrence and no significant body weight loss of mice were observed. Thus, the developed light-activatable MN with a unique embeddable feature offers an effective, user-friendly, and low-toxicity option for patients requiring long-term and multiple cancer treatments.

Effect of one-off complete tumor radiofrequency ablation on liver function and postoperative complication in small hepatocellular carcinoma.

OBJECTIVE: Radiofrequency ablation (RFA) is effective in treating hepatocellular carcinoma (HCC) and less invasive than surgical resection. However, 'one-off' complete tumor ablation on liver function has not been reported. METHODS: We retrospectively reviewed 36 HCCs which met the criteria of 'one-off' complete tumor ablation: (1) tumor was completed covered by the ablated zone (confirmed by postoperative enhanced CT) with a single RFA and, (2) no sign of recurrence for at least 6 months. We categorized tumors into two groups: near vascular tumor (NVT) if the distance was less than 5 mm, and far vascular tumor (FVT) otherwise. RESULTS: Thirteen HCCs met the criteria of NVTs, and 23 HCCs met that of FVTs. The Average tumor size was 2.6 ± 0.3 cm in FVTs and 2.5 ± 0.3 cm in NVTs. Although restored to normal range by postoperative day (POD) 7, ALT, AST, total bilirubin (TB), albumin and prothrombin time showed more significant fluctuation in NVTs compared to those in FVTs on POD1 through POD5. Moreover, 53.9% (7/13) patients in NVT group and 26.1% (6/23) in FVT group developed post-RFA transient ascites (OR = 5.1, 95% CI = 1.1-24.4). Incidence of post-RFA pleural effusion were 61.5% (8/13) in NVT but only 17.4% (4/23) in FVTs (OR = 7.6, 95% CI = 1.6-35.9). CONCLUSION: 'One-off' complete tumor ablation may impair liver function and led to more postoperative complication if a tumor is within 5 mm away from a large blood vessel (≥ 3 mm). Particular caution should be made in preoperative assessment on the anatomic relation between tumor and large blood vessel for patients.

Treatment Outcomes after Endoscopic Submucosal Dissection of Large Superficial Rectosigmoid Colon Tumors / 대한소화기내시경학회지

BACKGROUND/AIMS: Endoscopic submucosal dissection (ESD) of a colorectal tumor is technically difficult. This study aimed to analyze the clinical outcomes of superficial large rectosigmoid tumors after ESD. METHODS: Medical records of 15 patients with large rectosigmoid tumors (more than 30 mm), in which ESD performed, were reviewed retrospectively. RESULTS: The mean tumor size was 42.5+/-14.3 mm (range, 30~78 mm). A histological examination revealed a well-differentiated adenocarcinoma in five cases (33.3%), adenoma with high-grade dysplasia in six cases (40%), and low-grade dysplasia in four cases (26.7%). The mean procedural time was 90.5+/-60.7 min (range, 22~246 min). The en bloc resection rate was 86.7%, and the complete resection rate 100%. The lateral resection margin was positive in four cases (26.6%), but no cases with a positive vertical margin were observed. Bleeding occurred in three cases (20%), and all were treated successfully using endoscopic measures. Perforations occurred in three cases (20%); two cases were treated by clipping and the other by a laparotomy. CONCLUSIONS: ESD is a treatment option for superficial large rectosigmoid tumors. Further studies with larger cases and a longer term follow-up are needed to establish the efficacy and safety of ESD for colorectal tumors.