Development of nanoparticles incorporated with quercetin and ACE2-membrane as a novel therapy for COVID-19.

INTRODUCTION: Angiotensin-converting enzyme 2 (ACE2) and AXL tyrosine kinase receptor are known to be involved in the SARS-CoV-2 entry of the host cell. Therefore, targeting ACE2 and AXL should be an effective strategy to inhibit virus entry into cells. However, developing agents that can simultaneously target ACE2 and AXL remains a formidable task. The natural compound quercetin has been shown to inhibit AXL expression. MATERIALS AND METHODS: In this study, we employed PLGA nanoparticles to prepare nanoparticles encapsulated with quercetin, coated with ACE2-containing cell membranes, or encapsulated with quercetin and then coated with ACE-2-containing cell membranes. These nanoparticles were tested for their abilities to neutralize or inhibit viral infection. RESULTS: Our data showed that nanoparticles encapsulated with quercetin and then coated with ACE2-containing cell membrane inhibited the expression of AXL without causing cytotoxic activity. Nanoparticles incorporated with both quercetin and ACE2-containing cell membrane were found to be able to neutralize pseudo virus infection and were more effective than free quercetin and nanoparticles encapsulated with quercetin at inhibition of pseudo virus and SARS-CoV-2 infection. CONCLUSIONS: We have shown that the biomimetic nanoparticles incorporated with both ACE-2 membrane and quercetin showed the most antiviral activity and may be further explored for clinical application.

The role and metabolic adaptations of neutrophils in premetastatic niches.

It has been found that tumor cells create microenvironments in distant organs that promote their survival and growth in advance of their arrival. These predetermined microenvironments are referred to as "pre-metastatic niches". Increasing attention is being paid to neutrophils' role in forming the pre-metastatic niche. As major components of the pre-metastatic niche, tumor-associated neutrophils (TANs) play an important role in the formation of the pre-metastatic niche through communication with multiple growth factors, chemokines, inflammatory factors, and other immune cells, which together create a pre-metastatic niche well suited for tumor cell seeding and growth. However, how TANs modulate their metabolism to survive and exert their functions in the process of metastasis remains largely to be discovered. Accordingly, the objective of this review is to assess the role that neutrophils play in the formation of pre-metastatic niche and to explore the metabolism alteration of neutrophils in cancer metastasis. A better understanding of the role of TANs in pre-metastatic niche will help us discover new mechanisms of metastasis and develop new therapies targeting TANs.

Lipid-based nanoformulation optimization for achieving cutaneous targeting: Niosomes as the potential candidates to fulfill this aim.

The present study screened the utility of topically-applied nanoformulations to target the drugs/actives into the skin reservoir with the reduction of possible systemic absorption. The lipid-based nanoformulations selected in this study included solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), nanoemulsions (NEs), liposomes, and niosomes. We loaded flavanone and retinoic acid (RA) as the penetrants. The prepared nanoformulations were assessed for their average diameter, polydispersity index (PDI), and zeta potential. An in vitro permeation test (IVPT) was utilized to determine the skin delivery into/across pig skin, atopic dermatitis (AD)-like mouse skin, and photoaged mouse skin. We found an increased skin absorption of lipid nanoparticles following the increase of solid lipid percentage in the formulations (SLNs > NLCs > NEs). The use of liposomes even reduced the dermal/transdermal selectivity (S value) to lessen the cutaneous targeting. The niosomes resulted in significantly greater RA deposition and reduced permeation in the Franz cell receptor compared to the other nanoformulations. The S value of the RA delivery via stripped skin was increased by 26-fold in the niosomes compared to the free RA. The dye-labeled niosomes displayed a strong fluorescence in the epidermis and upper dermis through the visualization of fluorescence and confocal microscopies. The cyanoacrylate skin biopsy manifested greater hair follicle uptake of the niosomes compared to the free penetrants by 1.5 to three-fold. The 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assay indicated an increase in antioxidant ability from 55% to 75% after flavanone entrapment in the niosomes. In the activated keratinocytes, the niosomal flavanone could suppress the overexpressed CCL5 to the baseline control because of the facile cell internalization. After the formulation optimization, the niosomes with higher phospholipid amount had a superior effect in delivering penetrants into the skin reservoir, with limited permeation to the receptors.

The role of fatty acid desaturase 2 in multiple tumor types revealed by bulk and single-cell transcriptomes.

BACKGROUND: Previous studies have demonstrated the important role of fatty acid desaturase 2 (FADS2) in governing tumorigenesis and tumor metastasis. Although FADS2 is an essential regulator of fatty acid metabolism, its prognostic and immunotherapeutic value remains uncertain. METHODS: The role of FADS2 was investigated across different types of tumors. Besides, the relationship between FADS2 and survival prognosis, clinicopathologic features, tumor-infiltrating immune cells, immunoregulatory genes, chemokines, chemokines receptor, tumor mutational burden (TMB), and microsatellite instability (MSI) was also explored. FADS2-related genes enrichment analysis was performed to further explore the molecular function of FADS2. Finally, the relationship between FADS2 expression and altered functional states in single-cell levels across different tumor cells was explored. RESULTS: FADS2 was increased in most tumor tissues. Elevated FADS2 expression was associated with a poor overall survival (OS) and disease-free survival (DFS). FADS2 amplification was germane to worse progress-free survival (PFS). In addition, FADS2 correlated with the majority of tumor-infiltrating immune cells, immunoregulatory genes, and chemokines. Especially, FADS2 expression positively correlated with cancer-associated fibroblast (CAFs) infiltration. Gene Ontology and KEGG analysis demonstrated that FADS2 was involved in the fatty acid metabolic process, arachidonic acid metabolism, RAS, PPAR, and VEGF pathway. FADS2 had a positive relationship with tumor biological behaviors such as inflammation, cell cycle, proliferation, DNA damage, and DNA repair response in single-cell levels. CONCLUSIONS: FADS2 can serve as a potential prognostic and immunotherapeutic biomarker for multiple tumors, revealing new insights and evidence for cancer treatment.

Numerical simulation and experimental research on mechanical behaviour of hydraulic disc brakes based on multi-body dynamics.

As a vital road construction machine, the bridge erecting machine works in a very complex environment. The brake as an important link to maintain the safety and stability of the bridge erecting machine, it will have serious consequences if it is failed. Establishing the brake simulation model and specifying the fault characteristics according to the actual operation status will make it more efficient to find the cause of faults and maintain the safety of machine for a long time. A simulation model of brake of the bridge erecting machine was established by Adams. The brake arms and center axis with obvious data characteristics were flexibly processed, and finite elements were analysed using Abaqus. To verify the accuracy of simulation models, rectangular rosettes were applied to special geometric points, and the strain data were gathered by using the DH3816N collector and compared with the simulation model. The Adams kinematic simulation model was used to simulate the actual operating conditions by the experiment of the disc springs. Two typical fault phenomena were selected: reduced insufficient of disc spring and oil pressure, and two fault characteristics were extracted: variation of the brake shoe clearance and variation of the braking system pressure. When the brake generates the fault characteristics, the normal operation of the brake will not be affected if the fault characteristics are in the first stage. When the fault characteristics are beyond the critical threshold, the faults phenomena of the brake are generated. The results of the simulation experiments proved that the method of using the simulation model to extract the fault characteristics of the braking system and distinguish the causes of the fault was feasible.

Comparison of three-dimensional-printed template-guided and traditional implantation of 125I seeds for gynecological tumors: A dosimetric and efficacy study.

OBJECTIVE: The objective of the study was to compare the dose parameter and clinical efficacy of three-dimensional-printed template (3D-PT)-guided and traditional 125I seed implantation in treatment of gynecological tumors. MATERIALS AND METHODS: A total of 28 patients with gynecological tumors treated with radioactive seed implantation in Hebei General Hospital from January 2016 to December 2018 were retrospectively analyzed. Twelve patients (template group) were guided by 3D-PT and the remaining 16 patients (traditional group) were guided by computed tomography (CT) with traditional technique. Preoperative treatment plan (preplan) was completed through a treatment planning system. In the template group, 3D-PT was printed according to preplan and seeds were implanted under the guidance of 3D-PT and CT. In the traditional group, seeds were implanted under the guidance of single CT directly according to the preplan. Postoperative verification plan (post-plan) was completed. Dose-volume histogram (DVH) was calculated and D80, D90, V90, V100, and V150 were obtained according to DVH. Then, deviation of the dosimetric parameters D80, D90, V90, V100, and V150 between the preplan and postplan were compared within the two groups. The difference and percentage of difference of the above dosimetric parameters between the preplan and postplan within the two groups were calculated using the formula Xd = Xpost-plan- Xpre-plan, and Xd% = (Xpost-plan- Xpre-plan)/Xpre-plan × 100%. Doses were calculated to determine whether the differences there were statistically significant. Efficacy evaluation was completed according to RECISIT 1.1. Local control rate and effective rate of 2-months postplan were compared between the two groups. Survival analysis was completed by the Kaplan-Meier method. The patients were followed up for 12 months, and their survival rate was calculated and compared. RESULTS: There was no significant difference between the two groups for all the parameters, except for D80 of the preplan and postplan in the traditional group (P = 0.000). All the differences and percentage of difference were calculated and it was found that the Xd difference of D80 (P = 0.035), D90 (P = 0.023), V90 (P = 0.047), V100 (P = 0.032), and V150 (P = 0.031), as well as the Xd% difference of D80 (P = 0.032), D90 (P = 0.034), V90 (P = 0.042), V100 (P = 0.036), and V150 (P = 0.044) of the two groups was statistically significant, thus indicating that the dosimetric parameter fluctuation in the template group was more stable. The result of the curative effect after 2 months were as follows: the local control rate and effective rate of the template group were 100% (12/12) and 83.3% (10/12), while those of the traditional group were 100% (16/16) and 81.2% (13/16). There was no statistically significant difference in the curative effect between the two groups. After 6-27 months (median = 12 months) of follow-up, the median survival time of the template group and traditional group were 17 (10-23) and 16 (11-20) months, respectively, and the 1-year overall survival rate was 63% and 79% (P = 0.111), respectively, with no statistically significant difference observed. CONCLUSION: 3D-PT-guided 125I seed implantation is safe and effective in the treatment of gynecological tumors.

Dosimetry study of three-dimensional print template for 125I implantation therapy.

BACKGROUND: 125I seed implantation has been found to show good therapeutic effects on tumors. Recent studies showed that three-dimensional (3D) print template-assisted 125I seed implantation can optimize radiation dose distribution. This study aimed to compare the dose distribution differences in 125I seed implantation among 3D print noncoplanar template- (3DPNCT), 3D print coplanar template- (3DPCT) assisted implantation and traditional free-hand implantation. METHODS: We systematically searched the PubMed, EMbase, Cochrane Library, Wan Fang Med Online, China National Knowledge Infrastructure (CNKI) from the earliest to November 2020 without time or language restrictions. And the references of primary literature were also searched. The outcome measures were dosimetry and operation time. This meta-analysis was carried out using Stata 12.0. RESULTS: A total of 16 original articles were selected for inclusion. The differences of D90, D100, V90, and V100 values pre- and post-implantation with traditional free-hand implantation showed statistically significant (p < 0.05). The differences of D90, D100, V100, V150, V200, and D2cc of organs at risk (OAR) values pre- and post-implantation with 3D print template showed no statistically significant (p > 0.05). Compared with traditional free-hand implantation without any templates, 3D print template could improve postoperative D90 (Standard mean difference, SMD = 0.67, 95% confidence interval (CI) = 0.35 to 0.98, p < 0.001), D100 (SMD = 0.82, 95%CI = 0.40 to 1.23, p < 0.001), V90 (SMD = 1.48, 95%CI = 0.95 to 2.00, p < 0.001), V100 (SMD = 1.41, 95%CI = 0.96 to 1.86, p < 0.001), and reduce operation time (SMD = - 0.93, 95%CI = - 1.34 to - 0.51, p < 0.001). In three studies, both 3DPNCT and 3DPCT plans were designed for all patients. The prescribed dose and seed activity were same. Pooled analysis of D90, D100, V100, D2cc of OAR, number of seeds and number of needles showed no significant differences between 3DPNCT and 3DPCT groups (p > 0.05). However, in 3DPNCT group, V150 and V200 were increased (SMD = 0.35, 0.49; 95%CI = 0.04 to 0.67, 0.02 to 0.96; p = 0.028, 0.043); the number of through bone needles was reduced (SMD = - 1.03, 95%CI = - 1.43 to - 0.64, p < 0.001). CONCLUSIONS: Compared with traditional free-hand implantation, 3D print template-assisted 125I seeds implantation can optimize dose distribution and reduce the implantation time at the same time. Compared with 3D print coplanar template, 3D print noncoplanar template can increase the volume of high dose within tumor target and is more safer in the respect of puncture route.

Analysis of the efficacy and safety of iodine-125 seeds implantation in the treatment of patients with inoperable early-stage non-small cell lung cancer.

PURPOSE: To evaluate the efficacy and safety of iodine-125 (125I) seeds implantation for inoperable early-stage non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: PubMed, Cochrane Library, Embase, China Biology Medicine disc (CBM), China National Knowledge Infrastructure (CNKI), and Wanfang Data were searched from inception until April 2020. Data were collected concerning overall survival, short-term efficacy, and complications. Meta-analysis was performed using R software (version 3.6.3). RESULTS: Nine studies involving 308 patients were included. Meta-analysis showed that the 1-, 2-, and 3-year survival rates were 0.98% (95% CI: 0.95-0.99%), 0.83% (95% CI: 0.77-0.89%), and 0.65% (95% CI: 0.55-0.75%), respectively; short-term local control rate (LCR) and effective rates were 0.99% (95% CI: 0.98-1.00%) and 0.92% (95% CI: 0.83-0.98%), respectively; 1-, 2-, and 3-year LCRs were 0.96% (95% CI: 0.83-1.00%), 0.94% (95% CI: 0.85-0.99%), and 0.95% (95% CI: 0.76-1.00%), respectively. Sub-group analysis of the prescribed dose found that when the prescribed dose was > 120 Gy, short-term efficacy and 1-year LCR were increased significantly (p < 0.01). The incidence of bleeding, pneumothorax, and radiation lung injury was 0.14% (95% CI: 0.07-0.21%), 0.19% (95% CI: 0.11-0.28%), and 0.00% (95% CI: 0.00-0.03%), respectively. Two studies involving 106 patients compared 125I seeds combined with chemotherapy versus chemotherapy alone for NSCLC. Results showed that compared with chemotherapy alone, 125I seeds combined with chemotherapy could improve short-term LCR (RR = 1.34, 95% CI: 1.09-1.65%, p = 0.005) and short-term effective rate (RR = 1.49, 95% CI: 1.14-1.96%, p = 0.004). CONCLUSIONS: 125I seeds implantation is safe and effective approach for the treatment of inoperable early-stage NSCLC, but high-quality clinical research is still needed to further confirm the findings.

Sublobar resection with intraoperative brachytherapy versus sublobar resection alone for early-stage non-small-cell lung cancer: a meta-analysis.

OBJECTIVES: The purpose of this study was to compare the clinical outcomes for sublobar resection (SR) or SR plus intraoperative brachytherapy (SRB) for clinical stage I non-small-cell lung cancer. METHODS: A systematic search was performed in the EMBASE, PubMed and Cochrane Library databases to identify related studies comparing SR to SRB. Data were collected on local recurrence (LR) as a primary outcome and regional or distant recurrence, overall survival and disease-free survival (DFS) as secondary outcomes. Meta-analysis was carried out using Stata 12.0. RESULTS: A total of 476 patients received SRB, and 617 received SR across 5 studies. Meta-analysis of LR, regional or distant recurrence, overall survival and disease-free survival rates showed no significant difference between SRB and SR groups. However, when biologically effective dose (BED) was >100 Gy, LR rate was lower in the SRB group than in the SR group (Relative risk [RR] = 0.143, 95% confidence interval [CI]: 0.051-0.397) (p < 0.001). When BED was <100 Gy, no significant difference was found in LR rate between SRB and SR groups (SRB versus SR: RR = 1.132, 95%CI: 0.704-1.821) (p = 0.608). CONCLUSIONS: Intraoperative brachytherapy was not associated with reduced risk of regional or distant metastasis or improved outcomes for patients with clinical stage I non-small-cell lung cancer; however, it might reduce the LR rate when BED was >100 Gy.

Development of flavanone and its derivatives as topical agents against psoriasis: The prediction of therapeutic efficiency through skin permeation evaluation and cell-based assay.

Flavonoids inhibit skin inflammation. Previous study suggests that the flavonoids with flavanone backbone were beneficial to penetrate into the skin. We aimed to investigate the possibility of psoriasis treatment by topically applied flavanone and its derivatives including naringenin, hesperetin, 6-hydroxyflavanone, flavanone, and 6-bromoflavone. The skin absorption of the compounds was determined by Franz cells. Molecular modeling was used to compute the physicochemical and molecular parameters of the penetrants in order to elucidate the correlation between structure and permeation. Among the compounds tested, flavanone showed the greatest skin absorption. The in vitro skin absorption predicted efficient skin targeting of 6-bromoflavone with minimal risk of circulation absorption. The permeation of naringenin was remarkably enhanced 13-fold in the barrier-defective skin mimicking inflamed skin. The penetrants with fewer hydrogen bond number, total polarity surface, and molecular volume were advantageous for facile skin absorption. In the cell-based study, IL-1ß inhibition in imiquimod (IMQ)-stimulated keratinocytes was increased following the increase in compound lipophilicity. Naringenin, a flavanone analog with three hydroxyl moieties, could suppress IL-6 overexpression to baseline control. We assessed the anti-inflammatory potency of the chemicals in comparison with tacrolimus as reference in a psoriasis-like mouse model. Flavanone was found to mitigate scaling and epidermal hyperplasia at a higher level than naringenin. Flavanone lessened IL-6 overexpression by 80% in the psoriasiform plaque. The skin barrier function recorded by transepidermal water loss (TEWL) was recovered by naringenin but not flavanone. The experimental data indicate that naringenin and flavanone are potential candidates for anti-psoriatic therapy.

The effectiveness and prognostic factors of radioactive iodine-125 seed implantation for the treatment of cervical lymph node recurrence of esophageal squamous cell carcinoma after external beam radiation therapy.

PURPOSE: To analyze factors influencing the efficacy of 125I seed implantation in the treatment of in-field cervical lymph node recurrence of esophageal squamous cell carcinoma (ESCC) after external beam radiation therapy. MATERIAL AND METHODS: We conducted a retrospective review of 36 patients with in-field cervical metastatic lymph nodes recurrence of esophageal squamous cell carcinoma (CML-ESCC) after external beam radiation therapy treatment, who underwent 125I seed implantation in our department from 2013 to 2019. Previous cumulative external irradiation dose ranged from 20 to 66 Gy (median, 60 Gy). The post-implant efficacy was evaluated by response evaluation criteria in solid tumors (RECIST) version 1.1, and an adverse event was evaluated by the Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer Late Radiation Morbidity Score (EORTC). COX proportional hazards model was used to analyze risk factors affecting effectiveness. RESULTS: Among 36 patients, 31 patients (86.1%) received fluorouracil-based chemotherapy (1-6 cycles) after 125I seed implantation. Local control rates at 3, 6, 12, and 24 months after implantation were 51%, 30%, 30%, and 18%, respectively, with a median of 9 months (95% CI: 6.106-11.894); survival rates after 3, 6, 12, and 24 months were 55%, 41%, 22%, and 22%, respectively, with a median of 8 months (95% CI: 5.753-10.247). Multivariate analysis showed that D90 and short-term efficacy were independent factors related to local control and survival rate (p = 0.005, < 0.001, 0.010, < 0.001). There were 2 cases (5.6%) with grade 1 skin toxicity, 1 case (2.8%) with grade 4 skin toxicity, 3 cases (8.3%) with grade 1 mucosal ulcer, and 3 cases (8.3%) with grade 1 xerostomia. CONCLUSIONS: 125I seed implantation as an effective salvage treatment shows definite efficacy and safety for patients with in-field cervical lymph node recurrence of ESCC after external beam radiation therapy.

Post-irradiation recovery time strongly influences fractional laser-facilitated skin absorption.

Fractional CO2 laser treatment has been used in some clinical trials to promote topical drug delivery. Currently, there is no standard for laser settings to achieve a feasible therapy. The cutaneous recovery following laser treatment and its influence on drug absorption have not been well explored. This study evaluated the kinetics of laser-treated skin-barrier restoration and drug permeation in nude mice. The skin recovery and observation of the process were characterized by transdermal water loss (TEWL), erythema measurement, gross appearance, optical microscopy, and scanning electron microscopy (SEM). The skin absorption of a lipophilic small permeant (tretinoin), a hydrophilic small permeant (acyclovir), and a large molecule (fluorescein isothiocyanate dextran 4 kDa, FD4) was examined in vitro using Franz cell. TEWL suggested that the laser-treated skin restored its barrier function at 16 h after irradiation. The fractional laser produced microchannels of about 150 µm in diameter and 25 µm in depth that were surrounded with thermal coagulation. The bright-field imaging indicated that the micropores were progressively closed during the recovery period but had not completely closed even after a 16-h recovery. The laser treatment led to a rapid tretinoin penetration across the skin immediately after irradiation, with a 5-fold enhancement compared to intact skin. This enhancement was gradually reduced following the increase of recovery time. Conversely, the acyclovir and FD4 permeation peaked at 1-2 h post-irradiation. The FD4 flux was even elevated as the recovery time increased. The reasons for this could have been the subsequent inflammation after laser exposure and the deficient tight junction (TJ) barrier. The confocal imaging demonstrated the perpendicular diffusion of rhodamine B and FD4 through microchannels immediately after laser exposure. The lateral diffusion from the microchannels was observed at 2 h post-irradiation. Our results revealed a time-dependent recovery of skin permeation. The time frame for applying the drugs after laser irradiation was dependent upon the permeants and their various physicochemical properties.

Elucidating the Skin Delivery of Aglycone and Glycoside Flavonoids: How the Structures Affect Cutaneous Absorption.

Flavonoids are bioactive phytochemicals that exhibit protective potential against cutaneous inflammation and photoaging. We selected eight flavonoid aglycones or glycosides to elucidate the chemistry behind their skin absorption capability through experimental and computational approaches. The skin delivery was conducted using nude mouse and pig skins mounted on an in vitro Franz cell assembly. The anti-inflammatory activity was examined using the O2•.

Antifatigue properties of tanshinone IIA in mice subjected to the forced swimming test.

CONTEXT: Tanshinone IIA (Tan IIA) is a constituent of Danshen Salvia miltiorrhiza Bunge (Lamiaceae); however, its antifatigue activity remains unclear. OBJECTIVE: To study the antifatigue properties of Tan IIA and its underlying mechanisms. MATERIALS AND METHODS: In program I, three mouse groups were separately subjected to three gavages with 0, 1 and 6 mg/kg Tan IIA and forced swimming test (FST) weekly for 8 weeks; in program II, one gavage with 0, 2 and 10 mg/kg Tan IIA was administered plus FST weekly for 4 weeks. Serum glucose, lactate, superoxide dismutase (SOD), malondialdehyde (MDA) and blood urea nitrogen (BUN) were determined after final FST. RESULTS: Tan IIA significantly prolonged swimming durations in program I but not in program II. Swimming times were 3208 ± 1054 and 2443 ± 1054 s for the 1 and 6 mg/kg treatments and 856 ± 292 s for the vehicle control. The two doses significantly reduced serum glucose levels (40.3 ± 8.5 and 60.0 1 ± 11.8 mg/kg) and lactate levels (61.3 ± 27.5 and 68.8 ± 8.5 mg/kg) in treated mice compared with those in control mice (137.5 ± 38.6 mg/kg and 122.7 ± 18.2 mg/kg, respectively). However, no significant differences were observed regarding SOD, MDA or BUN levels. DISCUSSION AND CONCLUSIONS: Tan IIA has antifatigue activity and is associated with reductions in serum glucose and lactate levels. Further studies should assess muscle hypertrophy and efficient aerobic glycolysis caused by Tan IIA. Tan IIA has potential as a pharmacological agent for fatigue resistance.

Exploring the structure-permeation relationship of topical tricyclic antidepressants used for skin analgesia.

The purpose of this study was to evaluate the skin permeation of tricyclic antidepressants (TCAs) with propamine moiety to select candidates for the development of topical analgesics to treat cutaneous pain. We sought to establish the structure-permeation relationship (SPR) of topical TCAs. The lipophilicity, melting point, and aqueous solubility were determined to develop the physicochemical characterization. The TCA permeation into pig and nude mouse skins was estimated using Franz diffusion cell. TCAs and lidocaine were comparatively examined for cutaneous analgesia by pinprick assay. Cutaneous tolerance to TCAs was assessed using nude mouse skin. The skin deposition increased following the increase of lipophilicity after excluding the effect of solubility, with clomipramine exhibiting the highest skin retention. A contrary result was observed for TCA penetration into the receptor. Of the permeants tested, clomipramine demonstrated the best skin-targeting ability. Nortriptyline and clomipramine demonstrated selective uptake into the hair follicles, exhibiting a 2.5-fold higher follicular accumulation than desipramine. Replacement of nitrogen with carbon in the seven-member ring increased skin absorption. The tertiary amine TCAs demonstrated higher absorption than the secondary amine TCAs. The position of the double bond also affected skin transport. Topical clomipramine had a longer duration of analgesic action than lidocaine (240min versus 60min). Exploring the SPR revealed that clomipramine could be an analgesic candidate drug for future development.