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Liposomal doxorubicin/ Doxil biodistribution. Mice carrying HCC1954 tumors were intravenously injected with PBS, Doxil (1 mg/kg), or JO-1 (2 mg/kg) followed by Doxil 1 hour later. Two hours after PBS or Doxil injection, mice were sacrificed, blood was flushed from the system, and
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Epithelial junctions between tumor cells inhibit the penetration of anticancer drugs into tumors. We previously reported on recombinant adenovirus serotype 3-derived protein (JO-1), which triggers transient opening of intercellular junctions in epithelial tumors through binding to desmoglein 2 (DSG2), and enhances the antitumor effects of several t...
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... JO-1 was shown to enhance the antitumor effects of liposomal doxorubicin in the prostate cancer model (Fig. 1C) and the model with subcutaneous tumors derived from primary ovarian cancer cells (ref. 16; Supplementary Fig. S3A). The residual tumor mass seen in JO-1 plus chemotherapy treated mice in Fig. 1A and C only contained tumor stroma and infiltrating leukocytes upon histologic inspection. ...
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... of these drugs into tumors. If our hypothesis is correct, JO-1-mediated junction opening should have less effects on drugs smaller than 500 Da. To test this hypothesis, we evaluated the effects of JO-1 cotherapy on cisplatin, which has a molecular weight of 300 Da in models of breast (Fig. 1D), lung ( Fig. 1E), and ovarian (Supple- mentary Fig. S3B). Notably, it has been shown before that the cell lines used in this study were sensitive to cisplatin in culture (16,17). Further support for the hypothesis that larger drugs benefit more from JO-1 cotherapy comes from a study with cyclophosphamide (molecular weight 260), in which JO-1 also did not significantly enhance the thera- ...
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... the drug exposure to normal tissue thus providing a larger therapeu- tic window. In support of this speculation, using an ELISA to measure PEGylated compounds in tissues (13), we found significantly more liposomal doxorubicin in tumors and less in other tissues in mice that received JO-1 prior to intravenous liposomal doxorubicin injection (Fig. 3A). Immunofluorescence analysis of tissue sections revealed more Doxil signals in tumors of JO-1 þ Doxil-treated mice (Fig. 3B). In these animals, Doxil was found more dispersed over a greater distance from blood vessels, suggesting better intratumoral penetration and absorption by tumor tissue (Fig. ...
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... an ELISA to measure PEGylated compounds in tissues (13), we found significantly more liposomal doxorubicin in tumors and less in other tissues in mice that received JO-1 prior to intravenous liposomal doxorubicin injection (Fig. 3A). Immunofluorescence analysis of tissue sections revealed more Doxil signals in tumors of JO-1 þ Doxil-treated mice (Fig. 3B). In these animals, Doxil was found more dispersed over a greater distance from blood vessels, suggesting better intratumoral penetration and absorption by tumor tissue (Fig. ...
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... intravenous liposomal doxorubicin injection (Fig. 3A). Immunofluorescence analysis of tissue sections revealed more Doxil signals in tumors of JO-1 þ Doxil-treated mice (Fig. 3B). In these animals, Doxil was found more dispersed over a greater distance from blood vessels, suggesting better intratumoral penetration and absorption by tumor tissue (Fig. ...
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Citations
... Recent reports have shown that Ad3 fiber knob-containing recombinant junction opening proteins (JO-1,2,3,4) are able to bind to and trigger DSG2 shedding, causing a junctional opening (141). Relevant to this review, when administered in vivo in combination with chemotherapy, JO1/4 increased the efficacy of chemotherapeutic drugs, resulting in decreased tumor growth and delayed drug resistance (142)(143)(144). Capitalizing on this biological function for better cancer outcomes is yet to be fully realized and warrants careful consideration. ...
Desmoglein-2 (DSG2) is a calcium-binding single pass transmembrane glycoprotein and a member of the large cadherin family. Until recently, DSG2 was thought to only function as a cell adhesion protein embedded within desmosome junctions designed to enable cells to better tolerate mechanical stress. However, additional roles for DSG2 outside of desmosomes are continuing to emerge, particularly in cancer. Herein, we review the current literature on DSG2 in cancer and detail its impact on biological functions such as cell adhesion, proliferation, migration, invasion, intracellular signaling, extracellular vesicle release and vasculogenic mimicry. An increased understanding of the diverse repertoire of the biological functions of DSG2 holds promise to exploit this cell surface protein as a potential prognostic biomarker and/or target for better patient outcomes. This review explores the canonical and non-canonical functions of DSG2, as well as the context-dependent impacts of DSG2 in the realm of cancer.
... Furthermore, preclinical studies proved the safety of this treatment in Macaca fascicularis [25]. Currently, the JO-1 protein and its high-affinity version JO-4 protein are under evaluation for clinical application [26,27]. Recent research developed an Ad5-based helper-dependent adenovirus (HDAd) vector with an Ad3 fiber knob containing the JO4 mutation (HDAd5/3+) [28]. ...
... The recombinant Ad3 PtDd, named junction opener protein (JO-1), can bind to DSG2 and trigger intracellular signaling, resulting in the transient opening of junctions between epithelial cells. The opening of tight junctions with JO-1 protein increased the monoclonal antibody and chemotherapy penetration of tumor masses, leading to the greater efficacy of immuno-and chemotherapy [26,45]. Interestingly, not only the co-administration but also the expression of a secreted form of JO-1 protein in Ad5-based oncolytic adenovirus presented a significantly greater antitumor effect than the parental vector [46]. ...
... To further increase the therapeutic effect, JO-4 protein, a high-affinity junction opener, was previously generated [22]. Both JO-1 and JO-4 have been shown to be well tolerated in vivo and are being developed as cancer co-therapeutics [26,45]. ...
Carcinomas are characterized by a widespread upregulation of intercellular junctions that create a barrier to immune response and drug therapy. Desmoglein 2 (DSG2) represents such a junction protein and serves as one adenovirus receptor. Importantly, the interaction between human adenovirus type 3 (Ad3) and DSG2 leads to the shedding of the binding domain followed by a decrease in the junction protein expression and transient tight junction opening. Junction opener 4 (JO-4), a small recombinant protein derived from the Ad3 fiber knob, was previously developed with a higher affinity to DSG2. JO-4 protein has been proven to enhance the effects of antibody therapy and chemotherapy and is now considered for clinical trials. However, the effect of the JO4 mutation in the context of a virus remains insufficiently studied. Therefore, we introduced the JO4 mutation to various adenoviral vectors to explore their infection properties. In the current experimental settings and investigated cell lines, the JO4-containing vectors showed no enhanced transduction compared with their parental vectors in DSG2-high cell lines. Moreover, in DSG2-low cell lines, the JO4 vectors presented a rather weakened effect. Interestingly, DSG2-negative cell line MIA PaCa-2 even showed resistance to JO4 vector infection, possibly due to the negative effect of JO4 mutation on the usage of another Ad3 receptor: CD46. Together, our observations suggest that the JO4 vectors may have an advantage to prevent CD46-mediated sequestration, thereby achieving DSG2-specific transduction.
... Co-administration of JO-1 was previously shown to facilitate the intratumoral penetration and therapeutic efficacy of monoclonal antibodies (mAbs) such as the anti-Her2/neu mAb trastuzumab (Herceptin) and the EGFR inhibitor cetuximab (Erbitux) (Beyer et al., 2011;Wang et al., 2018). Furthermore, JO-1 was tested in combination with several chemotherapeutic drugs, including paclitaxel (Taxol), irinotecan (Camptosar), nanoparticle albumin-bound paclitaxel (Abraxane), and liposomal doxorubicin (Doxil) (Beyer et al., 2011;Beyer et al., 2012;Wang et al., 2018). JO-1 co-therapy enhanced the efficacy of these drugs and overcame drug resistance in several tumor models while reducing the drug doses necessary for therapeutic effect (Beyer et al., 2012). ...
... Furthermore, JO-1 was tested in combination with several chemotherapeutic drugs, including paclitaxel (Taxol), irinotecan (Camptosar), nanoparticle albumin-bound paclitaxel (Abraxane), and liposomal doxorubicin (Doxil) (Beyer et al., 2011;Beyer et al., 2012;Wang et al., 2018). JO-1 co-therapy enhanced the efficacy of these drugs and overcame drug resistance in several tumor models while reducing the drug doses necessary for therapeutic effect (Beyer et al., 2012). JO-1 and variants of this protein (such as the affinity-enhanced version, JO-4) are, therefore, interesting for clinical application (Wang et al., 2018). ...
Conventional chemotherapy lacking target selectivity often leads to severe side effects, limiting the effectiveness of chemotherapy. Therefore, drug delivery systems ensuring both selective drug release and efficient intracellular uptake at the target sites are highly demanded in chemotherapy to improve the quality of life of patients with low toxicity. One of the effective approaches for tumor-selective drug delivery is the adoption of functional ligands that can interact with specific receptors overexpressed in malignant cancer cells. Various functional ligands including folic acid, hyaluronic acid, transferrin, peptides, and antibodies, have been extensively explored to develop tumor-selective drug delivery systems. Furthermore, cell-penetrating peptides or ligands for tight junction opening are also actively pursued to improve the intracellular trafficking of anticancer drugs. Sometimes, multiple ligands with different roles are used in combination to enhance the cellular uptake as well as target selectivity of anticancer drugs. In this review, the current status of various functional ligands applicable to improve the effectiveness of cancer chemotherapy is overviewed with a focus on their roles, characteristics, and preclinical/clinical applications.
... In 2011, we identified DSG2 as a receptor for species B adenoviruses, 9 and this led to research that was mostly focused on its role as an epithelial junction protein. 9,10,20,[41][42][43][44][45] The presence of DSG2 on HSCs was first reported by Ebert et al 13 and then further elucidated in this study. The ubiquitous presence of DSG2 on HSCs, together with the finding that DSG2 is also elevated on endothelial progenitor cells, points toward a potential role of DSG2 in linking HSCs and bone marrow endothelial cells, thereby retaining HSCs in the bone marrow. ...
We developed a new in vivo hematopoietic stem cell (HSC) gene therapy approach that involves only intravenous injections and does not require myeloablation/conditioning and HSC transplantation. In this approach, HSCs are mobilized from the bone marrow into the peripheral blood stream and transduced with intravenously injected helper-dependent adenovirus (HDAd) vectors. A fraction of transduced HSCs returns to the bone marrow and persists there long-term. Here, we report desmoglein 2 (DSG2) as a new receptor that can be employed for in in vivo HSC transduction. We developed HDAd5/3+ vectors that use DSG2 as a high-affinity attachment receptor and studied in vivo HSC transduction and safety after intravenous injection of an HDAd5/3+GFP vector in G-CSF/AMD3100(Plerixafor)-mobilized rhesus macaques. Unlike previously used CD46-targeting HDAd5/35++ vectors, HDAd5/3+ virions were not sequestered by rhesus erythrocytes and therefore mediated ~10-fold higher GFP marking rates in primitive HSCs (CD34+/CD45RA-/CD90+ cells) in the bone marrow at day 7 after vector injection. To further increase the return of in vivo transduced, mobilized HSCs to the bone marrow, we transiently expressed CXC motif chemokine receptor 4 (cxcr4) in mobilized HSCs from the HDAd5/3+ vector. In vivo transduction with a HDAd5/3+GFP/cxcr4 vector at a low dose of 0.4x1012vp/kg resulted in up to 7% of GFP-positive CD34+/CD45RA-/CD90+ cells in the bone marrow. This transduction rate is a solid basis for in vivo base or prime editing in combination with natural or drug-induced expansion of edited HSCs. Furthermore, our study provides new insights into HSC biology and trafficking after mobilization in non-human primates.
... We have capitalized on this mechanism and created recombinant proteins that contain the minimal structural domains from Ad3 that are required for junction opening 7,8 . We have shown that intravenous injection of junction opener proteins increases intratumoral penetration and efficacy of monoclonal antibodies and chemotherapeutic drugs in a broad range of human xenograft models 9,10 . ...
... This demonstrates the therapeutic potency of c-JO4 in vivo. Notably, we have previously shown in tumor xenograft models (including 11,18 , breast cancer 7,9 , and prostate cancer 9 models) that JO4 (r-JO4) alone does not exert antitumor activity, i.e. tumor growth was not significantly different between groups that were injected with PBS or JO4 alone. Importantly, in all of these models, intravenous injection of JO4 one hour before the administration of chemotherapy drugs significantly enhanced chemotherapy. ...
... Three c-JO4 doses (4, 12, and 24 mg/kg) were tested, and each group had 2 female monkeys (Fig. 2B). The dose range was based on the efficacy studies in xenograft tumor models 9,10,19,20 , safety studies in DSG2 transgenic mice (see above), and pilot studies in cynomolgus monkeys that were performed with 2 mg/kg r-JO4 11 . c-JO4 was well tolerated when administered intravenously to female monkeys at dose levels up to 24 mg/kg. ...
Our goal is to overcome treatment resistance in ovarian cancer patients which occurs in most cases after an initial positive response to chemotherapy. A central resistance mechanism is the maintenance of desmoglein-2 (DSG2) positive tight junctions between malignant cells that prevents drug penetration into the tumor. We have generated JO4, a recombinant protein that binds to DSG2 resulting in the transient opening of junctions in epithelial tumors. Here we present studies toward the clinical translation of c-JO4 in combination with PEGylated liposomal doxorubicin/Doxil for ovarian cancer therapy. A manufacturing process for cGMP compliant production of JO4 was developed resulting in c-JO4. GLP toxicology studies using material from this process in DSG2 transgenic mice and cynomolgus macaques showed no treatment-related toxicities after intravenous injection at doses reaching 24 mg/kg. Multiple cycles of intravenous c-JO4 plus Doxil (four cycles, 4 weeks apart, simulating the treatment regimen in the clinical trial) elicited antibodies against c-JO4 that increased with each cycle and were accompanied by elevation of pro-inflammatory cytokines IL-6 and TNFα. Pretreatment with steroids and cyclophosphamide reduced anti-c-JO4 antibody response and blunted cytokine release. Our data indicate acceptable safety of our new treatment approach if immune reactions are monitored and counteracted with appropriate immune suppression.
... To effectively penetrate the tumor through anatomical barriers and actively diffuse within solid tumors, therapeutic agents must bypass the intercellular contacts that seal the boundaries of normal endothelial cells and intercellular spaces within the tumor. To date, the most promising agents that open up cell contacts are the junction opener proteins (JO) obtained from human adenovirus serotype 3 [8][9][10][11]. Protein JO-1 and its improved variant JO-4 bind to desmoglein 2 on the cell surface, which leads to the activation of MAP-kinases that activate the metalloprotease ADAM17, which breaks down desmoglein of cell contacts [10]. Activation of MAP-kinases leads to transient transdifferentiation of epithelial cells, including a decrease in the expression of adhesion and blocking cell contact proteins, thus solving the problem of the diffusion of drugs within the tumor [9]. ...
... JO-4 was obtained by screening mutant variants and has a higher affinity for desmoglein-2 than JO-1. JO proteins are able to induce the opening of cell contacts in the normal stratified epithelium; however, JO-1 has been shown to preferentially act on intercellular contacts of tumors and does not cause serious side effects at therapeutic doses [9,11,12]. This was confirmed for JO-1 in xenograft models [9,12], the safety of JO-4 has also been shown in macaques [8]. ...
... Thus, JO proteins can be used to overcome anatomical barriers and improve the diffusion of therapeutic agents within a tumor. At the same time, the change in the cellular phenotype of the tumor is temporary, and long-term experiments have shown that the use of JO in vivo does not increase the likelihood of metastases [11]. ...
The development of non-invasive photothermal therapy (PTT) methods utilizing nanoparticles as sensitizers is one of the most promising directions in modern oncology. Nanoparticles loaded with photothermal dyes are capable of delivering a sufficient amount of a therapeutic substance and releasing it with the desired kinetics in vivo. However, the effectiveness of oncotherapy methods, including PTT, is often limited due to poor penetration of sensitizers into the tumor, especially into solid tumors of epithelial origin characterized by tight cellular junctions. In this work, we synthesized 200 nm nanoparticles from the biocompatible copolymer of lactic and glycolic acid, PLGA, loaded with magnesium phthalocyanine, PLGA/Pht-Mg. The PLGA/Pht-Mg particles under the irradiation with NIR light (808 nm), heat the surrounding solution by 40 °C. The effectiveness of using such particles for cancer cells elimination was demonstrated in 2D culture in vitro and in our original 3D model with multicellular spheroids possessing tight cell contacts. It was shown that the mean inhibitory concentration of such nanoparticles upon light irradiation for 15 min worsens by more than an order of magnitude: IC50 increases from 3 µg/mL for 2D culture vs. 117 µg/mL for 3D culture. However, when using the JO-4 intercellular junction opener protein, which causes a short epithelial–mesenchymal transition and transiently opens intercellular junctions in epithelial cells, the efficiency of nanoparticles in 3D culture was comparable or even outperforming that for 2D (IC50 = 1.9 µg/mL with JO-4). Synergy in the co-administration of PTT nanosensitizers and JO-4 protein was found to retain in vivo using orthotopic tumors of BALB/c mice: we demonstrated that the efficiency in the delivery of such nanoparticles to the tumor is 2.5 times increased when PLGA/Pht-Mg nanoparticles are administered together with JO-4. Thus the targeting the tumor cell junctions can significantly increase the performance of PTT nanosensitizers.
... Some of these side effects were described as critical, e.g., severe vomiting, diarrhea, myelosuppression, and liver and renal impairments [7]. However, continuous trials have attempted to provide alternative dosage forms for chemotherapeutic agents and co-administration with other curative drugs to solve this problem [8][9][10][11]. ...
The study aimed to develop a new glutathione (GSH) oral formulation to enhance the delivery of GSH and counter the nephrotoxicity of the anticancer drug, cyclophosphamide (CP). A nanostructured lipid carrier glutathione formulation (GSH-NLCs) composed of glutathione (500 mg), stearic and oleic acid (300 mg, each), and Tween ® 80 (2%, w/v) was prepared through the emul-sification-solvent-evaporation technique, which exhibited a 452.4 ± 33.19 nm spheroidal-sized particulate material with narrow particle size distributions, −38.5 ± 1.4 mV zeta potential, and an en-trapment efficiency of 79.8 ± 1.9%. The GSH formulation was orally delivered, and biologically tested to ameliorate the CP-induced renal toxicity in a rat model. Detailed renal morphology, before and after the GSH-NLCs administration, including the histopathological examinations, confirmed the ameliorating effects of the prepared glutathione formulation together with its safe oral delivery. CP-induced oxidative stress, superoxide dismutase depletion, elevation of malondialdehyde levels, depletion of Bcl-2 concentration levels, and upregulated NF-KB levels were observed and were controlled within the recommended and near normal/control levels. Additionally, the inflammatory mediator marker, IL-1β, serum levels were marginally normalized by delivery of the GHS-NLCs formulation. Oral administration of the pure glutathione did not exhibit any ameliorating effects on the renal tissues, which suggested that the pure glutathione is reactive and is chemically transformed during the oral delivery, which affected its pharmacological action at the renal site. The protective effects of the GSH-NLCs formulation through its antioxidant and anti-inflammatory effects suggested its prominent role in containing CP-induced renal toxicity and renal tissue damage, together with the possibility of administrating higher doses of the anticancer drug, cyclophospha-mide, to achieve higher and effective anticancer action in combination with the GSH-NLCs formulation. Citation: Ahmad, A.M.; Mohammed, H.A.; Faris, T.M.; Hassan, A.S.; Mohamed, H.B.; El Dosoky, M.I.; Aboubakr, E.M. Nano-Structured Lipid Carriers-Based Oral Glutathione Formulation Mediates Renoprotection against Cyclophosphamide-Induced Nephrotoxicity, and Improves Oral-Bioavailability of Glutathione Confirmed through RP-HPLC Micellar Liquid Chromatography. Molecules 2021, 26, 7491. https://
... The dose range was based on e cacy studies in xenograft tumor models 10,[18][19][20] , safety studies in DSG2 transgenic mice (see above), and pilot studies in cynomolgus monkeys that were performed with 2 mg/kg r-JO4 11 . c-JO4 was well tolerated when administered intravenously to female monkeys at dose levels up to 24 mg/kg. ...
Our goal is to overcome treatment resistance in ovarian cancer patients, which occurs in most cases after an initial positive response to chemotherapy. A central resistance mechanism is the maintenance of desmoglein-2 (DSG2)-positive tight junctions between malignant cells, which prevents drug penetration into the tumor. We generated JO4, a recombinant protein that binds to DSG2, resulting in the transient opening of junctions in epithelial tumors. Here, we present studies on the clinical translation of JO4 in combination with PEGylated liposomal doxorubicin/Doxil® for ovarian cancer therapy. A manufacturing process for cGMP-compliant production of JO4 was developed. GLP toxicology studies using material from this process in DSG2 transgenic mice and cynomolgus macaques showed no treatment-related toxicities after intravenous injection at doses reaching 24 mg/kg. Multiple cycles of intravenous JO4 plus Doxil® (4 cycles, 4 weeks apart, simulating the treatment regimen in the clinical trial) elicited antibodies against JO4 that increased with each cycle and were accompanied by elevation of pro-inflammatory cytokines IL6 and TNF. Pretreatment with steroids and cyclophosphamide reduced the anti-JO4 antibody response and blunted cytokine release. Our data indicate acceptable safety of our new treatment approach if immune reactions are monitored and counteracted with appropriate immune suppression.
... The traditional administration of chemotherapeutics is intravenous injection. The drugs are rapidly distributed throughout the body through the blood circulation [13,14]. It generally results in a short blood half-life and prominent off-target accumulation in multiple healthy organs. ...
A limitation of current anticancer nanocarriers is the contradiction between multiple functions and favorable biocompatibility. Thus, we aimed to develop a compatible drug delivery system loaded with paclitaxel (PTX) for hepatocellular carcinoma (HCC) therapy. A basic backbone, PTX-loaded poly (3-hydroxybutyrate-co-3-hydroxyvalerate) PHBV nanoparticle (PHBV-PTX-NPs), was prepared by emulsion solvent evaporation. As a gatekeeper, the pH-sensitive coating was formed by self-polymerization of dopamine (PDA). The HCC-targeted arginine-glycine-aspartic acid (RGD)-peptide and PDA-coated nanoparticles (NPs) were combined through the Michael addition. Subsequently, the physicochemical properties of RGD-PDA-PHBV-PTX-NPs were characterized by dynamic light scattering-autosizer, transmission electron microscope, fourier transform infrared spectroscopy, differential scanning calorimetry, thermogravimetry and X-ray spectroscopy. As expected, the RGD-PDA-PHBV-PTX-NPs showed robust anticancer efficacy in a xenograft mouse model. More importantly, they exhibited lower toxicity than PTX to normal hepatocytes and mouse in vitro and in vivo, respectively. Taken together, these results indicate that the RGD-PDA-PHBV-PTX-NPs are potentially beneficial for easing conflict between multifunction and biocompatible characters of nanocarriers.
... Additionally, the importance of the type of formulation can be decisive as not all TJMs can be formulated in solid or liquid form. JO-1 has been proven to be selective for tumors [162,266], and a conjugation to TLR3 agonist poly(I:C) has been designed as an immune-oncologic agent to trigger apoptosis in tumoral cells [275]. ...
... JO-1 co-administration also increased efficacy of drugs such as PEGylated liposomal doxorubicin (Doxil®), irinotecan (Camptosar®), and nanoparticle albumin-bound (nab) paclitaxel (Abraxane®). As JO-1 co-administration increased the therapeutic index of chemotherapeutic drugs, the dose of these drugs can be reduced, thereby reducing their side effects[266]. JO-1 was also shown to target predominantly tumor cells compared to normal cells, due to higher expression of DSG-2 in the former. An improved version of JO-1, namely JO-4, has recently been studied for safety and biodistribution when co-administered with Doxil® in transgenic mice and Macaca fasicularis. ...
... This raises the question of whether JO-1 might facilitate metastasis[267]. However, none of the in vivo studies conducted in all models used has reported any evidence of increased tumor growth or macroscopic/microscopic signs of metastasis after treatment with JO-1 alone.Moreover, JO-1 injection into Her2/neu-positive HCC1954 tumor bearing mice did not cause any significant increase in the percentage of Her2/neu-positive cells circulating in the blood[266]. Hence, the hypothesis that the modulation of tumor tight junctions might promote metastasis remains to be validated using wellcontrolled experiments. ...
Intercellular tight junctions represent a formidable barrier against paracellular drug absorption at epithelia (e.g., nasal, intestinal) and the endothelium (e.g., blood-brain barrier). In order to enhance paracellular transport of drugs and increase their bioavailability and organ deposition, active excipients modulating tight junctions have been applied. First-generation of permeation enhancers (PEs) acted by unspecific interactions, while recently developed PEs address specific physiological mechanisms. Such target specific tight junction modulators (TJMs) have the advantage of a defined specific mechanism of action. To date, merely a few of these novel active excipients has entered into clinical trials, as their lack in safety and efficiency in vivo often impedes their commercialisation. A stronger focus on the development of such active excipients would result in an economic and therapeutic improvement of current and future drugs.
