{"title":"Nanostructured Hybrid Polymer-Lipid Drug Delivery Platforms for Rapamycin Repositioning in Anticancer Therapy","authors":"Cinzia Scialabba, Silvia Codenotti, Delia Mandracchia, Marta Cabibbo, Alessandro Fanzani, Emanuela Fabiola Craparo, Gennara Cavallaro","doi":"10.1002/adtp.202400143","DOIUrl":"10.1002/adtp.202400143","url":null,"abstract":"<p>Here, hybrid polymer-lipid nanoparticles are designed as colloidal carriers for Rapamycin, to improve the aqueous drug stability and to support the drug repositioning for cancer treatment, that is, against rhabdomyosarcoma (RMS). With this aim, Rapamycin – loaded hybrid nanoparticles are produced by using as nanoparticle core a graft copolymer obtained from the functionalization of the α,β-poly(<i>N</i>-2-hydroxyethyl)-DL-aspartamide (PHEA) with Rhodamine B (RhB), Polylactic acid (PLA), the PHEA-<i>g</i>-RhB<i>-g-</i>PLA, and different phospholipids, that is, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) coated, pegylated and Mannose/PEG, for the surface coating. The drug loading of these samples allows for controlled release, and improves drug stability at pH 5.5 and 7.4 compared to the free drug. Chemical-physical characterization confirms the nanostructure size below 200 nm, ideal for systemic administration, and easy re-dispersibility in aqueous media. Moreover, biological characterization to test the potential use as antitumor agent shows induction of cytotoxicity in human rhabdomyosarcoma (RD) and macrophage (RAW) cell lines in a time- and concentration – dependent manner, and stimulated autophagy, comparable to the free drug. The uptake study following the fluorescence of the copolymer reveals that the hybrid nanoparticles are internalized by both tested cell lines, with a significantly higher amounts of internalized particles in the case of surface mannosylated and/or pegylated systems.</p>","PeriodicalId":7284,"journal":{"name":"Advanced Therapeutics","volume":"7 9","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141936782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Minghao Xu, Ao Zhu, Yunzhi Pan, Zainab Suleman, Junping Cheng, Mi Liu
{"title":"PLGA Nanoparticles Coated with Activated Dendritic Cell Membrane Can Prolong Protein Expression and Improve the Efficacy of mRNA","authors":"Minghao Xu, Ao Zhu, Yunzhi Pan, Zainab Suleman, Junping Cheng, Mi Liu","doi":"10.1002/adtp.202400180","DOIUrl":"10.1002/adtp.202400180","url":null,"abstract":"<p>In future, mRNA drugs likely play crucial roles in vaccines and protein replacement therapy etc. Lipid nanoparticles (LNPs) are the only formulation approved for mRNA delivery. However, in cancer vaccine, the mRNA encapsulated in LNP can only encode limited (20–40) tumor antigens. Due to highly heterogeneous of tumor cells and tumor antigens, including more diverse antigens could improve the efficacy of cancer vaccines. Including both strong immunogenic antigens and more diverse antigens could maximize the efficacy of cancer vaccines. Herein, poly (lactic-co-glycolic acid) (PLGA) nanoparticles and activated dendritic cell membrane were designed as mRNA delivery platforms, which possess merits such as prolonged protein expression, lyophilized formulation, and greater efficacy etc. Dendritic cells were activated with particles loading whole tumor antigens which can activate broad range antigen-specific T cells. The sustained release of mRNA in PLGA nanoparticles can significantly prolong protein expression in APCs, and lyophilization improved the stability of mRNA formulation. Compared with LNPs, these nanovaccines significantly improved the therapeutic efficacy of mRNA. In addition, tumor antigen-specific T cells in mice treated with nanovaccines was significantly greater than that treated with LNPs. Overall, a new platform for delivering mRNA was demonstrated, that can prolong protein expression and have better efficacy.</p>","PeriodicalId":7284,"journal":{"name":"Advanced Therapeutics","volume":"7 10","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141936783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Federica Foglietta, Marta Giacone, Gianni Durando, Roberto Canaparo, Loredana Serpe
{"title":"Sonodynamic Treatment Triggers Cancer Cell Killing by Doxorubicin in P-Glycoprotein-Mediated Multidrug Resistant Cancer Models","authors":"Federica Foglietta, Marta Giacone, Gianni Durando, Roberto Canaparo, Loredana Serpe","doi":"10.1002/adtp.202400070","DOIUrl":"10.1002/adtp.202400070","url":null,"abstract":"<p>Doxorubicin is a widely used chemotherapeutic agent that can be hampered in its efficacy by the occurrence of multidrug resistance (MDR), due to the overexpression of the drug efflux transporter P-glycoprotein. As overcoming MDR still remains an unmet clinical need, this work aims at investigating an innovative strategy. Sonodynamic therapy (SDT) selectively kills cancer cells by combining low-intensity ultrasound (US) with a responsive chemical agent (sonosensitiser) that can be activated to produce reactive oxygen species (ROS). Therefore, the efficacy of SDT, using doxorubicin as sonosensitiser, is studied on human MDR ovarian (A2780/MDR) and colon (HT-29/MDR) cancer cells. The ultrasound exposure of MDR cells pre-incubated with non-cytotoxic concentrations of doxorubicin for 1 h has induced a statistically significant decrease of cell proliferation after 72 h. Interestingly, US has selectively triggered the ROS-mediated cytotoxicity of the doxorubicin entrapped into the cancer cell membrane leading to necrotic cancer cell death by lipid peroxidation. Moving from 2D to 3D HT-29/MDR cell cultures, the ability of SDT to reduce the growth of MDR spheroids by inducing significant necrotic cancer cell death is also confirmed. In conclusion, SDT can have a role in treating MDR tumors by eliciting the ROS-mediated cytotoxicity of doxorubicin.</p>","PeriodicalId":7284,"journal":{"name":"Advanced Therapeutics","volume":"7 9","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/adtp.202400070","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141882532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Miji Kim, Wonhyoung Park, Hee Seung Kim, Soo Jin Park, Whasun Lim, Gwonhwa Song, Sunwoo Park
{"title":"Dimethyl Fumarate Ameliorates the Endometriosis Through Anti-Inflammatory and Anti-Proliferation Mechanisms In Vitro and In Vivo","authors":"Miji Kim, Wonhyoung Park, Hee Seung Kim, Soo Jin Park, Whasun Lim, Gwonhwa Song, Sunwoo Park","doi":"10.1002/adtp.202400237","DOIUrl":"10.1002/adtp.202400237","url":null,"abstract":"<p>Dimethyl fumarate is a widely known therapeutic agent with anti-inflammatory properties for psoriasis and multiple sclerosis. Despite the current attempts to use dimethyl fumarate for treating various inflammatory diseases, its effects on endometriosis have not been previously reported. Endometriosis is a genital disease that causes various health problems in women, and treatment methods targeting the inflammatory environment are being attempted. Therefore, it is hypothesized that dimethyl fumarate has therapeutic effects on endometriosis through its anti-inflammatory effects. Dimethyl fumarate exerted remarkable effects on cellular mechanisms, including reactive oxygen species production, activation of mitogen‑activated protein kinase signals, loss of mitochondrial function, and disruption of calcium ion homeostasis in the immortalized human ovarian endometrial stromal cells. In an endometriosis mouse model, dimethyl fumarate downregulated cell cycle-related genes and induced inhibitory effects on endometriosis lesion growth. In particular, the immune cell population and expression of inflammatory cytokines such as IL-1β, IL-6, and IL-10 are regulated by dimethyl fumarate. These results support its potential as a therapeutic agent to control the excessive inflammatory environment in patients with endometriosis. This study identifies for the first time that dimethyl fumarate, which is already in clinical use, can be used to treat endometriosis.</p>","PeriodicalId":7284,"journal":{"name":"Advanced Therapeutics","volume":"7 11","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141882656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"KS-133/KS-487 Nanoparticles Exhibit Potent Antitumor Effects through Synergistic LRP1 Targeting and VIPR2 Inhibition: Therapeutic Nanoarchitectonics for Solid Tumors","authors":"Kotaro Sakamoto, Taisei Nishiyama, Eijiro Miyako","doi":"10.1002/adtp.202400278","DOIUrl":"10.1002/adtp.202400278","url":null,"abstract":"<p>VIPR2 is associated with psychiatric disorders, breast cancer metastasis, and cancer immunostimulation. The VIPR2 antagonist KS-133 changes the polarity of macrophages to the M1 type, and nanoparticles (NPs) releasing KS-133 exhibit antitumor effects against mouse colon cancer cells (CT26) in vivo. To enhance the antitumor effect of KS-133 NPs, KS-133 NPs are combined with the peptide KS-487 targeting LRP1, which is expressed on CT26 cells. Subcutaneous injection of NPs containing indocyanine green (ICG) fluorescent dye and presenting KS-487 in CT26 subcutaneous tumor-bearing mice resulted in significant accumulation of ICG in the CT26 tumor compared to administration of NPs without KS-487. NPs containing KS-133 and presenting KS-487 (KS-133/KS-487 NPs) exhibited dose-dependent antitumor effects in CT26 subcutaneous tumor-bearing mice; the antitumor effects are more potent than the effects of KS-133 NPs without KS-487. In addition, CD8-positive T cells and macrophages significantly infiltrated into CT26 tumors after injection of KS-133/KS-487 NPs. Thus, KS-133/KS-487 NPs efficiently deliver KS-133 to CT26 tumors via LRP1-targeting and activate immune system cells such as CD8 positive T cells and macrophages via KS-133 inhibition of VIPR2 signaling, resulting in antitumor effects. These results demonstrate the potential of KS-133/KS-487 NPs as a therapeutic candidate for treating solid tumors.</p>","PeriodicalId":7284,"journal":{"name":"Advanced Therapeutics","volume":"7 11","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141882533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Francesco Bisconti, Beatrice Vilardo, Gaia Corallo, Francesca Scalera, Giuseppe Gigli, Annalisa Chiocchetti, Alessandro Polini, Francesca Gervaso
{"title":"An Assist for Arthritis Studies: A 3D Cell Culture of Human Fibroblast-Like Synoviocytes by Encapsulation in a Chitosan-Based Hydrogel","authors":"Francesco Bisconti, Beatrice Vilardo, Gaia Corallo, Francesca Scalera, Giuseppe Gigli, Annalisa Chiocchetti, Alessandro Polini, Francesca Gervaso","doi":"10.1002/adtp.202400166","DOIUrl":"10.1002/adtp.202400166","url":null,"abstract":"<p>Osteoarthritis (OA) and Rheumatoid arthritis (RA) are the most common arthritis in which the synovium is involved, but the cellular and molecular basis of these pathologies still need better elucidation. Fibroblast-like synoviocytes (FLS), one of the cellular elements of the synovium, play a key role in RA, an autoimmune disease characterized by joint inflammation and systemic symptoms that afflicts 1% of worldwide population. Despite articular damage starts from synovium and then proceeds involving cartilage till bone erosion, several 3D in vitro models are reported for cartilage and bone while only a few studies focused on the synovial component. Here, a hydrogel formulation suitable for 3D culturing human fibroblast-like synoviocytes and evaluated its suitability with non-RA and RA patients derived-cells is developed. Among different formulations, a chitosan (Cs)-based hydrogel, constituted by 70% of Cs and 30% of Matrigel, showed the best results in terms of stability as well as cell growth and morphology: non-RA and RA FLS are able to grow within the hydrogel forming a complex 3D network. Thanks to the low cost, and high market availability of chitosan, this system represents a good alternative to the use of sole Matrigel for encapsulating human synoviocytes.</p>","PeriodicalId":7284,"journal":{"name":"Advanced Therapeutics","volume":"7 12","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/adtp.202400166","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141886816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Ring Finger Protein 217 Inhibits Ovarian Cancer Progression by Down-Regulating HAX1 Expression","authors":"Lili Zhou, Junbo Liu, Min Zhou, Lan Xu","doi":"10.1002/adtp.202400123","DOIUrl":"10.1002/adtp.202400123","url":null,"abstract":"<p>Ring finger protein 217 (RNF217) has been found to interact with the antiapoptotic protein HS-1-associated protein X-1 (HAX-1) in myeloid leukemia cells. However, the understanding of RNF217 in ovarian cancer progression remains limited. The relative expression of <i>RNF217</i> is screened in ovarian cancer using the GEPIA database and calculated its correlation with MKI67, CCNB1, and CDK4. OVCAR-3 and SK-OV-3 cells are transfected with <i>RNF217</i>-overexpression plasmids. Cell-counting kit-8 assay is utilized to assess proliferation. Immunoprecipitation is performed to reveal the interaction between RNF217 and HAX-1, and a cycloheximide chase assay is performed to analyze HAX-1 degradation. The GEPIA database indicated down-regulated expression of <i>RNF217</i> in ovarian cancer, negatively correlated with <i>MKI67</i> (R = -0.26, <i>P</i> = 1.8e-09), <i>CCNB1</i> (R = -0.37, <i>P</i> = 3.2e-18), and <i>CDK4</i> expression (R = -0.24, <i>P</i> = 3.4e-08). <i>RNF217</i> overexpression down-regulated the relative expression of <i>MKI67</i>, <i>CCNB1</i>, and <i>CDK4</i> in OVCAR-3 and SK-OV-3 cells, resulting in diminished proliferation. In vivo studies using OVCAR-3 and SK-OV-3 cell line-derived xenograft models also showed that <i>RNF217</i> overexpression reduced ovarian cancer volume and weight. Furthermore, RNF217 overexpression in SK-OV-3 cells inhibited the protein expression of HAX1 by reducing its stability. In conclusion, RNF217 inhibits ovarian cancer progression by down-regulating HS-1-associated protein X-1 expression.</p>","PeriodicalId":7284,"journal":{"name":"Advanced Therapeutics","volume":"7 9","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141866459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Uncovering the Elusive Structures and Mechanisms of Prevalent Antidepressants","authors":"Jieye Lin, Guanhong Bu, Johan Unge, Tamir Gonen","doi":"10.1002/adtp.202400117","DOIUrl":"10.1002/adtp.202400117","url":null,"abstract":"<p>Most treatments to alleviate major depression work by either inhibiting human monoamine transporters, vital for the reuptake of monoamine neurotransmitters, or by inhibiting monoamine oxidases, which are vital for their degradation. The analysis of the experimental 3D structures of those antidepressants in their drug formulation state is key to precision drug design and development. In this study, microcrystal electron diffraction (MicroED) is applied to reveal the atomic 3D structures for the first time of five of the most prevalent antidepressants (reboxetine, pipofezine, ansofaxine, phenelzine, and bifemelane) directly from the commercially available powder of the active ingredients. Their modes of binding are investigated by molecular docking, revealing the essential contacts and conformational changes into the biologically active state. This study underscores the combined use of MicroED and molecular docking to uncover elusive drug structures and mechanisms to aid in further drug development pipelines.</p>","PeriodicalId":7284,"journal":{"name":"Advanced Therapeutics","volume":"7 9","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/adtp.202400117","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141866458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lei Chen, Qi Liu, Pingping Li, Shuanghong Wei, Yanguang Guo, Ping Chen, Haiyong Ni, Shizhong Wei, Xingxing Huo
{"title":"The Near-Infrared Light Emitted by LiScO2:Cr3+ Phosphor Used to Induce Gland Secretion for Sjogren's Syndrome","authors":"Lei Chen, Qi Liu, Pingping Li, Shuanghong Wei, Yanguang Guo, Ping Chen, Haiyong Ni, Shizhong Wei, Xingxing Huo","doi":"10.1002/adtp.202400125","DOIUrl":"10.1002/adtp.202400125","url":null,"abstract":"<p>Photobiomodulation is promisingly used as a noninvasive new weapon against Sjogren's syndrome, which is a disorder of immune system with two main symptoms of dry eyes and a dry mouth. This work reports a new NIR LED device made from LiScO<sub>2</sub>:Cr<sup>3+</sup> phosphor for the application. The absorbance, internal, and external quantum efficiency of the optimal Li(Sc<sub>0.98</sub>Cr<sub>0.02</sub>)O<sub>2</sub> phosphor reach 40.9%, 34.5%, and 14.1%, respectively; and the output power and energy conversion efficiency of the LED device packaged using the phosphor driven under 20 mA are 4.23 mW, respectively. The emission spectrum of the LED device can well cover the action spectrum of oxidized Cu<sub>A</sub> in cytochrome c oxidase molecules. Both the pathological changes of mice submandibular gland and the expression of human submandibular gland epithelial cells (HSG) in AQP5, M3R andEGR1 confirm that the NIR light has great potential application for treating Sjogren's syndrome. Moreover, study with mice approved that the therapy using the NIR light is more efficient than the conventional medicine treatment using hydroxychloroquine sulfate.</p>","PeriodicalId":7284,"journal":{"name":"Advanced Therapeutics","volume":"7 9","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141866460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}