Yixia Liang, R. Lei, Jiabao Tan, Junyue Fang, Lin Yu, Shiyu Tan, Yan Nie, Q. Jiang, Xiaoyun Xiao, Phei Er Saw
Antibody-drug conjugates (ADCs) have the following advantages: target specificity; wide therapeutic index; and prolonged circulation half-life. A key limitation of ADCs, however, is the large size (∼150 kDa), which markedly slows diffusion through the interstitium of solid tumors and prevents efficient penetration. To address the size issue of ADCs in targeted drug delivery, we developed a HER2-targeting peptide-mertansine conjugate (HER2-TPMC) and conducted a head-to-head comparison with HER2-targeting antibody-mertansine conjugate (HER2-TAMC) as a possible alternative for high-penetration breast cancer therapeutics. As expected, a pharmacokinetic (PK) assay revealed that HER2-TP had lower levels persisting in the circulation after 1 h (∼75%) compared to 85% of HER2-targeting antibody (HER2-TA). The cellular cytotoxic effect of HER2-TPMC was similar to HER2-TAMC in the HER2+ BT474 breast cancer cell line, thus demonstrating similar bioactivity of both conjugates. HER2-TPMC not only revealed higher uptake and specificity in in vitro 3D spheroid cultures compared to the parental drug, mertansine, but HER2-TPMC also had a significant retention in the spheroids. This finding was in stark contrast to HER2-TAMC, a large-sized conjugate which was not able to penetrate the spheroid barrier, thus resulting minimal penetration. In vivo tumoral uptake in a BT474 orthotopic model indicated increased tumor uptake and penetration of HER2-TP compared to parental drug and HER2-TAMC. To summarize, we successfully developed a HER2-targeting peptide-mertansine conjugate with specific cellular uptake that resulted in longer retention times in vitro and in vivo. HER2-TPMC (∼5 kDa in size) exhibited rapid tissue penetration and enhanced tumoral uptake and retention in vitro and in vivo. Therefore, HER2-TPMC is a reasonable alternative for HER2-positive cancer chemotherapeutics.
{"title":"HER2-targeting Peptide Drug Conjugate with Better Penetrability for Effective Breast Cancer Therapy","authors":"Yixia Liang, R. Lei, Jiabao Tan, Junyue Fang, Lin Yu, Shiyu Tan, Yan Nie, Q. Jiang, Xiaoyun Xiao, Phei Er Saw","doi":"10.15212/bioi-2023-0006","DOIUrl":"https://doi.org/10.15212/bioi-2023-0006","url":null,"abstract":"\u0000 Antibody-drug conjugates (ADCs) have the following advantages: target specificity; wide therapeutic index; and prolonged circulation half-life. A key limitation of ADCs, however, is the large size (∼150 kDa), which markedly slows diffusion through the interstitium of solid tumors and prevents efficient penetration. To address the size issue of ADCs in targeted drug delivery, we developed a HER2-targeting peptide-mertansine conjugate (HER2-TPMC) and conducted a head-to-head comparison with HER2-targeting antibody-mertansine conjugate (HER2-TAMC) as a possible alternative for high-penetration breast cancer therapeutics. As expected, a pharmacokinetic (PK) assay revealed that HER2-TP had lower levels persisting in the circulation after 1 h (∼75%) compared to 85% of HER2-targeting antibody (HER2-TA). The cellular cytotoxic effect of HER2-TPMC was similar to HER2-TAMC in the HER2+ BT474 breast cancer cell line, thus demonstrating similar bioactivity of both conjugates. HER2-TPMC not only revealed higher uptake and specificity in in vitro 3D spheroid cultures compared to the parental drug, mertansine, but HER2-TPMC also had a significant retention in the spheroids. This finding was in stark contrast to HER2-TAMC, a large-sized conjugate which was not able to penetrate the spheroid barrier, thus resulting minimal penetration. In vivo tumoral uptake in a BT474 orthotopic model indicated increased tumor uptake and penetration of HER2-TP compared to parental drug and HER2-TAMC. To summarize, we successfully developed a HER2-targeting peptide-mertansine conjugate with specific cellular uptake that resulted in longer retention times in vitro and in vivo. HER2-TPMC (∼5 kDa in size) exhibited rapid tissue penetration and enhanced tumoral uptake and retention in vitro and in vivo. Therefore, HER2-TPMC is a reasonable alternative for HER2-positive cancer chemotherapeutics.\u0000","PeriodicalId":431549,"journal":{"name":"BIO Integration","volume":"56 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114161481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Previous studies have reported the critical roles of tumor cells and the tumor microenvironment in tumor prognosis and immunotherapeutic response. However, how Tenascin-XB (TNXB) expression relates to glioma prognosis and to the levels of tumor-infiltrating immune cells in various cancers has remained elusive. Therefore, this work aimed to investigate the expression, prognostic value, biological function and correlation between TNXB expression and the levels of tumor-infiltrating immune cells in glioma tissues.Methods: First, we explored TNXB expression in glioma tissues by using online biological databases. Second, we assessed the clinical importance of TNXB expression with chi-squared tests, Cox regression and Kaplan-Meier curve analyses. Third, we examined the relationship between TNXB expression and the levels of tumor-infiltrating immune cells in glioma tissues in an online database. Additionally, we assessed the associations of TNXB expression with genetic markers of immune cells and common immune-checkpoint molecules.Results: Elevated TNXB expression in glioma tissues correlated with tumor grade, according to several databases. Elevated TNXB expression was significantly associated with negative clinicopathological manifestations and poorer prognosis, on the basis of TCGA (n=510) data. Furthermore, univariate and multivariate Cox regression indicated that TNXB was an independent indicator of glioma prognosis. Pathway enrichment analyses suggested that TNXB participates in the immune response, humoral immune response and interferon-gamma-mediated signaling pathways. Importantly, TNXB expression was significantly associated with higher levels of tumor-infiltrating immune cells in diverse cancers. Furthermore, TNXB expression was strongly associated with genetic markers of immune cells and common immune-checkpoint molecules (e.g., PD-1, PD-L1, CTLA4, TIM-3, LAG3, PDCD1LG2, TIGIT and Siglec-15).Conclusions: TNXB expression correlates with poorer prognosis and higher levels of tumor-infiltrating immune cells in several cancers. In addition, TNXB expression is likely to contribute to the regulation of dendritic cells, exhausted T cells, regulatory T cells and tumor-associated macrophages in gliomas. Consequently, TNXB may serve as an important prognostic marker and may play an immunomodulatory role in tumors.
{"title":"Roles of Tenascin-XB in the Glioma Immune Microenvironment","authors":"Chaofu Mao, Ouwen Qiu, Chengying Huang, Jing Huang, Shanqiang Qu","doi":"10.15212/bioi-2022-0014","DOIUrl":"https://doi.org/10.15212/bioi-2022-0014","url":null,"abstract":"\u0000 Background: Previous studies have reported the critical roles of tumor cells and the tumor microenvironment in tumor prognosis and immunotherapeutic response. However, how Tenascin-XB (TNXB) expression relates to glioma prognosis and to the levels of tumor-infiltrating immune cells in various cancers has remained elusive. Therefore, this work aimed to investigate the expression, prognostic value, biological function and correlation between TNXB expression and the levels of tumor-infiltrating immune cells in glioma tissues.Methods: First, we explored TNXB expression in glioma tissues by using online biological databases. Second, we assessed the clinical importance of TNXB expression with chi-squared tests, Cox regression and Kaplan-Meier curve analyses. Third, we examined the relationship between TNXB expression and the levels of tumor-infiltrating immune cells in glioma tissues in an online database. Additionally, we assessed the associations of TNXB expression with genetic markers of immune cells and common immune-checkpoint molecules.Results: Elevated TNXB expression in glioma tissues correlated with tumor grade, according to several databases. Elevated TNXB expression was significantly associated with negative clinicopathological manifestations and poorer prognosis, on the basis of TCGA (n=510) data. Furthermore, univariate and multivariate Cox regression indicated that TNXB was an independent indicator of glioma prognosis. Pathway enrichment analyses suggested that TNXB participates in the immune response, humoral immune response and interferon-gamma-mediated signaling pathways. Importantly, TNXB expression was significantly associated with higher levels of tumor-infiltrating immune cells in diverse cancers. Furthermore, TNXB expression was strongly associated with genetic markers of immune cells and common immune-checkpoint molecules (e.g., PD-1, PD-L1, CTLA4, TIM-3, LAG3, PDCD1LG2, TIGIT and Siglec-15).Conclusions: TNXB expression correlates with poorer prognosis and higher levels of tumor-infiltrating immune cells in several cancers. In addition, TNXB expression is likely to contribute to the regulation of dendritic cells, exhausted T cells, regulatory T cells and tumor-associated macrophages in gliomas. Consequently, TNXB may serve as an important prognostic marker and may play an immunomodulatory role in tumors.\u0000","PeriodicalId":431549,"journal":{"name":"BIO Integration","volume":"65 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128680033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Voice Series: Interview with Prof. Kwang Soo Kim, Harvard Medical School","authors":"","doi":"10.15212/bioi-2020-0041","DOIUrl":"https://doi.org/10.15212/bioi-2020-0041","url":null,"abstract":"","PeriodicalId":431549,"journal":{"name":"BIO Integration","volume":"8 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129209269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bone marrow mesenchymal stem cells play an important role in osteogenic differentiation, and they complete this important biological process through the coordination of various transcription factors and signal pathways. In recent years, studies have clearly confirmed that long non-coding RNAs (lncRNAs) are involved in osteogenic differentiation, which plays an important biological role in the occurrence and development of osteogenesis-related bone disease. This article reviews the roles and related mechanisms of lncRNAs in osteogenic differentiation, as well as their potential effects on a variety of bone diseases. This understanding may help researchers identify potential therapeutic targets and biological markers in the future.
{"title":"The Roles of Long Non-coding RNAs in Osteogenic Differentiation and Bone Diseases","authors":"Sen Qin, Dahua Liu, Zimo Zhou, Senxiang Chen","doi":"10.15212/bioi-2021-0025","DOIUrl":"https://doi.org/10.15212/bioi-2021-0025","url":null,"abstract":"\u0000 Bone marrow mesenchymal stem cells play an important role in osteogenic differentiation, and they complete this important biological process through the coordination of various transcription factors and signal pathways. In recent years, studies have clearly confirmed that long non-coding RNAs (lncRNAs) are involved in osteogenic differentiation, which plays an important biological role in the occurrence and development of osteogenesis-related bone disease. This article reviews the roles and related mechanisms of lncRNAs in osteogenic differentiation, as well as their potential effects on a variety of bone diseases. This understanding may help researchers identify potential therapeutic targets and biological markers in the future.\u0000","PeriodicalId":431549,"journal":{"name":"BIO Integration","volume":"76 3-4","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"120910606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiuling Li, Tiing Jen Loh, Jia Jia Lim, P. Saw, Yong Liao
{"title":"Glycan-RNA: a new class of non-coding RNA","authors":"Xiuling Li, Tiing Jen Loh, Jia Jia Lim, P. Saw, Yong Liao","doi":"10.15212/bioi-2021-0032","DOIUrl":"https://doi.org/10.15212/bioi-2021-0032","url":null,"abstract":"<jats:p>\u0000 \u0000 </jats:p>","PeriodicalId":431549,"journal":{"name":"BIO Integration","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"121198469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Asghar, R. Yousuf, M. Shoaib, M. Asghar, N. Mumtaz
The unique size and surface morphology of nanoparticles (NPs) have substantially influenced all aspects of human life, making nanotechnology a novel and promising field for various applications in biomedical sciences. Metallic NPs have gained immense interest over the last few decades due to their promising optical, electrical, and biological properties. However, the aggregation and the toxic nature of these NPs have restricted their utilization in more optimized applications. The optimum selection of biopolymers and biological macromolecules for surface functionalization of metallic NPs will significantly improve their biological applicability and biocompatibility. The present mini-review attempts to stress the overview of recent strategies involved in surface functionalization of metallic NPs, their specific biomedical applications, and comparison of their in vitro, ex vivo, and in vivo toxicities with non-functionalized metallic NPs. In addition, this review also discusses the various challenges for metallic NPs to undergo human clinical trials.
{"title":"A Review on Toxicity and Challenges in Transferability of Surface-functionalized Metallic Nanoparticles from Animal Models to Humans","authors":"M. Asghar, R. Yousuf, M. Shoaib, M. Asghar, N. Mumtaz","doi":"10.15212/BIOI-2020-0047","DOIUrl":"https://doi.org/10.15212/BIOI-2020-0047","url":null,"abstract":"\u0000 The unique size and surface morphology of nanoparticles (NPs) have substantially influenced all aspects of human life, making nanotechnology a novel and promising field for various applications in biomedical sciences. Metallic NPs have gained immense interest over the last few decades due to their promising optical, electrical, and biological properties. However, the aggregation and the toxic nature of these NPs have restricted their utilization in more optimized applications. The optimum selection of biopolymers and biological macromolecules for surface functionalization of metallic NPs will significantly improve their biological applicability and biocompatibility. The present mini-review attempts to stress the overview of recent strategies involved in surface functionalization of metallic NPs, their specific biomedical applications, and comparison of their in vitro, ex vivo, and in vivo toxicities with non-functionalized metallic NPs. In addition, this review also discusses the various challenges for metallic NPs to undergo human clinical trials.\u0000","PeriodicalId":431549,"journal":{"name":"BIO Integration","volume":"134 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126864856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zebrafish provide a convenient and unique model for studying human cancers, owing to the high similarity between zebrafish and human genomes, the availability of genetic manipulation technologies, and the availability of large numbers and transparency of zebrafish embryos. Many researchers have recently used zebrafish cancer models to examine the functions of macrophages in tumorigenesis, tumor growth and metastasis. Here, we present evidence that zebrafish cancer cells produce signals that are conserved with respect to those in humans and lead to the recruitment of heterogeneously activated macrophages in response to specific tumor types and tumorigenic stages, thereby promoting cancer initiation and progression. We also summarize how cancer cells interact with macrophages, emphasizing live imaging studies for visualization of dynamic material interchange.
{"title":"Zebrafish: An Emerging Model for Studying Macrophage Functions in Cancer","authors":"Xiuting Guo, Linjia Jiang","doi":"10.15212/bioi-2022-0023","DOIUrl":"https://doi.org/10.15212/bioi-2022-0023","url":null,"abstract":"\u0000 Zebrafish provide a convenient and unique model for studying human cancers, owing to the high similarity between zebrafish and human genomes, the availability of genetic manipulation technologies, and the availability of large numbers and transparency of zebrafish embryos. Many researchers have recently used zebrafish cancer models to examine the functions of macrophages in tumorigenesis, tumor growth and metastasis. Here, we present evidence that zebrafish cancer cells produce signals that are conserved with respect to those in humans and lead to the recruitment of heterogeneously activated macrophages in response to specific tumor types and tumorigenic stages, thereby promoting cancer initiation and progression. We also summarize how cancer cells interact with macrophages, emphasizing live imaging studies for visualization of dynamic material interchange.\u0000","PeriodicalId":431549,"journal":{"name":"BIO Integration","volume":"47 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127224543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shishi He, Yanni Fu, Zicong Tan, Qun Jiang, K. Huang, Phei Er Saw, Yan Nie, M. Guo
Nanoparticle delivery of drugs to the brain is hindered by the blood-brain barrier (BBB). In malignant glioma (MG), small disruptions in the BBB may allow nanoparticles smaller than 20 nm to penetrate the dysfunctional barrier. We previously developed ultra-small nanoparticles called hyper-cell permeable micelles (HCPMis) with a radius of ∼12 nm and found that a PEGylated HCPMi system showed enhanced cell permeability and cellular uptake, and remarkable anti-tumor properties in MG treatment. However, no study had examined the delivery of temozolomide (TMZ), the first-line drug for MG, with the HCPMi platform. Herein, we use a simple PEGylation increment system (30 wt % PEG, 40 wt % PEG and 50 wt % PEG) to develop a robust optimized HCPMi nanoplatform for TMZ delivery. All optimized HCPMi systems showed greater stability than the non-PEGylated parent formulation. Compared with commercially available micelles (DSPE-PEG2000), all optimized HCPMi systems showed greater cellular uptake in vitro. Although a higher percentage of PEGylation was associated with better cellular uptake and anti-cancer properties, the difference was statistically insignificant. Furthermore, in vitro cytotoxicity assays revealed that all optimized HCPMi-encapsulated TMZ formulations showed significantly stronger anti-cancer properties than the parent drug TMZ and TMZ encapsulated DSPE-PEG2000, thus indicating the feasibility of using this nanoplatform for the delivery of TMZ to treat brain malignancies.
{"title":"Optimization of Ultra-Small Nanoparticles for Enhanced Drug Delivery","authors":"Shishi He, Yanni Fu, Zicong Tan, Qun Jiang, K. Huang, Phei Er Saw, Yan Nie, M. Guo","doi":"10.15212/bioi-2022-0015","DOIUrl":"https://doi.org/10.15212/bioi-2022-0015","url":null,"abstract":"\u0000 Nanoparticle delivery of drugs to the brain is hindered by the blood-brain barrier (BBB). In malignant glioma (MG), small disruptions in the BBB may allow nanoparticles smaller than 20 nm to penetrate the dysfunctional barrier. We previously developed ultra-small nanoparticles called hyper-cell permeable micelles (HCPMis) with a radius of ∼12 nm and found that a PEGylated HCPMi system showed enhanced cell permeability and cellular uptake, and remarkable anti-tumor properties in MG treatment. However, no study had examined the delivery of temozolomide (TMZ), the first-line drug for MG, with the HCPMi platform. Herein, we use a simple PEGylation increment system (30 wt % PEG, 40 wt % PEG and 50 wt % PEG) to develop a robust optimized HCPMi nanoplatform for TMZ delivery. All optimized HCPMi systems showed greater stability than the non-PEGylated parent formulation. Compared with commercially available micelles (DSPE-PEG2000), all optimized HCPMi systems showed greater cellular uptake in vitro. Although a higher percentage of PEGylation was associated with better cellular uptake and anti-cancer properties, the difference was statistically insignificant. Furthermore, in vitro cytotoxicity assays revealed that all optimized HCPMi-encapsulated TMZ formulations showed significantly stronger anti-cancer properties than the parent drug TMZ and TMZ encapsulated DSPE-PEG2000, thus indicating the feasibility of using this nanoplatform for the delivery of TMZ to treat brain malignancies.\u0000","PeriodicalId":431549,"journal":{"name":"BIO Integration","volume":"20 3 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133960162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：