- Email: [email protected]
Microfluidics analysis of cancer cell microenvironments and targeted destruction of cancer stem cells by nanomedicine
452
ChinaNanomedicine Abstracts / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 449–575
Tumor microenvironment and nanodrug delivery Lei Miao, Yuhua Wang, Leaf Huang, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA E-mail address: [email protected] (L. Huang) Tumor microenvironment (TME) of a mature solid tumor is made of three components: tumor cell clusters or nests, stroma and immune cells. Most of the microvessels are located in the stroma, which is made of extracellular matrix and tumor associated fibroblasts (TAF). Circulating nanoparticles (NP) extravasating through the leaky microvessels first encounter the stroma and are taken up by TAF. Some NP will also penetrate through the stroma and reach tumor nests, depending on the particle size. In a stroma rich bladder cancer model, TAF are the major cells taken up small LPC NP which contain ~80% cisplatin. Genome damaged TAF secrete Wnt16 which in a paracrine manner activates tumor cells for drug resistance and for epithelial-to-mesenchymal transition. It also induces neighboring naïve fibroblast to become drug resistance and the endothelial cells to undergo angiogenesis. After repeated LPC administration, the bladder tumor becomes highly Wnt16 positive and highly drug resistant. Tumor rapidly regrows soon after LPC dosing is completed. Delivery of Wnt16 siRNA by LPH NP to the tumor can down-regulate Wnt16, inhibit the development of tumor drug resistance and enhance tumor growth inhibition by LPC. In advanced murine B16F10 melanoma, tumor does not contain a lot of stroma, and is relatively resistant to a nano-vaccine. LPH delivery of TGFβ siRNA, PLGA NP delivery of CDDO-Me (an anti-inflammatory) or Sunitinib (a broad-spectrum kinase inhibitor), or PEGylated curcumin micelles, can all downregulate the Th2 type cytokines, inhibit Treg cells and myeloid-derived suppressor cells and enhance tumor infiltrating CD8+ T-cells in the treated tumor. These immune modulators significantly enhance the tumor growth inhibition by a nano vaccine designed to boost the CTL response against the melanoma. Thus, we conclude that both siRNA and small molecule inhibitors can be delivered to modulate TME to facilitate either chemo or immune therapy, or both. Work supported by NIH grants CA149363, CA151652, CA149387 and DK100664.
Microfluidics analysis of cancer cell microenvironments and targeted destruction of cancer stem cells by nanomedicine Dandan Liua,b, Heng Zoua, Wai-Kin Yua, Wanqing Yuea,b, Timothy T.C. Yipc, Chi-Chun Fonga,b, Joseph S.K. Auc, Mengsu (Michael) Yanga,b,⁎, aDepartment of Biomedical Sciences, City University of Hong Kong, Hong Kong, b Shenzhen Key Laboratory of Biochip Technology, City University of Hong Kong, Hong Kong, cDepartment of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong ⁎Corresponding author at: Department of Biomedical Sciences, City University of Hong Kong, Hong Kong.
Our research interests focus on the study of cancer cell communications by microfluidics and the development of nanotechnology to detect and destruct cancer cells. Recent studies reveal that solid tumors consist of heterogeneous types of cells with distinct phenotypes and functions. We have investigated the interaction and inter-conversion between cancer cells and the so-called cancer stem cells (CSCs), which consist of a small subset of cells responsible for sustaining tumorigenesis and drug resistance. We have developed a microfluidic system for co-culturing cancer cells and generating multiple gradients to study the effects of microenvironments on cell growth, migration and interactions. Our results showed the dynamic sensitivity and heterogeneity of lung cancer cells in chemotaxis and also showed for the first time the acceleration of cancer cells during chemotaxis caused by increasing local concentration in different gradients. We have also developed multifunctional nanoparticles by integrating specific antibodies for targeting CSC surface markers, magnetic cores for externally activated heat generation, and chemotherapeutic agents for interrupting specific pathways in the CSCs. Our results showed that in vitro cancer cell growth and in vivo tumor growth were effectively inhibited by the nanomedicine through the combined effects of thermotherapy and chemotherapy.
http://dx.doi.org/10.1016/j.nano.2015.12.011 This work was supported by the National Basic Research Program of China (2012CB933302), the Key Laboratory Funding Scheme of Shenzhen Municipal Government, and the Innovation and Technology Fund of Hong Kong SAR Government (ITS/100/14FP).
Highly sensitive detection of pandemic viruses, biomarkers, and small molecules by using Aptamer nanobiosensors Man Bock Gu, Department of Biotechnology, Korea University, Anam-dong, Seongbuk-Gu, Seoul, Republic of Korea E-mail address: [email protected] (M.B. Gu) Aptamers are single-stranded nucleic acids having molecular recognition properties similar to antibodies, and isolated by in vitro selection and amplification process, SELEX. Aptamer engineering includes innovative screening and modification of aptamers for maximizing their function. This talk will start with how the aptamers are innovatively screened, for the first time in world, by using a new nano-material, graphene oxide, without needing the immobilization of targets. A few of successful examples for a couple of pandemic viruses and diabetes type 2 biomarkers will be presented based on the aptamer duo screened by GO-SELEX, including a noble aptamer-duo story, i.e., inevitable in a stripe-type sandwich assay platform. Once the aptamers are successfully screened out, the aptamers can be further engineered, by truncation. In this talk, it will be presented how the aptamer candidates are analyzed and heuristically engineered for developing the world shortest aptamer, octamer, with highly enhanced affinity. This sequence-based engineering of aptamers has resulted in a very successful ultrasensitive biosensing, especially for the detection of antibiotics, which can never been able to be reached without engineering of aptamers. In addition, the benefits of using nano-sized materials for biosensing will be presented with scientifically proven clear examples of different hybrid forms of nanomaterials and aptamers, such as aptamers–gold nanoparticle composites, aptamers-inliposome, and aptamers-on-nanofiber. http://dx.doi.org/10.1016/j.nano.2015.12.012
http://dx.doi.org/10.1016/j.nano.2015.12.013
Improved delivery of anticancer agents via a dual function nanocarrier Xiaolan Zhang, Yixian Huang, Song Li, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA E-mail address: [email protected] (S. Li) Polymeric micelles represent a promising drug carrier system that has gained considerable attention due to its simplicity, small size, and the ability to solubilize water-insoluble drugs and accumulate specifically at the tumors. Most of the carrier materials in polymeric drug delivery systems (including lipid-core micellar systems) utilize “inert” excipients that lack therapeutic effect. The use of excess amounts of carrier materials not only adds to the cost, but also potentially imposes safety issues. In addition, most micellar systems are designed to load drugs solely based on hydrophobic/hydrophobic interactions. However, most of the existing drugs or drug candidates are only moderately hydrophobic agents. The carrier/drug incompatibility may account for, among others, the limited drug loading capacity and formulation stability. One interesting approach in the design of a carrier is that components of the carrier system exhibit favorable biological activity. We have recently developed a dual-function carrier that is based on PEG-derivatized S-trans, transfarnesylthiosalicylic acid (FTS) (PEG5k-FTS2). FTS is a synthetic farnesylcysteine mimetic that acts as a potent and especially nontoxic Ras antagonist. In addition to retention of anti-Ras activity, PEG5k-FTS2 forms small-sized micelles that are capable of synergistic delivery of various hydrophobic agents. In this study, we are examining whether the performance of PEG5k-FTS2 can be further improved via incorporation of Fmoc based on our recent discovery of Fmoc as a novel and potent
ChinaNanomedicine Abstracts / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 449–575
Tumor microenvironment and nanodrug delivery Lei Miao, Yuhua Wang, Leaf Huang, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA E-mail address: [email protected] (L. Huang) Tumor microenvironment (TME) of a mature solid tumor is made of three components: tumor cell clusters or nests, stroma and immune cells. Most of the microvessels are located in the stroma, which is made of extracellular matrix and tumor associated fibroblasts (TAF). Circulating nanoparticles (NP) extravasating through the leaky microvessels first encounter the stroma and are taken up by TAF. Some NP will also penetrate through the stroma and reach tumor nests, depending on the particle size. In a stroma rich bladder cancer model, TAF are the major cells taken up small LPC NP which contain ~80% cisplatin. Genome damaged TAF secrete Wnt16 which in a paracrine manner activates tumor cells for drug resistance and for epithelial-to-mesenchymal transition. It also induces neighboring naïve fibroblast to become drug resistance and the endothelial cells to undergo angiogenesis. After repeated LPC administration, the bladder tumor becomes highly Wnt16 positive and highly drug resistant. Tumor rapidly regrows soon after LPC dosing is completed. Delivery of Wnt16 siRNA by LPH NP to the tumor can down-regulate Wnt16, inhibit the development of tumor drug resistance and enhance tumor growth inhibition by LPC. In advanced murine B16F10 melanoma, tumor does not contain a lot of stroma, and is relatively resistant to a nano-vaccine. LPH delivery of TGFβ siRNA, PLGA NP delivery of CDDO-Me (an anti-inflammatory) or Sunitinib (a broad-spectrum kinase inhibitor), or PEGylated curcumin micelles, can all downregulate the Th2 type cytokines, inhibit Treg cells and myeloid-derived suppressor cells and enhance tumor infiltrating CD8+ T-cells in the treated tumor. These immune modulators significantly enhance the tumor growth inhibition by a nano vaccine designed to boost the CTL response against the melanoma. Thus, we conclude that both siRNA and small molecule inhibitors can be delivered to modulate TME to facilitate either chemo or immune therapy, or both. Work supported by NIH grants CA149363, CA151652, CA149387 and DK100664.
Microfluidics analysis of cancer cell microenvironments and targeted destruction of cancer stem cells by nanomedicine Dandan Liua,b, Heng Zoua, Wai-Kin Yua, Wanqing Yuea,b, Timothy T.C. Yipc, Chi-Chun Fonga,b, Joseph S.K. Auc, Mengsu (Michael) Yanga,b,⁎, aDepartment of Biomedical Sciences, City University of Hong Kong, Hong Kong, b Shenzhen Key Laboratory of Biochip Technology, City University of Hong Kong, Hong Kong, cDepartment of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong ⁎Corresponding author at: Department of Biomedical Sciences, City University of Hong Kong, Hong Kong.
Our research interests focus on the study of cancer cell communications by microfluidics and the development of nanotechnology to detect and destruct cancer cells. Recent studies reveal that solid tumors consist of heterogeneous types of cells with distinct phenotypes and functions. We have investigated the interaction and inter-conversion between cancer cells and the so-called cancer stem cells (CSCs), which consist of a small subset of cells responsible for sustaining tumorigenesis and drug resistance. We have developed a microfluidic system for co-culturing cancer cells and generating multiple gradients to study the effects of microenvironments on cell growth, migration and interactions. Our results showed the dynamic sensitivity and heterogeneity of lung cancer cells in chemotaxis and also showed for the first time the acceleration of cancer cells during chemotaxis caused by increasing local concentration in different gradients. We have also developed multifunctional nanoparticles by integrating specific antibodies for targeting CSC surface markers, magnetic cores for externally activated heat generation, and chemotherapeutic agents for interrupting specific pathways in the CSCs. Our results showed that in vitro cancer cell growth and in vivo tumor growth were effectively inhibited by the nanomedicine through the combined effects of thermotherapy and chemotherapy.
http://dx.doi.org/10.1016/j.nano.2015.12.011 This work was supported by the National Basic Research Program of China (2012CB933302), the Key Laboratory Funding Scheme of Shenzhen Municipal Government, and the Innovation and Technology Fund of Hong Kong SAR Government (ITS/100/14FP).
Highly sensitive detection of pandemic viruses, biomarkers, and small molecules by using Aptamer nanobiosensors Man Bock Gu, Department of Biotechnology, Korea University, Anam-dong, Seongbuk-Gu, Seoul, Republic of Korea E-mail address: [email protected] (M.B. Gu) Aptamers are single-stranded nucleic acids having molecular recognition properties similar to antibodies, and isolated by in vitro selection and amplification process, SELEX. Aptamer engineering includes innovative screening and modification of aptamers for maximizing their function. This talk will start with how the aptamers are innovatively screened, for the first time in world, by using a new nano-material, graphene oxide, without needing the immobilization of targets. A few of successful examples for a couple of pandemic viruses and diabetes type 2 biomarkers will be presented based on the aptamer duo screened by GO-SELEX, including a noble aptamer-duo story, i.e., inevitable in a stripe-type sandwich assay platform. Once the aptamers are successfully screened out, the aptamers can be further engineered, by truncation. In this talk, it will be presented how the aptamer candidates are analyzed and heuristically engineered for developing the world shortest aptamer, octamer, with highly enhanced affinity. This sequence-based engineering of aptamers has resulted in a very successful ultrasensitive biosensing, especially for the detection of antibiotics, which can never been able to be reached without engineering of aptamers. In addition, the benefits of using nano-sized materials for biosensing will be presented with scientifically proven clear examples of different hybrid forms of nanomaterials and aptamers, such as aptamers–gold nanoparticle composites, aptamers-inliposome, and aptamers-on-nanofiber. http://dx.doi.org/10.1016/j.nano.2015.12.012
http://dx.doi.org/10.1016/j.nano.2015.12.013
Improved delivery of anticancer agents via a dual function nanocarrier Xiaolan Zhang, Yixian Huang, Song Li, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA E-mail address: [email protected] (S. Li) Polymeric micelles represent a promising drug carrier system that has gained considerable attention due to its simplicity, small size, and the ability to solubilize water-insoluble drugs and accumulate specifically at the tumors. Most of the carrier materials in polymeric drug delivery systems (including lipid-core micellar systems) utilize “inert” excipients that lack therapeutic effect. The use of excess amounts of carrier materials not only adds to the cost, but also potentially imposes safety issues. In addition, most micellar systems are designed to load drugs solely based on hydrophobic/hydrophobic interactions. However, most of the existing drugs or drug candidates are only moderately hydrophobic agents. The carrier/drug incompatibility may account for, among others, the limited drug loading capacity and formulation stability. One interesting approach in the design of a carrier is that components of the carrier system exhibit favorable biological activity. We have recently developed a dual-function carrier that is based on PEG-derivatized S-trans, transfarnesylthiosalicylic acid (FTS) (PEG5k-FTS2). FTS is a synthetic farnesylcysteine mimetic that acts as a potent and especially nontoxic Ras antagonist. In addition to retention of anti-Ras activity, PEG5k-FTS2 forms small-sized micelles that are capable of synergistic delivery of various hydrophobic agents. In this study, we are examining whether the performance of PEG5k-FTS2 can be further improved via incorporation of Fmoc based on our recent discovery of Fmoc as a novel and potent