Immobilization of anticoagulant-loaded liposomes on cell surfaces by DNA hybridization
Department of Reparative Materials, Institute for Frontier Medical Sciences, Kyoto University, 53 Kawara-Cho, Shogoin, Sakyo-Ku, Kyoto 606-8507, Japan.Biomaterials (Impact Factor: 8.56). 11/2011; 32(31):7971-7. DOI: 10.1016/j.biomaterials.2011.07.002
An unresolved obstacle in transplantation of islets of Langerhans is the early graft loss caused by thrombotic reactions on the surface of islets after intraportal transplantation. We investigated a versatile method for modifying the surface of islets with liposomes carrying the anticoagulant argatroban using an amphiphilic poly(ethylene glycol)-phospholipid conjugate derivative (PEG-lipid) and DNA hybridization. Argatroban was gradually released from the liposomes on the islets, and antithrombic activity was detected in culture medium. Modified islets retained the ability to control insulin release in response to glucose concentration changes. Although we mainly examined surface modification of islets, this technique may be useful for immobilizing various types of small molecules on cells and tissues and thus may have many applications in cell therapy and regenerative medicine.
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- "In this section, we will introduce a method for immobilizing a low-molecular-weight anticoagulant , argatroban, onto the islet surface. First, we attempted to attach argatroban to the islet surface. However, it is not possible to apply the same methods developed for immobilizing high-molecular-weight proteins on the islet surface, because low-molecular-weight molecules typically have few or no functional groups available for immobilization. "
ABSTRACT: Transplantation of the pancreatic islets of Langerhans (islets) is a promising cell therapy for treating insulin-dependent type 1 diabetes mellitus. Islet transplantation is a minimally-invasive technique involving relatively simple surgery. However, after intraportal transplantation, the transplanted islets are attacked by the recipient's immune system, because they activate a number of systems, including coagulation, complement response, inflammation, immune rejection, and recurrence of autoimmune disease. We have developed a surface modification and microencapsulation technique that protects cells and islets with biomaterials and bioactive substances, which may be useful in clinical settings. This approach employs amphiphilic polymers, which can interact with lipid bilayer membranes, without increasing cell volume. Molecules attached to these polymers can protect transplanted cells and islets from attack by the host immune system. We expect that this surface modification technique will improve graft survival in clinical islet transplantation.
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- "Furthermore, studies have demonstrated that derivatives of the PEG-lipids can be used to modify cellular surface . Recently, Iwata et al.   developed technologies to immobilize bioactive substances, such enzymes , low-molecular weight drugs , and even living cells on the surface of pancreatic islets using PEG-lipids . The PEG-lipids provided an ultra-thin coating on the cell surface of pancreatic islet cells, and demonstrated the suppression of IBMIR in two islet transplantation studies  . "
ABSTRACT: Hepatocyte-based therapies are promising regenerative approaches for liver diseases. In this study, we sought to develop a versatile method to modify the surface of hepatocytes by immobilizing synthetic polymers around the cells. The surface of murine primary hepatocytes was modified using poly(ethylene glycol)-phospholipids conjugate bearing FITC (FITC-PEG-lipid) in suspension. Hepatocyte function was assessed in vitro by examining cell viability, plating efficiency, protein production, metabolizing activity, hepatocyte-specific gene expressions, and cytochrome P450 induction. The engraftment of the PEG-lipid modified cells was studied following transplantation to both the liver or alternate ectopic sites. Among the types of phospholipids analyzed in our study, 1,2-dimyristoil -sn-glycerol-3-phosphatidylethanolamine (DMPE) was found to be uniformly anchored to the hepatocyte cell membrane (>99% of hepatocytes). Cell surface modification using FITC-PEG-DMPE did not result in any loss of in vitro functional parameters nor affect the engraftment potential in vivo by the modified cells. This modification was also successfully performed on dispersed hepatocytes and engineered hepatocyte sheets. In all, the ability to modify the surface of isolated hepatocytes with functional proteins, instead of FITC as shown in our proof-of-concept study, has the potential to move hepatocyte-based cell therapy another step forward as a viable therapeutic application.
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ABSTRACT: Sertoli cells play a crucial role in creating the immunoprivileged environment of the testis. We examined the survival of islets of Langerhans after co-transplantation with Sertoli cells. Sertoli cells near islets should protect the graft from rejection. In this study, conjugates of single stranded oligonucleotides, poly(ethylene glycol) and phospholipids (ssDNA-PEG-DPPE) were used to immobilize Sertoli cells on islets. The 20-mer of deoxyadenylic acid (oligo(dA)20) and 20-mer of deoxythymidylic acid (oligo(dT)20) were presented as ssDNAs on the surfaces of Sertoli cells and islets, respectively, through the hydrophobic interaction between a lipid unit of the conjugates and the cell membrane. The Sertoli cells were immobilized on the islets through hybridization between oligo(dA)20 and oligo(dT)20. When Sertoli cell-immobilized islets were infused into the liver of mice through the portal vein, the Sertoli cells remained around the islets.
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