In order to create a soft tissue surplus, implantable volume expanders are often utilized in dental surgery. Implanted tissue expanders should gradually increase their volume, exerting a constant pressure on the surrounding tissue for weeks. Current tissue expanders are based predominantly on externally inflatable balloons or on osmotically active tissue expanders that use soft hydrogels wrapped in perforated plastic coatings, which limit fluid entry and swelling. We have designed and examined tissue expanders based on the controlled rate expansive hydrogels synthesized from copolymers of selected methacrylates and N-vinylpyrrolidone, cross-linked with a combination of non-degradable (glycol dimethacrylates) and hydrolytically degradable (N,O-dimethacryloylhydroxylamine) cross-linkers. These copolymers have close-to-linear volume expansion rates (up to 6-9 times their original volume) and exert an increasing swelling pressure in vitro. The anesthetic benzocaine has been incorporated into the hydrogels, and kinetic release experiments have shown that most of the drug (90%) was released within 48 h. Our proposed hydrogel expanders are homogeneous and have suitable mechanical properties, thus simplifying the surgical manipulations required. Further studies will be needed to completely evaluate their biocompatibility and tissue response to the implants.

• MeSH
• Anesthetics administration & dosage   MeSH
• Biocompatible Materials chemistry   MeSH
• Hydrogels chemistry   MeSH
• Hydroxylamines chemistry   MeSH
• Kinetics MeSH
• Humans MeSH
• Methacrylates chemistry   MeSH
• Polymers chemistry   MeSH
• Cross-Linking Reagents chemistry   MeSH
• Oral Medicine methods   MeSH
• Tissue Expansion Devices * MeSH
• Pressure MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anesthetics MeSH
• Biocompatible Materials MeSH
• Hydrogels MeSH
• Hydroxylamines MeSH
• Methacrylates MeSH
• N,O-dimethacryloylhydroxylamine MeSH Browser
• Polymers MeSH
• Cross-Linking Reagents MeSH

Diffusion in the extracellular space (ECS) of the brain is constrained by the volume fraction and the tortuosity and a modified diffusion equation represents the transport behavior of many molecules in the brain. Deviations from the equation reveal loss of molecules across the blood-brain barrier, through cellular uptake, binding, or other mechanisms. Early diffusion measurements used radiolabeled sucrose and other tracers. Presently, the real-time iontophoresis (RTI) method is employed for small ions and the integrative optical imaging (IOI) method for fluorescent macromolecules, including dextrans or proteins. Theoretical models and simulations of the ECS have explored the influence of ECS geometry, effects of dead-space microdomains, extracellular matrix, and interaction of macromolecules with ECS channels. Extensive experimental studies with the RTI method employing the cation tetramethylammonium (TMA) in normal brain tissue show that the volume fraction of the ECS typically is approximately 20% and the tortuosity is approximately 1.6 (i.e., free diffusion coefficient of TMA is reduced by 2.6), although there are regional variations. These parameters change during development and aging. Diffusion properties have been characterized in several interventions, including brain stimulation, osmotic challenge, and knockout of extracellular matrix components. Measurements have also been made during ischemia, in models of Alzheimer's and Parkinson's diseases, and in human gliomas. Overall, these studies improve our conception of ECS structure and the roles of glia and extracellular matrix in modulating the ECS microenvironment. Knowledge of ECS diffusion properties is valuable in contexts ranging from understanding extrasynaptic volume transmission to the development of paradigms for drug delivery to the brain.

• MeSH
• Diffusion MeSH
• Extracellular Space chemistry   diagnostic imaging   physiology   MeSH
• Quaternary Ammonium Compounds MeSH
• Humans MeSH
• Brain Chemistry physiology   MeSH
• Brain cytology   physiology   MeSH
• Neuroglia physiology   MeSH
• Neurons physiology   MeSH
• Radionuclide Imaging MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Quaternary Ammonium Compounds MeSH
• tetramethylammonium MeSH Browser

PURPOSE: Two different monoclonal antibody-targeted HPMA copolymer-doxorubicin conjugates, classic and starlike, were synthesized to be used for site-specific cancer therapy. The anti-mouse Thy-1.2 (IgG3) and two anti-human CD71/A (IgG1) and CD71/B (IgG2a) monoclonal antibodies were used as targeting structures. METHODS: Their binding and cytotoxic activity in vitro, body distribution, and anticancer activity in vivo were evaluated. RESULTS: The results of flow cytometric analysis showed comparable binding of classic and starlike conjugates to the target cells. The in vitro cytotoxic effect was 10-fold higher if cancer cells were exposed to the starlike conjugate compared to the classic one. Biodistribution studies showed that the starlike conjugate remained in a relatively high concentration in blood, whereas the classic conjugate was found in a 6.5-times lower amount. In contrast to the low antitumor activity of free doxorubicin and nontargeted HPMA copolymer-doxorubicin conjugate, both anti-Thy-1.2 targeted conjugates (classic and starlike) cured all mice bearing T-cell lymphoma EL4. On the other hand, starlike conjugates containing anti-CD71/A or anti-CD71/B monoclonals as targeting structures were more effective against human colorectal cancer SW 620 than the classic one. CONCLUSIONS: We have shown that the starlike conjugates are more effective systems for targeted drug delivery and cancer treatment than classic conjugates.

• MeSH
• Cell Division drug effects   MeSH
• Doxorubicin chemistry   pharmacokinetics   pharmacology   MeSH
• Colorectal Neoplasms drug therapy   MeSH
• Humans MeSH
• Lymphoma, T-Cell drug therapy   MeSH
• Methacrylates chemistry   pharmacology   MeSH
• Molecular Structure MeSH
• Antibodies, Monoclonal chemistry   metabolism   MeSH
• Mice, Inbred BALB C MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Prodrugs chemistry   pharmacology   MeSH
• Antibiotics, Antineoplastic chemistry   pharmacokinetics   pharmacology   MeSH
• In Vitro Techniques MeSH
• Tissue Distribution MeSH
• Neoplasm Transplantation MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Names of Substances
• Doxorubicin MeSH
• hydroxypropyl methacrylate MeSH Browser
• Methacrylates MeSH
• Antibodies, Monoclonal MeSH
• Prodrugs MeSH
• Antibiotics, Antineoplastic MeSH

Integrative optical imaging was used to show that long-chain synthetic poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) polymers in a range of molecular weights from 7.8 to 1057 kDa were able to diffuse through the extracellular space in rat neocortical slices. Tortuosity (square root of ratio of diffusion coefficient in aqueous medium to that in brain) measured with such polymers averaged 1.57, a value similar to that obtained previously with tetramethylammonium, a small cation. When PHPMA was conjugated with bovine serum albumin (BSA) to make a bulky polymer with molecular weight 176 kDa, the tortuosity rose to 2.27, a value similar to that obtained previously with BSA alone and with 70-kDa dextran. The method of image analysis was justified with diffusion models involving spherical and nonspherical initial distributions of the molecules.

• MeSH
• Dextrans chemistry   pharmacokinetics   MeSH
• Diffusion MeSH
• Extracellular Space metabolism   MeSH
• Microscopy, Fluorescence MeSH
• Rats MeSH
• Polymethacrylic Acids chemistry   pharmacokinetics   MeSH
• Drug Delivery Systems MeSH
• Models, Neurological MeSH
• Molecular Weight MeSH
• Neocortex metabolism   MeSH
• Optics and Photonics MeSH
• Rats, Sprague-Dawley MeSH
• Serum Albumin, Bovine chemistry   pharmacokinetics   MeSH
• Cattle MeSH
• In Vitro Techniques MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Cattle MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH
• Names of Substances
• Dextrans MeSH
• Duxon MeSH Browser
• Polymethacrylic Acids MeSH
• Serum Albumin, Bovine MeSH