Journal of Bioactive and Compatible Polymers

N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer-adriamycin (ADR) conjugate (P-aconityl-ADR) was synthesized by the attachment of cis-aconityl-ADR to an HPMA copolymer precursor using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) as the condensing agent. The ADR release from the HPMA copolymer conjugate was pH sensitive. After 48 h incubation at pH 5, 6, and 7, the amount of ADR released was 63.4, 9.2, and 2.8% respectively. The in vitro cytotoxicity of the conjugate was evaluated toward A2780 sensitive and A2780/AD resistant human ovarian carcinoma cells. An HPMA copolymer, containing ADR bound via a tetrapeptide (GFLG) sequence susceptible to cleavage catalyzed by lysosomal enzymes (P-GFLG-ADR), was used as control. The IC₅₀ doses seemed to indicate that the total hydrolysis of P-aconityl-ADR in prelysosomal and lysosomal compartments proceeded faster than the release of ADR from P-GFLG-ADR catalyzed by lysomal cysteine proteinases. Both HPMA copolymer-ADR conjugates appeared to overcome the ATP-driven P-glycoprotein efflux pump expressed in A2780/AD cells.

Poly(ethylene glycol) (PEG) and Pluronic® F-127 (PF127) were silylated with 3-isocyanatopropyltriethoxysilane to synthesize PEG-based hydrogels by sol-gel transition of silane. Silanes on different PEG molecules formed covalent bonds by acid-catalyzed hydrolysis and condensation. Addition of monosilylated PEG resulted in the incorporation of dangling PEG chains, which increased the swelling ratio of the hydrogels slightly. PEG hydrogels in microspheres were prepared by emulsifying aqueous silylated PEG solution in oil followed by curing. Crosslinked PF127 hydrogels displayed inverse thermosensitivity. The previously swollen PF127 hydrogels shrank immediately at high temperatures (e.g., 6000), but the welling of shrunken hydrogels at low temperature (e.g., 5°C) took much longer. The release of fluorescein from the PF127 hydrogels was dependent on the temperature of the environment. The release of fluorescein from the PF127 hydrogels was faster at 45°C than at 5°C. This was most likely due to shrinking of the hydrogels leading to squeezing of the incorporated fluorescein. The ability of hydrogel formation by simple sol-gel transition of silylated PEG can be used to prepare new drug delivery systems and biomaterials.

One of the key technologies for regeneration of damaged and lost tissue is the sustained release of biologically active growth factors. The present study was undertaken to investigate sorption and desorption of various growth factors from biodegradable hydrogels prepared through glutaraldehyde crosslinking of gelatin with isoelectric points (IEPs) of 5.0 and 9.0, which are named "acidic" and "basic" gelatins, respectively, based on their overall charge. Basic bFGF and TGF-β1 were markedly sorbed with time in the acidic gelatin hydrogels, while less sorption took place in the basic gelatin hydrogels. This behavior was explained in terms of an electrostatic interaction between the basic growth factors and the acidic gelatin. However, BMP-2 was sorbed into the acidic gelatin hydrogel to a lesser extent than the other two growth factors, even though its IEP is also greater than 7.0. An in vivo experiment revealed that the acidic gelatin hydrogel was degraded with time, while growth factors were retained in the body for a longer time period as the in vitro sorption to the acidic gelatin hydrogel was larger. These findings indicate that the growth factors sonically complexes to the acidic gelatin hydrogel were released in vivo as a result of hydrogel degradation. Furthermore, animal experiments revealed that the biological performance of growth factors was enhanced by their sustaned release, in marked contrast to the growth factors administered in the solution form.

Poly(methylmethacrylate-co-2-hydroxyethylmethacrylate) microbeads in the size range of 1.5-2.0μm were prepared by a phase inversion polymerization. The hydroxyl groups were activated by periodate oxidation, and the active ligand, i.e., protein A was immobilized via a spacer-arm, i.e., hexamethylene diamine (HDMA) by using a cross-linker, i.e., glutaraldehyde and protein A. The optimal concentration obtained for modifications are as follows: sodium periodate concentration: 0.467 × 10⁻²mmol/mL; HMDA concentration: 3.5 × 10⁻²mmol/mL; and glutaraldehyde concentration: 0.7 × 10⁻⁶mmol/mL. Yields of immobilization of protein A onto the plain and periodate oxidized microbeads were found very close, and were in the range of 0.01-0.02 mg protein A/g microbeads. The optimal conditions for immobilization are as follows: the initial protein A concentration: 0.1 mg/mL; temperature: 25°C; pH: 9.5; and immobilization time:120 min. Incorporation of protein A at these conditions resulted in 0.825 mg protein A/g microbeads. The HIgG adsorption onto these protein A incorporated microbeads was 41 mg HIgG/g microbeads.

Segmented poly(tartaramide)s were prepared by polycondensation of monodispersed α,ω-diaminooligo(ethyleneglycol)s, with oligomerization degree included between 2 and 6, with two optically active dialkyl tartrates. The diamines were obtained from the relevant commercial glycols using a modified Gabriel synthesis. The polycondensations were performed in methanol at 55°C with triethylamine as catalyst. By this route, optically active poly(tartaramide)s, with oligomerization degree in the 4-10 range, were obtained in fairly high yields. Solubility and thermal properties of the polycondensation products were found to be related to the length of the oligo(oxyethylene) segment and to the presence of free hydroxyl groups.