The purpose of this study is to examine the potential of low-molecular-weight poly(trimethylene carbonate) for localized delivery for acid-sensitive drugs. Poly(trimethylene carbonate) of various molecular weights is prepared by ring-opening polymerization initiated by octan-1-ol and co-initiated/catalyzed by tin 2-ethylhexanoate. The resultant polymers are amorphous with low glass transition temperatures and viscosities at 37 degrees C that permit their injection through an 18(1\2) G 1.5'' needle. Their biocompatibility and the influence of the molecular weight on the rate of degradation are assessed in vivo through subcutaneous implantation in rats over 40 weeks. The polymers are well tolerated in vivo, and degrade in a fashion dependent on their initial molecular weight. For very low initial molecular weight (620 Da) and for high initial molecular weight (2,400 Da), polymer mass loss is a result of dissolution of the soluble low molecular chains from the bulk. This is contrasted by the results obtained for an intermediate initial molecular weight (1,600 Da), for which polymer mass loss is a result of both dissolution and enzymatic hydrolysis or oxidation as a result of reactive species secreted by activated macrophages at the implant surface.
Background: Low molecular mass hyaluronan (LMHA) is proinflammatory, but the role of the N-acetyl moieties is unknown. Results: Chemical reacetylation of LMHA results in maximal proinflammatory cytokine production by human macrophages, compared with other N-acylations. Partial N-butyrylation blocks cytokine stimulation.
Conclusion:The N-acetyl moieties of glucosamine are critical for LMHA proinflammatory properties. Significance: N-Acetylation and butyrylation of LMHA modulate proinflammatory cytokine production.
Liquid, injectable hydrophobic polymers are potentially useful as depot systems for localized drug delivery. Low molecular weight polymers of 5-ethylene ketal ε-caprolactone and copolymers of this monomer with D,L-lactide were prepared and their properties assessed with respect to their suitability for this purpose. The polymers were amorphous and of low viscosity, and the viscosity was adjustable by choice of initiator and/or by copolymerizing with D,L-lactide. Lower viscosity polymers were attained by using 350 Da methoxy poly(ethylene glycol) as an initiator in comparison to octan-1-ol, while copolymerization with D,L-lactide increased viscosity. The initiator used had no significant effect on the rate of mass loss in vitro, and copolymers with D,L-lactide (DLLA) degraded faster than 5-ethylene ketal ε-caprolactone (EKC) homopolymers. For the EKC-based polymers, a nearly constant degradation rate was observed. This finding was attributed to the hydrolytic susceptibility of the EKC-EKC ester linkage, which was comparable to that of DLLA-DLLA, coupled with a higher molecular weight of the water-soluble degradation product and the low initial molecular weight of the EKC-based polymers. Cytotoxicity of the hydrolyzed EKC monomer to 3T3 fibroblast cells was comparable to that of ε-caprolactone, suggesting that polymers prepared from EKC may be well tolerated upon in vivo implantation.
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