ABSTRACT
High resolution photoelectron spectra of the n-methylvinoxide anion and its deuterated isotopologue are obtained by slow electron velocity-map imaging. Transitions between the XÌ(1)A' anion ground electronic state and the radical XÌ(2)A" and Ã(2)A' states are observed. The major features in the spectra are attributed to transitions involving the lower energy cis conformers of the anion and neutral, while the higher energy trans conformers contribute only a single small peak. Franck-Condon simulations of the XÌ(2)A" â XÌ(1)A' and Ã(2)A' â XÌ(1)A' transitions are performed to assign vibrational structure in the spectrum and to aid in identifying peaks in the cis-n-methylvinoxy XÌ (2)A" band that occur only through vibronic coupling. The experimental electron affinity and à state term energy are found to be EA = 1.6106 ± 0.0008 eV and T(0) = 1.167 ± 0.002 eV for cis-n-methylvinoxy.
ABSTRACT
We describe a six-step synthesis to water-soluble doxorubicin (DOX)-loaded biodegradable PEGylated star-comb polymers with favorable pharmaceutical properties by atom transfer radical polymerization (ATRP) starting with a commercially available tripentaerythritol carrying eight reactive sites. The low polydispersity polymers degrade in a stepwise manner into lower molecular weight (MW) fragments by 15 days at 37 °C at either pH 5.0 or pH 7.4. The half-life of the star-comb polymers in blood is dependent upon the molecular weight; the 44 kDa star-comb has a t(1/2, ß) of 30.5 ± 2.1 h, which is not significantly changed (28.6 ± 2.7 h) when 6.6 wt % of DOX is attached to it via a pH-sensitive hydrazone linker. The star-comb polymers have low accumulation in organs but a high accumulation in C26 flank tumors implanted in Balb/C mice. The hydrodynamic diameter of polymer-DOX conjugates measured by dynamic light scattering increases from 8 to 35 to 41 nm as the loading is increased from 6.6 to 8.4 to 10.2 wt %. Although there is no significant difference in the t(1/2, ß) or in the accumulation of polymer-DOX in C-26 tumors, the uptake of polymer in the spleen is significantly higher for polymers with DOX loadings greater than 6.6 wt %. Polymer accumulation in other vital organs is independent of the DOX loading. The facile synthesis, biodegradability, long circulation time, and high tumor accumulation of the attached drug suggests that the water-soluble star-comb polymers have promise in therapeutic applications.
Subject(s)
Doxorubicin/chemistry , Polyethylene Glycols/chemical synthesis , Polyethylene Glycols/pharmacokinetics , Animals , Female , Mice , Mice, Inbred BALB C , Models, Molecular , Molecular Structure , Particle Size , Polyethylene Glycols/chemistry , Surface Properties , Tissue DistributionABSTRACT
PEGylated dendrimers are attractive for biological applications due to their tunable pharmacokinetics and ability to carry multiple copies of bioactive molecules. The rapid and efficient synthesis of a robust and biodegradable PEGylated dendrimer based on a polyester-polyamide hybrid core is described. The architecture is designed to avoid destructive side reactions during dendrimer preparation while maintaining biodegradability. Therefore, a dendrimer functionalized with doxorubicin (Dox) was prepared from commercial starting materials in nine, high-yielding linear steps. Both the dendrimer and Doxil were evaluated in parallel using equimolar dosage in the treatment of C26 murine colon carcinoma, leading to statistically equivalent results with most mice tumor-free at the end of the 60 day experiment. The attractive features of this dendritic drug carrier are its simple synthesis, biodegradability, and versatility for application to a variety of drug payloads with high drug loadings.
