Phad Research Articles

Enhanced anti-tumor efficacy and safety profile of tumor microenvironment-responsive oncolytic adenovirus nanocomplex by systemic administration

Oncolytic adenovirus (Ad) holds great promise as a potential gene therapy for cancer. However, intravenously administered Ad may encounter difficulties due to unfavorable host responses, non-specific interactions, and the heterogeneity of the tumor cell population. As an approach to combine the advantages of oncolytic Ad and synthetic polymers and to address the associated difficulties, Ad was physically complexed with a pH-sensitive block copolymer, methoxy poly(ethylene glycol)-b-poly(l-histidine) (mPEG-b-pHis). The in vitro transduction efficiency at an acidic extracellular pH was remarkably enhanced in cancer cells when treated with the Ad expressing green fluorescent protein (GFP) coated with mPEG-b-pHis (c-dE1/GFP) as compared to that of naked Ad (n-dE1/GFP). Time-lapse total internal reflection fluorescence microscopic imaging revealed a significantly enhanced cellular uptake rate of c-dE1/GFP at acidic tumor pH when compared with that at neutral pH or naked cognate Ad (n-dE1/GFP). In addition, c-dE1/GFP remained relatively stable in human serum-containing media, and considerably reduced both the innate and adaptive immune response against Ad. Moreover, the therapeutic efficacy and survival benefit of mPEG-b-pHis-complexed oncolytic Ad (c-H5mT/Luc) by systemic treatment was significantly enhanced compared to that with naked oncolytic Ad (n-H5mT/Luc) in both coxsackie and adenovirus receptor-positive and -negative tumors. Whole-body bioluminescence imaging showed 7.3-fold higher luciferase expression at the tumor site and 23.0-fold less luciferase expression in liver tissue for c-H5mT/Luc relative to that for naked oncolytic Ad (n-H5mT/Luc). Considering the heterogeneity of tumor tissue, these results are important for guiding the development of more potent and specific treatment of devastating metastatic cancers using this viral system. Statement of significanceAlthough adenoviral systems have shown considerable promise and undergone extensive evaluation attempts to specifically target Ad vectors to cancer cells have met limited success. This shortcoming is due to the strong immune response stimulated by Ad and the hepatotoxicity of the viral particles. To overcome restricted vector issues, we generated Ad/mPEG-b-pHis for tumor microenvironment-targeting hybrid vector systems, an oncolytic Ad coated with a pH-responsive polymer, mPEG-b-pHis. The Ad/mPEG-b-pHis exhibited pH-dependent transduction efficiency and cancer-cell killing effects. Moreover, systemic administration of oncolytic Ad/mPEG-b-pHis led to marked suppression of tumor growth and tumor-specific viral replication. Ad successfully avoided the innate and adaptive immune responses and liver accumulation with the help of mPEG-b-pHis on its surface.

1-Aza-1,3-butadiene complexes of tantalum: preparation and alkylation of TaCl 2(η 5-C 5Me 5)(η 4-1-aza-1,3-butadiene)

We have synthesized half-metallocene 1-aza-1,3-butadiene (abbr. AD) complexes of tantalum and have demonstrated the unique coordination mode and reactivity of the AD ligand. Treatments of a dimeric complex [TaCl 2Cp*] 2 ( 2) (Cp*=pentamethylcyclopentadienyl) with one equivalent of 1,4-diphenyl-1-aza-1,3-butadiene (abbr. Ph-AD) and 1- p-methoxyphenyl-4-phenyl-1-aza-1,3-butadiene (abbr. p-MeOC 6H 4–AD) afforded purple complexes of the formula TaCl 2Cp*(supine-η 4-AD) ( 3: AD=Ph-AD; 4: AD= p-MeOC 6H 4–AD), whose formulation and supine-η 4-coordination mode with a contribution of η 1-N-η 3-allyl canonical form were elucidated by their combustion analysis and NMR spectroscopy along with the X-ray crystal structure determination for the complex 3. Reaction of 3 with one equivalent of MgMe 2 gave a dimethyl complex TaMe 2Cp*(supine-η 4-Ph-AD) ( 6) in 96% yield, whereas the methylation reaction using MeLi or MeMgX did not afford 6. Benzylation of 3 and 4 using one equivalent of Mg(CH 2Ph) 2 in toluene led to the formation of dibenzyl complexes Ta(CH 2Ph) 2Cp*(η 2-C,N-AD) ( 9: AD=Ph–AD; 11: AD= p-MeOC 6H 4–AD) in modest yield, while reaction of 3 with 0.5 equivalent of Mg(CH 2Ph) 2 gave a monobenzylated complex TaCl(CH 2Ph)Cp*(supine-η 4-Ph–AD) ( 13). When complex 3 reacted with one equivalent of Mg(CH 2Ph) 2 in THF, we obtained a product mixture of 9 and a metallacyclic tantalum–carbene complex 10. Similarly, reaction of 4 with Mg(CH 2Ph) 2 in THF gave 11 and a metallacyclic tantalum–carbene complex 12. The carbene complexes 10 and 12 might be respectively derived from nascent benzylidene species, Ta(CHPh)Cp*(η 4-AD) ( 14: AD=Ph–AD; 15: AD= p-MeOC 6H 4–AD), which may abstract the H 4 proton of the AD ligand.

Comparative effects of pH and hypoxemia on minute coronary, mesenteric and skeletal muscle arteries.

Comparative effects of pH and hypoxemia on minute coronary, mesenteric and skeletal muscle arteries.

Observations on Peripheral Nerves Following Local Injections of (1) Isotonic Solutions of Varying ph aNd (2) "Iso-pH" Solutions of Varying Tonicity

Observations on Peripheral Nerves Following Local Injections of (1) Isotonic Solutions of Varying ph aNd (2) "Iso-pH" Solutions of Varying Tonicity