Tuesday, February 4, 2014

PEG-prodrug AE08

In addition to a variety of block copolymers and others, Polyscitech (www.polyscitech.com) also distributes highly specialized polymers. These include PEG-b-polymaleic hydrazide-graft-doxorubicin. (PolyVivo AE08).  PEG-prodrug block copolymers like this have shown great promise for targeting tumor cells due to their pH sensitivity. Read more at Zhou, Lei, Ru Cheng, Huiquan Tao, Shoubao Ma, Weiwei Guo, Fenghua Meng, Haiyan Liu, Zhuang Liu, and Zhiyuan Zhong. "Endosomal pH-activatable poly (ethylene oxide)-graft-doxorubicin prodrugs: synthesis, drug release, and biodistribution in tumor-bearing mice." Biomacromolecules 12, no. 5 (2011): 1460-1467. http://pubs.acs.org/doi/abs/10.1021/bm101340u

“ABSTRACT: Novel poly(ethylene oxide)-graft-doxorubicin (PEO-g-DOX) prodrugs with DOX covalently conjugated to PEO via a pH-sensitive hydrazone bond were developed. PEO-g-DOX conjugates could be readily prepared in the following steps: (i) anionic ring-opening copolymerization of ethylene oxide (EO) and allyl glycidyl ether (AGE) afforded functional PEO with controlled molecular weights, low polydispersities, and multiple pendant double bonds (PEO-g-allyl); (ii) conjugation of PEO-g-allyl with methyl mercaptoacetate, followed by treating with hydrazine hydrate, quantitatively transformed allyl into hydrazide groups (PEO-g-hydrazide); and (iii) DOX was covalently immobilized to PEO-g-hydrazide via acid-labile hydrazone bonds (PEO-g-DOX). Here on the basis of PEO-g-allyl4.4 (Mn GPC = 22 400, PDI = 1.19) and PEO-g-allyl7.1 (Mn GPC = 15 300, PDI = 1.16, the subscription refers to number of allyl groups per chain) two freely water-soluble PEO-g-DOX prodrugs with 2.9 and 3.6 DOX per molecule (denoted as PEO-g-DOX2.9 and PEO-g-DOX3.6, corresponding to drug loading content of 5.6 and 9.0 wt %, respectively) were obtained. The in vitro release studies confirmed much faster release of DOX at pH 5.0 and 6.0 than at pH 7.4. For example, approximately 16, 52, and 61% of drug were released in 22 h, and 23, 83, and 92% of drug were released in 120 h from PEO-g-DOX2.9 at pH 7.4, 6.0 and 5.0, respectively. Notably, confocal laser scanning microscope (CLSM) observations revealed that DOX was released and delivered into the nuclei of RAW 264.7 cells following 24 h of incubation. MTT assays demonstrated that PEO-g-DOX2.9 had pronounced cytotoxic effects to RAW 264.7, HeLa, and 4T1 breast tumor cells with IC50 values of about 26.5, 42.5, and 32.0 μg DOX equiv/mL, whereas the corresponding polymer carrier PEO-g-hydrazide4.4 was nontoxic. The In Vivo pharmacokinetics and biodistribution studies in mice showed that PEO-g-DOX2.9 prodrugs had significantly prolonged circulation time and enhanced drug accumulation in the tumor as compared with free DOX. We are convinced that endosomal pH-activatable PEO-g-DOX prodrugs have tremendous potential for targeted cancer therapy.”
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