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Synthesis and preliminary biological evaluation of high-drug-load paclitaxel-antibody conjugates for tumor-targeted chemotherapy.

Abstract：

:The goal of this study was to design paclitaxel (PTX)-monoclonal antibody (mAb) prodrug conjugates (PTXMAbs) with the ability to deliver therapeutically significant doses of the drug to the tumor while avoiding the previously observed solubility limitations of conjugates with PTX:mAb molar ratios of >3. New PTX conjugates were synthesized using the discrete poly(ethylene glycol) (dPEG) as linkers. These compounds, PTX-L-Lys[(dPEG12)(3)-dPEG4]-dPEG6-NHS (9a and 9b, for L = GL or SX, respectively), were then conjugated to the antiepidermal growth factor receptor mAb, C225 at increasing PTX:C225 ratios, producing completely soluble conjugates. Unlike the earlier PTXMAbs, buffered solutions of these conjugates remained homogeneous for extended periods of time. Fluorescence-activated cell sorting (FACS) analysis indicated preserved immunogenicity of the conjugates at all four substitution ratios, while cytotoxicity studies in MDA-MB-468 breast cancer cells indicated preservation of drug cytotoxicity. These conjugates may have potential in the development of high-drug-load tumor-targeting taxanes.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Quiles S,Raisch KP,Sanford LL,Bonner JA,Safavy A

doi

10.1021/jm900899g

subject

Has Abstract

pub_date

2010-01-28 00:00:00

pages

586-94

issue

2

eissn

0022-2623

issn

1520-4804

journal_volume

53

pub_type

杂志文章

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