US EPA

4220312 

Journal Article 

Thiolactone Chemistry-Based Combinatorial Methodology to Construct Multifunctional Polymers for Efficacious Gene Delivery 

Zha, Z; Hu, Y; Mukerabigwi, JF; Chen, W; Wang, Y; He, C; Ge, Z 

2018 

Yes 

Bioconjugate Chemistry
ISSN: 1043-1802
EISSN: 1520-4812 

American Chemical Society 

29 

1 

23-28 

English 

29232506 

10.1021/acs.bioconjchem.7b00672 

WOS:000423012800004 

Hydrophobic segments and amino moieties in polymeric nonviral gene vectors play important roles in overcoming a cascade of barriers for efficient gene delivery. However, it remains a great challenge to facilely construct well-defined multifunctional polymers through optimization of the amino and hydrophobic groups. Herein, we choose thiolactone chemistry to perform the ring opening reaction of varying hydrophobic groups-modified thiolactones by various amines to generate mercapto groups for further Michael addition reaction with poly[2-(acryloyloxy)ethyl methacrylate] (PAOEMA). Based on the combinatorial methodology, a series of multifunctional polymers were prepared and screened. The polymer (P3D) from tetraethylenepentamine and heptafluorobutyric acid-functionalized thiolactone is the most efficacious one with significantly higher gene transfection efficiency and lower cytotoxicity compared with polyethylenimine (PEI) (branched average Mw ∼ 25 000 Da) and Lipofectamine 2000. Cellular uptake and intracellular distribution studies indicate that P3D complexes show high-efficiency endocytosis and excellent endosomal escape. Accordingly, thiolactone chemistry-based combinatorial methodology allows for facile integration of multifunctional groups to prepare simultaneous efficacious and low-cytotoxic gene delivery vectors.