Reactive Self-Assembly of Polymers and Proteins to Reversibly Silence a Killer Protein.
Conjugation of biologically active proteins to polymeric materials is of great interest in the treatment of cancer and other diseases of protein deficiency. The conjugation of such biomacromolecules is challenging both due to their hydrophilicity and propensity to denature under non-native conditions. We describe a novel reactive self-assembly approach to "wrap" a protein with polymers, simultaneously protecting its delicate folded state and silencing its enzymatic activity. This approach has been demonstrated using caspase-3, an apoptosis-inducing protein, as the first case study. The protein-polymer conjugation is designed to be reversed under the native conditions for caspase-3, that is, the reducing environment found in the cytosol. The current strategy allowed release and recovery of up to 86% of caspase activity and nanogel-caspase-3 conjugates induced 70-80% apoptotic cell death shortly thereafter. This approach is widely generalizable and should be applicable to the intracellular delivery of a wide range of therapeutic proteins for treatment of complex and genetic diseases.
Department of Chemistry, University of Massachusetts , Amherst, Massachusetts 01003, United States.
Judy
J
Ventura
Department of Chemistry, University of Massachusetts , Amherst, Massachusetts 01003, United States.
Scott J
SJ
Eron
Department of Chemistry, University of Massachusetts , Amherst, Massachusetts 01003, United States.
Daniella C
DC
González-Toro
Department of Chemistry, University of Massachusetts , Amherst, Massachusetts 01003, United States.
Kishore
K
Raghupathi
Department of Chemistry, University of Massachusetts , Amherst, Massachusetts 01003, United States.
Feng
F
Wang
Department of Chemistry, University of Massachusetts , Amherst, Massachusetts 01003, United States.
Jeanne A
JA
Hardy
Department of Chemistry, University of Massachusetts , Amherst, Massachusetts 01003, United States.
S
S
Thayumanavan
D000595:Amino Acid Sequence; D000818:Animals; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011108:Polymers / Q000737:chemistry*; D011506:Proteins / Q000737:chemistry*
D011108:Polymers; D011506:Proteins