Cys34-PEGylated Human Serum Albumin for Drug Binding and Delivery.
Polyethylene glycol (PEG) derivatives were conjugated onto the Cys-34 residue of human serum albumin (HSA) to determine their effects on the solubilization, permeation, and cytotoxic activity of hydrophobic drugs such as paclitaxel (PTX). PEG(C34)HSA conjugates were prepared on a multigram scale by treating native HSA (n-HSA) with 5- or 20-kDa mPEG-maleimide, resulting in up to 77% conversion of the mono-PEGylated adduct. Nanoparticle tracking analysis of PEG(C34)HSA formulations in phosphate buffer revealed an increase in the number of nanosized aggregates relative to n-HSA, both in the absence and presence of PTX. Cell viability studies conducted with MCF-7 breast cancer cells indicated that PTX cytotoxicity was enhanced by PEG(C34)HSA when mixed at 10:1 mol ratios, up to a 2-fold increase in potency relative to n-HSA. The PEG(C34)HSA conjugates were also evaluated as PTX carriers across monolayers of HUVEC and hCMEC/D3 cells, and found to have permeation profiles nearly identical to those of n-HSA.
†Department of Chemistry ‡Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States.
Jonathan G
JG
Mehtala
†Department of Chemistry ‡Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States.
Chris
C
Kulczar
†Department of Chemistry ‡Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States.
Monika
M
Lavan
†Department of Chemistry ‡Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States.
Gregory
G
Knipp
†Department of Chemistry ‡Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States.
Alexander
A
Wei
D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003545:Cysteine / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D008301:Maleimides / Q000737:chemistry; D008958:Models, Molecular; D053758:Nanoparticles / Q000737:chemistry; D017239:Paclitaxel / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D010539:Permeability; D011092:Polyethylene Glycols / Q000737:chemistry*; D011487:Protein Conformation; D012709:Serum Albumin / Q000737:chemistry* / Q000378:metabolism*
D004337:Drug Carriers; D008301:Maleimides; D012709:Serum Albumin; C043592:maleimide; D011092:Polyethylene Glycols; C028210:monomethoxypolyethylene glycol; D003545:Cysteine; D017239:Paclitaxel