title: PPO/PEO modified hollow fiber membranes improved sensitivity of 3D cultured hepatocytes to drug toxicity via suppressing drug adsorption on membranes.
abstract: The three dimensional (3D) cell culture in polymer-based micro system has become a useful tool for in vitro drug discovery. Among those polymers, polysulfone hollow fiber membrane (PSf HFM) is commonly used to create a microenvironment for cells. However, the target drug may adsorb on the polymeric surface, and this elicits negative impacts on cell exposure due to the reduced effective drug concentration in culture medium. In order to reduce the drug adsorption, PSf membrane were modified with hydrophilic Pluronic (PEO-b-PPO-b-PEO) copolymers, L121, P123 and F127 (PEO contents increase from 10%, 30% to 70%), by physical adsorption. As a result, the hydrophilicity of HFMs increased at an order of PSf<L121<P123<F127 HFMs, while the negative surface charge decreased at the order of PSf>F127>P123>L121 HFMs. The three modified membrane all showed significant resistance to adsorption of acid/neutral drugs. More importantly, the adsorption of base drugs were largely reduced to an average value of 11% on the L121 HFM. The improved resistance to drug adsorption could be attributed to the synergy of hydrophobic/neutrally charged PPO and hydrophilic PEO. The L121 HFM was further assessed by evaluating the drug hepatotoxicity in 3D culture of hepatocytes. The base drugs, clozapine and doxorubicin, showed more sensitive hepatotoxicity on hepatocytes in L121 HFM than in PSf HFM, while the acid drug, salicylic acid, showed the similar hepatotoxicity to hepatocytes in both HFMs. Our finding suggests that PSf HFM modified by PEO-b-PPO-b-PEO copolymers can efficiently resist the drug adsorption onto polymer membrane, and consequently improve the accuracy and sensitivity of in vitro hepatotoxic drug screening.
authors.affiliation: Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Shen
authors.affiliation: Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China. Electronic address: mengq@zju.edu.cn.
authors.forename: Qin
authors.initials: Q
authors.lastname: Meng
authors.affiliation: Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: He
authors.affiliation: Micro Stamping Corporation, Somerset, NJ 08873, United States.
authors.forename: Qichen
authors.initials: Q
authors.lastname: Wang
authors.affiliation: College of Chemical Engineering and Materials Science, Zhejiang University of Technology, Hangzhou, China. Electronic address: guoliangz@zjut.edu.cn.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Zhang
mesh_terms: D000327:Adsorption; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003024:Clozapine / Q000737:chemistry / Q000493:pharmacokinetics; D004317:Doxorubicin / Q000737:chemistry / Q000493:pharmacokinetics; D022781:Hepatocytes / Q000378:metabolism; D008297:Male; D008567:Membranes, Artificial; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000737:chemistry*; D011409:Propylene Glycols / Q000009:adverse effects / Q000737:chemistry*; D051381:Rats
chemical_list: D008567:Membranes, Artificial; C116176:PEO-PPO-PEO; D011409:Propylene Glycols; D011092:Polyethylene Glycols; D004317:Doxorubicin; D003024:Clozapine
keywords: Drug adsorption; Hepatotoxicity; Hollow fiber membranes; Poly(phenylene oxide); Polyethylene glycol