Concave microwell array-mediated three-dimensional tumor model for screening anticancer drug-loaded nanoparticles.
We investigated the effect of anticancer drug-loaded functional polymeric nanoparticles on drug resistance of three-dimensional (3D) breast tumor spheroids. 3D tumor models were built using concave microwells with different diameters (300-700μm) and nanoparticles were prepared using thermo-responsive poly(N-isopropylacrylamide) (PNIPAM)-co-acrylic acid (AA). Upon culturing with doxorubicin-loaded PNIPAM-co-AA nanoparticles for 96hours, the smallest tumor spheroids were extensively disrupted, resulting in a reduction in spheroid diameter. In contrast, the sizes of the largest tumor spheroids were not changed. Scanning electron microscopy revealed that the circular shape of 3D spheroids treated with doxorubicin-loaded PNIPAM-co-AA nanoparticles had collapsed severely. Cell viability assays also demonstrated that the largest tumor spheroids cultured with doxorubicin-loaded PNIPAM-co-AA nanoparticles were highly resistant to the anticancer drug. We confirmed that tight cell-cell contacts within largest tumor spheroids significantly improved the anticancer drug resistance. Therefore, this uniform-sized 3D breast tumor model could be a potentially powerful tool for anticancer drug screening applications.


BACKGROUND
The battle against cancer is a big challenge. With new anti-cancer drugs being developed under the nanotechnology platform, there is a need to have a consistent and reliable testing system that mimics the in-vivo tumor scenario. The authors successfully designed a 3D tumor model using concave microwells to produce different tumor diameters. This will be of value for future drug screening.
NBIT, KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea.
AhRan
A
Kang
Department of Mechanical Engineering, Sogang University, Seoul, Korea.
Hye In
HI
Seo
Department of Mechanical Engineering, Sogang University, Seoul, Korea. Electronic address: bchung@sogang.ac.kr.
Bong Geun
BG
Chung
NBIT, KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea; Department of Biomedical Engineering, Korea University, Seoul, Korea. Electronic address: dbiomed@korea.ac.kr.
Sang-Hoon
SH
Lee
D000179:Acrylates / Q000737:chemistry*; D000180:Acrylic Resins / Q000737:chemistry*; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology; D000970:Antineoplastic Agents; D001940:Breast / Q000187:drug effects / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D018929:Cell Culture Techniques / Q000295:instrumentation / Q000379:methods*; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor / Q000295:instrumentation / Q000379:methods*; D004867:Equipment Design; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D053758:Nanoparticles / Q000737:chemistry*; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured
D000179:Acrylates; D000180:Acrylic Resins; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; C052970:poly-N-isopropylacrylamide; D004317:Doxorubicin; C036658:acrylic acid
Anticancer drug screening; Concave microwell array; Polymeric nanoparticle; Three-dimensional tumor model; Uniform-sized tumor