Raspberry-like poly(γ-glutamic acid) hydrogel particles for pH-dependent cell membrane passage and controlled cytosolic delivery of antitumor drugs.
In this research, we synthesized bioderived poly(amino acid) hydrogel particles that showed pH-dependent membrane-disrupting properties and controlled cytosolic delivery of antitumor drugs. Poly(γ-glutamic acid) (γ-PGA) that has been produced extensively using bacteria, especially those ofBacillus subtilisspecies, was modified with cholesterol (γ-PGA/Chol), and the γ-PGA/Chol conjugates were used to form polymeric nanoparticles the size of 21.0±1.1 nm in aqueous solution. When the polymeric nanoparticles were mixed with doxorubicin (Dox), raspberry-like hydrogel particles (RBHPs) were formed by the electrostatic interaction between the cationically charged Dox and the anionically charged nanoparticles. The average size and surface charge of the RBHPs in aqueous solution were 444.9±122.5 nm and -56.44 mV, respectively. The loaded amount of Dox was approximately 63.9 μg/mg of RBHPs. The RBHPs showed controlled drug release behavior in both in vitro and ex vivo cell-based experiments. Through fluorescence microscopy and fluorescence-activated cell sorting, the cellular uptake of RBHPs into human cervical cancer cells (HeLa) was analyzed. The cytotoxic effect, evaluated by the methyl tetrazolium salt assay, was dependent on both the concentration of RBHPs and the treatment time. The pH-dependent membrane-disrupting properties of the RBHPs and the subsequent cytosolic delivery of Dox were evaluated using a standard hemolysis assay. Upon an increase in hydrophobicity at the lysosomal acidic pH, RBHPs could easily interact, penetrate cell membranes, and destabilize them. Taken together, the data suggested that RBHPs could be used as drug delivery carriers after loading with other therapeutic drugs, such as proteins or small interfering RNA for cancer therapy.
SKKU Advanced Institute of Nanotechnology, School of Chemical Engineering, Sungkyunkwan University, Suwon, Gyeonggi-do.
Sun-Hee
SH
Cho
Graduate School of Analytical Science and Technology, Chungnam National University.
Ji Hyeon
JH
Hong
SKKU Advanced Institute of Nanotechnology, School of Chemical Engineering, Sungkyunkwan University, Suwon, Gyeonggi-do.
Young-Woock
YW
Noh
Graduate School of Analytical Science and Technology, Chungnam National University.
Eunji
E
Lee
Hazards Monitoring Bionano Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea.
Chang-Soo
CS
Lee
SKKU Advanced Institute of Nanotechnology, School of Chemical Engineering, Sungkyunkwan University, Suwon, Gyeonggi-do.
Yong Taik
YT
Lim
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects*; D003600:Cytosol / Q000378:metabolism; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology*; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D004912:Erythrocytes / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D065856:Rubus; D012756:Sheep; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; C511775:poly(gamma-glutamic acid); D011099:Polyglutamic Acid; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D004317:Doxorubicin
antitumor; controlled release; endosomal escape; hydrogel particles