Hyper-cell-permeable micelles as a drug delivery carrier for effective cancer therapy.
Although PEGylated liposomes (PEG-LS) have been intensively studied as drug-delivery vehicles, the rigidity and the hydrophilic PEG corona of liposomal membranes often limits cellular uptake, resulting in insufficient drug delivery to target cells. Thus, it is necessary to develop a new type of lipid-based self-assembled nanoparticles capable of enhanced cellular uptake, tissue penetration, and drug release than conventional PEGylated liposomes. Herein, we describe a simple modification of bicellar formulation in which the addition of a PEGylated phospholipid produced a dramatic physicochemical change in morphology, i.e., the disc-shaped bicelle became a uniformly distributed ultra-small (∼12 nm) spherical micelle. The transformed lipid-based nanoparticles, which we termed hyper-cell-permeable micelles (HCPMi), demonstrated not only prolonged stability in serum but also superior cellular and tumoral uptake compared to a conventional PEGylated liposomal system (PEG-LS). In addition, HCPMi showed rapid cellular uptake and subsequent cargo release into the cytoplasm of cancer cells. Cells treated with HCPMi loaded with docetaxel (DTX) had an IC50value of 0.16 μM, compared with 0.78 μM with PEG-LS loaded with DTX, a nearly five-fold decrease in cell viability, indicating excellent efficiency in HCPMi uptake and release. In vivo tumor imaging analysis indicated that HCPMi penetrated deep into the tumor core and achieved greater uptake than PEG-LS. Results of HCPMi (DTX) treatment of allograft and xenograft mice in vivo showed high tumoral uptake and appreciable tumor retardation, with ∼70% tumor weight reduction in the SCC-7 allograft model. Taken together, these findings indicate that HCPMi could be developed further as a highly competent lipid-based drug-delivery system.
Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, 60 Fenwood Road, Boston, MA, 02115, United States; KAIST Institute for the BioCentury, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Daejeon, 34141, South Korea.
Phei Er
PE
Saw
Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, 60 Fenwood Road, Boston, MA, 02115, United States.
Mikyung
M
Yu
KAIST Institute for the BioCentury, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Daejeon, 34141, South Korea.
Minsuk
M
Choi
KAIST Institute for the BioCentury, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Daejeon, 34141, South Korea.
Eunbeol
E
Lee
KAIST Institute for the BioCentury, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Daejeon, 34141, South Korea. Electronic address: syjon@kaist.ac.kr.
Sangyong
S
Jon
Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, 60 Fenwood Road, Boston, MA, 02115, United States. Electronic address: ofarokhzad@bwh.harvard.edu.
Omid C
OC
Farokhzad
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004655:Emulsions; D008081:Liposomes / Q000737:chemistry* / Q000648:ultrastructure; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D053769:Nanocapsules / Q000737:chemistry* / Q000648:ultrastructure; D009374:Neoplasms, Experimental / Q000737:chemistry* / Q000188:drug therapy* / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage* / Q000737:chemistry*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D004655:Emulsions; D008081:Liposomes; D008823:Micelles; D053769:Nanocapsules; D043823:Taxoids; D000077143:Docetaxel
Bicelles; Cancer therapy; Drug delivery; Lipid nanoparticles; Micelles