title: Localized delivery of doxorubicin in vivo from polymer-modified thermosensitive liposomes with MR-guided focused ultrasound-mediated heating.
abstract: Thermosensitive liposomes have emerged as a viable strategy for localized delivery and triggered release of chemotherapy. MR-guided focused ultrasound (MRgFUS) has the capability of heating tumors in a controlled manner, and when combined with thermosensitive liposomes can potentially reduce tumor burden in vivo. However, the impact of this drug delivery strategy has rarely been investigated. We have developed a unique liposome formulation modified with p(NIPAAm-co-PAA), a polymer that confers sensitivity to both temperature and pH. These polymer-modified thermosensitive liposomes (PTSL) demonstrated sensitivity to focused ultrasound, and required lower thermal doses and were more cytotoxic than traditional formulations in vitro. A set of acoustic parameters characterizing optimal release from PTSL in vitro was applied in the design of a combined MRgFUS/PTSL delivery platform. This platform more effectively reduced tumor burden in vivo when compared to free drug and traditional formulations. Histological analysis indicated greater tumor penetration, more extensive ECM remodeling, and greater cell destruction in tumors administered PTSL, correlating with improved response to the therapy.
authors.affiliation: Department of Biomedical Engineering, Boston University, 44 Cummington Street, Boston, MA 02215, USA. Electronic address: terence.ta@gmail.com.
authors.forename: Terence
authors.initials: T
authors.lastname: Ta
authors.affiliation: Department of Biomedical Engineering, Boston University, 44 Cummington Street, Boston, MA 02215, USA. Electronic address: ebartola22@gmail.com.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bartolak-Suki
authors.affiliation: Department of Radiology, Harvard Medical School, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, MA 02115, USA. Electronic address: eunjoo.park@gmail.com.
authors.forename: Eun-Joo
authors.initials: EJ
authors.lastname: Park
authors.affiliation: Department of Biomedical Engineering, Boston University, 44 Cummington Street, Boston, MA 02215, USA. Electronic address: kkarrobi@bu.edu.
authors.forename: Kavon
authors.initials: K
authors.lastname: Karrobi
authors.affiliation: Department of Radiology, Harvard Medical School, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, MA 02115, USA. Electronic address: njm@bwh.harvard.edu.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: McDannold
authors.affiliation: Department of Mechanical Engineering, Boston University, 110 Cummington Street, Boston, MA 02215, USA. Electronic address: tmp@bu.edu.
authors.forename: Tyrone M
authors.initials: TM
authors.lastname: Porter
mesh_terms: D000178:Acrylamides; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D016503:Drug Delivery Systems; D005079:Excipients; D006358:Hot Temperature; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008081:Liposomes / Q000737:chemistry*; D061986:MCF-7 Cells; D009682:Magnetic Resonance Spectroscopy; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D010316:Particle Size; D011108:Polymers; D051381:Rats; D011916:Rats, Inbred F344; D013696:Temperature; D014465:Ultrasonics
chemical_list: D000178:Acrylamides; D000903:Antibiotics, Antineoplastic; D005079:Excipients; D008081:Liposomes; C090629:N-isopropylacrylamide-acrylic acid copolymer; D011108:Polymers; D004317:Doxorubicin
keywords: Chemotherapy; Drug delivery; MR-guided focused ultrasound; NIPAAm; Smart polymers; Thermosensitive liposomes