title: Ultrasound-guided delivery of microRNA loaded nanoparticles into cancer.
abstract: Ultrasound induced microbubble cavitation can cause enhanced permeability across natural barriers of tumors such as vessel walls or cellular membranes, allowing for enhanced therapeutic delivery into the target tissues. While enhanced delivery of small (<1nm) molecules has been shown at acoustic pressures below 1MPa both in vitro and in vivo, the delivery efficiency of larger (>100nm) therapeutic carriers into cancer remains unclear and may require a higher pressure for sufficient delivery. Enhanced delivery of larger therapeutic carriers such as FDA approved pegylated poly(lactic-co-glycolic acid) nanoparticles (PLGA-PEG-NP) has significant clinical value because these nanoparticles have been shown to protect encapsulated drugs from degradation in the blood circulation and allow for slow and prolonged release of encapsulated drugs at the target location. In this study, various acoustic parameters were investigated to facilitate the successful delivery of two nanocarriers, a fluorescent semiconducting polymer model drug nanoparticle as well as PLGA-PEG-NP into human colon cancer xenografts in mice. We first measured the cavitation dose produced by various acoustic parameters (pressure, pulse length, and pulse repetition frequency) and microbubble concentration in a tissue mimicking phantom. Next, in vivo studies were performed to evaluate the penetration depth of nanocarriers using various acoustic pressures, ranging between 1.7 and 6.9MPa. Finally, a therapeutic microRNA, miR-122, was loaded into PLGA-PEG-NP and the amount of delivered miR-122 was assessed using quantitative RT-PCR. Our results show that acoustic pressures had the strongest effect on cavitation. An increase of the pressure from 0.8 to 6.9MPa resulted in a nearly 50-fold increase in cavitation in phantom experiments. In vivo, as the pressures increased from 1.7 to 6.9MPa, the amount of nanoparticles deposited in cancer xenografts was increased from 4- to 14-fold, and the median penetration depth of extravasated nanoparticles was increased from 1.3-fold to 3-fold, compared to control conditions without ultrasound, as examined on 3D confocal microscopy. When delivering miR-122 loaded PLGA-PEG-NP using optimal acoustic settings with minimum tissue damage, miR-122 delivery into tumors with ultrasound and microbubbles was 7.9-fold higher compared to treatment without ultrasound. This study demonstrates that ultrasound induced microbubble cavitation can be a useful tool for delivery of therapeutic miR loaded nanocarriers into cancer in vivo.
authors: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, School of Medicine, Stanford, CA, USA.
authors: Tzu-Yin
authors: TY
authors: Wang
authors: Department of Electrical Engineering, Stanford University, Stanford, CA, USA.
authors: Jung Woo
authors: JW
authors: Choe
authors: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, School of Medicine, Stanford, CA, USA.
authors: Kanyi
authors: K
authors: Pu
authors: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, School of Medicine, Stanford, CA, USA.
authors: Rammohan
authors: R
authors: Devulapally
authors: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, School of Medicine, Stanford, CA, USA.
authors: Sunitha
authors: S
authors: Bachawal
authors: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, School of Medicine, Stanford, CA, USA.
authors: Steven
authors: S
authors: Machtaler
authors: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, School of Medicine, Stanford, CA, USA.
authors: Sayan Mullick
authors: SM
authors: Chowdhury
authors: Department of Comparative Medicine, Stanford University, Stanford, CA, USA.
authors: Richard
authors: R
authors: Luong
authors: Department of Health, Research & Policy, Stanford University, Stanford, CA, USA.
authors: Lu
authors: L
authors: Tian
authors: Department of Electrical Engineering, Stanford University, Stanford, CA, USA.
authors: Butrus
authors: B
authors: Khuri-Yakub
authors: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, School of Medicine, Stanford, CA, USA.
authors: Jianghong
authors: J
authors: Rao
authors: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, School of Medicine, Stanford, CA, USA. Electronic address: paulmur8@stanford.edu.
authors: Ramasamy
authors: R
authors: Paulmurugan
authors: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, School of Medicine, Stanford, CA, USA. Electronic address: willmann@stanford.edu.
authors: Jürgen K
authors: JK
authors: Willmann
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003106:Colon / Q000473:pathology*; D003110:Colonic Neoplasms / Q000473:pathology / Q000628:therapy*; D016503:Drug Delivery Systems / Q000295:instrumentation*; D004867:Equipment Design; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000008:administration & dosage* / Q000493:pharmacokinetics; D045423:Microbubbles; D053758:Nanoparticles / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D013010:Sonication / Q000295:instrumentation; D014465:Ultrasonics / Q000295:instrumentation*
chemical_list: C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols
keywords: Cancer; Drug delivery; Image guidance; Nanocarriers; Therapy; Ultrasound