Nanoparticle-enabled, image-guided treatment planning of target specific RNAi therapeutics in an orthotopic prostate cancer model.
The abilities to deliver siRNA to its intended action site and assess the delivery efficiency are challenges for current RNAi therapy, where effective siRNA delivery will join force with patient genetic profiling to achieve optimal treatment outcome. Imaging could become a critical enabler to maximize RNAi efficacy in the context of tracking siRNA delivery, rational dosimetry and treatment planning. Several imaging modalities have been used to visualize nanoparticle-based siRNA delivery but rarely did they guide treatment planning. We report a multimodal theranostic lipid-nanoparticle, HPPS(NIR)-chol-siRNA, which has a near-infrared (NIR) fluorescent core, enveloped by phospholipid monolayer, intercalated with siRNA payloads, and constrained by apoA-I mimetic peptides to give ultra-small particle size (<30 nm). Using fluorescence imaging, we demonstrated its cytosolic delivery capability for both NIR-core and dye-labeled siRNAs and its structural integrity in mice through intravenous administration, validating the usefulness of NIR-core as imaging surrogate for non-labeled therapeutic siRNAs. Next, we validated the targeting specificity of HPPS(NIR)-chol-siRNA to orthotopic tumor using sequential four-steps (in vivo, in situ, ex vivo and frozen-tissue) fluorescence imaging. The image co-registration of computed tomography and fluorescence molecular tomography enabled non-invasive assessment and treatment planning of siRNA delivery into the orthotopic tumor, achieving efficacious RNAi therapy.
Princess Margaret Cancer Center and Techna Institute, UHN, TMDT 5-362, 101 College Street, Toronto, ON, M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Canada; Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science & Technology, Wuhan, 430074, China.
Qiaoya
Q
Lin
Cheng S
CS
Jin
Huang
H
Huang
Lili
L
Ding
Zhihong
Z
Zhang
Juan
J
Chen
Gang
G
Zheng
D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods*; D020868:Gene Silencing; D015316:Genetic Therapy / Q000379:methods*; D008081:Liposomes / Q000737:chemistry; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence / Q000379:methods; D053769:Nanocapsules / Q000737:chemistry / Q000648:ultrastructure; D010316:Particle Size; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics
D008081:Liposomes; D053769:Nanocapsules; D034741:RNA, Small Interfering
SR-BI; cytosolic delivery; multimodal imaging; nanoparticles; siRNA