Nanoparticle-Enabled, Image-Guided Treatment Planning of Target Specific RNAi Therapeutics in an Orthotopic Prostate Cancer Model

• Published in: Small (Weinheim an der Bergstrasse, Germany) Vol. 10; no. 15; pp. 3072 - 3082
• Main Authors: Lin, Qiaoya, Jin, Cheng S., Huang, Huang, Ding, Lili, Zhang, Zhihong, Chen, Juan, Zheng, Gang
• Format: Journal Article
• Language: English
• Published: Germany Blackwell Publishing Ltd 13.08.2014; Wiley Subscription Services, Inc
• Subjects: Animals; Cell Line, Tumor; cytosolic delivery; Dose-Response Relationship, Drug; Drug Monitoring - methods; Effectiveness; Fluorescence; Gene expression; Gene Silencing; Genetic Therapy - methods; Imaging; Liposomes - chemistry; Male; Medical imaging; Medical treatment; Mice; Microscopy, Fluorescence - methods; multimodal imaging; Nanocapsules - chemistry; Nanocapsules - ultrastructure; nanoparticles; Nanostructure; Nanotechnology; Particle Size; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Prostatic Neoplasms - therapy; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - genetics; siRNA; SR-BI; Therapy; Tomography; Tumors; cytosolic delivery; SR-BI; siRNA; nanoparticles; multimodal imaging
• ISSN: 1613-6810; 1613-6829; 1613-6829
• DOI: 10.1002/smll.201303842

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. Image‐guided treatment planning of target specific RNAi therapeutics by HPPS(NIR)‐chol‐siRNA. A multimodal theranostic HDL‐like nanoparticle is developed for in vivo non‐invasive assessment of siRNA accumulation in an orthotopic prostate tumor by tracing the NIR fluorescent surrogate using image co‐registration of computed tomography and fluorescence molecular tomography, which provides a useful mean for real‐time tracking siRNA delivery, rational dosimetry, and treatment planning for efficacious RNAi therapy.