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Nanoparticle-enabled, image-guided treatment planning of target specific RNAi therapeutics in an orthotopic prostate
Qiaoya Lin1, Cheng S Jin, Huang Huang
1Princess 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.
Abstract:
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.
Insights
This study introduces a novel imaging nanoparticle for RNA interference (RNAi) therapy. It enables tracking of small interfering RNA (siRNA) delivery and guides treatment planning for enhanced efficacy.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Molecular Imaging
Background:
- RNA interference (RNAi) therapy faces challenges in targeted delivery and efficiency assessment.
- Effective siRNA delivery, combined with genetic profiling, is crucial for optimal treatment outcomes.
- Current imaging modalities rarely guide treatment planning for RNAi therapy.
Purpose of the Study:
- To develop and validate a multimodal theranostic nanoparticle for enhanced RNAi therapy.
- To utilize near-infrared (NIR) fluorescence imaging for tracking siRNA delivery and assessing treatment.
- To enable non-invasive assessment and planning of siRNA delivery for efficacious RNAi therapy.
Main Methods:
- Synthesized a multimodal theranostic lipid-nanoparticle (HPPS(NIR)-chol-siRNA) with a NIR fluorescent core.
- Employed fluorescence imaging (in vivo, in situ, ex vivo, frozen-tissue) to validate cytosolic delivery and tumor targeting.
- Utilized image co-registration of computed tomography and fluorescence molecular tomography for treatment planning.
Main Results:
- Demonstrated cytosolic delivery of siRNA and nanoparticle structural integrity in mice via intravenous administration.
- Validated the NIR-core as an effective imaging surrogate for non-labeled therapeutic siRNAs.
- Confirmed HPPS(NIR)-chol-siRNA targeting specificity to orthotopic tumors.
- Achieved efficacious RNAi therapy through non-invasive assessment and treatment planning.
Conclusions:
- The developed HPPS(NIR)-chol-siRNA nanoparticle is a promising theranostic tool for RNAi therapy.
- Multimodal imaging, including NIR fluorescence and computed tomography, enables effective siRNA delivery tracking and treatment planning.
- This approach maximizes RNAi efficacy by guiding rational dosimetry and personalized treatment strategies.
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