BERKELEY, CA (UroToday.com) - Prostate cancer is the second leading cause of cancer-related death and the most common malignancy in North America. Nowadays, the concept of personalized medicine has been widely accepted by physicians and scientists for prostate cancer treatment. Its goal is to use the right drug at the right dose with minimal or no toxicity for the right patient treatment at the right time. Theranostics-combining imaging and therapeutic modalities play an increasingly important role in personalized medicine. With theranostics, drug delivery is no longer black box -- having only injected dose as input and clearance rate as output -- since imaging functionalities facilitate the detection of disease tissues, guide the surgery, quantify the intratumoral drug dose, and even predict the treatment response. Targeted delivery of theranostics via nanosized delivery systems exhibits vast advantages in prolonging systemic circulation, improving tumor specificity, evading host defenses, and integrating multifunctional properties in a single platform, to pursue maximum theranostic effects and minimal side effects.
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Recently, our lab developed a multimodal theranostic lipid-nanoparticle, HPPS(NIR)-chol-siRNA, (HPPS stands for high-density lipoprotein(HDL) mimicking peptide phospholipid nanoscaffold) 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). The NIR-core of nanoparticles can be utilized for non-invasive fluorescence imaging, while the siRNAs act as therapeutic function for cancer in a single platform. The NIR-core was first validated as a stable imaging surrogate for non-labeled therapeutic siRNAs delivery, both in vitro and in vivo, indicating the feasibility to real-time track siRNAs delivery in vivo using fluorescence imaging and without interrupting their RNAi function. The drug tracking can help physicians to find patients who might be positive to the treatment with high drug accumulation, and thus have strong possibilities of a favorable outcome. Using the fluorescence imaging modality, we then validated the targeting specificity of HPPS(NIR)-chol-siRNA to orthotopic prostate tumor in mouse model from anatomical level to microscopy level using sequential four-steps fluorescence imaging (in vivo, in situ, ex vivo and frozen-tissue). The high-contrast fluorescence displayed in the tumor provided a benefit for the early detection and diagnosis of cancer. In addition, the clear tumor delineation by in situ fluorescence imaging allowed for defining tumor margin precisely to guide the surgery.
Dosimetry, to accurately quantify the drug uptake for treatment planning, is another critical factor in personalized medicine. By using the CT-FMT (computed tomography-fluorescence molecular tomography) co-registration approach, we could, in real time, quantify the relative tumor uptake of nanoparticles in vivo (see Figure), optimize the treatment regimen by comparing different treatment regimens, and finally achieve efficacious RNAi therapy on orthotopic PC3 tumor mice. Therefore, theranostic property of the multifunctional HPPS(NIR)-chol-siRNA nanoparticles might provide physicians with a way to select the right patients at the right time using the right plan for successful treatment.
The last critical factor that no physician will ignore is the safety issue. The HPPS nanoparticle closely mimics the natural structural and functional properties of HDL, and all of its components are biocompatible. It is indeed a safe vector evidenced by the absence of adverse effects when 2000 mg/kg of HPPS was administered intravenously. During multiple dosage of HPPS(NIR)-chol-siRNA on orthotopic PC3 prostate cancer mice, no adverse effect was observed, suggesting non toxicity of the multimodal HPPS(NIR)-chol-siRNA.
In summary, the multimodal HPPS(NIR)-chol-siRNA enabled image-guided treatment planning of targeted RNAi therapeutics in orthotopic prostate cancer to achieve significant therapeutic effect, and without inducing any adverse effect. As clinical application of nanotheranostics also requires early assessment of treatment response, we will explore the nanotheronistic on predicting treatment response. In terms of this, the correlation between tumor accumulation of nanoparticles and treatment efficacy needs to be further validated.
- Jemal A, Siegel R, Ward E, et al. Cancer Statistics. CA Cancer J Clin 2007; 57: 43–66.
- Yang M, Chen J, Cao W et al. Attenuation of nontargeted cell-kill using a high-density lipoprotein-mimicking peptide- phospholipid nanoscaffold. Nanomedicine (Lond). 2011;6(4), 631–641.
Qiaoya Lin,a, b, e Cheng S. Jin,a, c Huang Huang,d Lili Ding,a Zhihong Zhang,e Juan Chen,a and Gang Zheng,a, b, c as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
aPrincess Margaret Cancer Center and Techna Institute, UHN, Toronto, ON, Canada
bDepartment of Medical Biophysics, University of Toronto, Toronto, Canada
cDepartment of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada
dDLVR Therapeutics Inc., Toronto, Canada
eBritton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science & Technology, Wuhan, China