Lack of safe and effective carriers for delivery of RNA therapeutics remains a barrier to its broad clinical application. We report the development of a cell tanscytosing magnetic nanovector engineered as an siRNA carrier. Iron oxide nanoparticles were modified with poly(ethylene glycol) (PEG), small interfering RNA (siRNA), and a catinionic polymer layer. Three nanovector formulations with cationic polymer coatings of poly arginine (pArg), polylysine (pLys), and polyethylimine (PEI), respectively, were prepared. The three nanovector formulations where evaluated for safety and ability to promote gene silencing in three types of cancer cells C6/GFP+, MCF7/GFP+, and TC2/GFP+, mimicing human cancers of the brain, breast, and prostate respectively. Cell viability and fluoresence quantification assays revealed that pArg-coated nanovectors were most effective in promoting gene-knockdown and least toxic of the three nanovector formulations tested. Transmission Electron Microscopy (TEM) imaging of nanovector treated cell further demonstrated that pArg-coated nanovectors enter cells through cell transcytosis, while pLys and PEI coated nanovectors enter cells endocytosis. Our findings suggest that NPs engineered to exploit the cell transcytosis intracellular trafficking pathway may offer a more safe and efficient route for siRNA delivery.
e17056 Background: Multiparametric Magnetic Resonance Imaging (mpMRI) has been increasingly utilized in prostate cancer (PCa) diagnosis and staging. While there is Level 1 data supporting MRI utility in identifying clinically significant PCa and guiding PCa diagnosis, there is little data on its ability to predict surgical outcomes and its utility as a staging study. We aimed to evaluate the accuracy of mpMRI in predicting common surgical pathology outcomes in patients who underwent radical prostatectomy (RP). Methods: Men who underwent either open radical prostatectomy (ORP) or robotic assisted laparoscopic prostatectomy (RALP) for prostate adenocarcinoma from January-December 2021 at a single tertiary level care academic medical center were identified. Chart review for relevant patient demographics, mpMRI related variables and final surgical pathology was completed. In patients who had pre-operative mpMRI, we evaluated the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of mpMRI in predicting relevant surgical outcomes, including presence of pT2N0 organ confined disease (OCD), extracapsular extension (ECE), seminal vesicle invasion (SVI), lymph node involvement (LNI), and bladder neck invasion (BNI). Results: 168 eligible patients were identified in a 12-month period. The mean age was 63.5±6.24 years and mean Prostate Specific Antigen (PSA) was 11.4±23.7, with 166 (98.8%) patients undergoing RALP and 115 (68.5%) having pre-operative mpMRI. Median GGG was 2 in both MRI and CT subsets (p = 0.580), and patients who had pre-op MRI were more likely to have higher PSA (12.7 ±28.1 vs 8.38± 6.32, p = 0.073) and clinically node positive disease (p < 0.001) than those with CT. However, there was no significant difference in final surgical pathology or positive surgical margin rates between these two groups. On subset analysis of the MRI subset, Table summarizes the sensitivity, specificity, PPV, and NPV of pre-op MRI to predict OCD, ECE, SVI, LNI, and BNI. While specificity of pre-op MRI was adequate for all outcomes (89.1-100%), sensitivity (2.9-49.2%), PPV (40-100%), and NPV (56.3-94.3%) were poor. Conclusions: At present, pre-op MRI of the prostate does not appear to be accurate in its ability to predict important pathologic outcomes at the time of radical prostatectomy and should be used cautiously as a local staging tool. More work is needed before MRI can be used as a reliable staging tool for PCa.[Table: see text]
e17112 Background: Immune Checkpoint Inhibitors (ICI) are increasingly utilized for genitourinary (GU) malignancies. However, data is lacking on the efficacy of these drugs in “real-world” populations - patients who do not fit the strict clinical trial criteria, but may still benefit from therapy. We performed a retrospective analysis of patients receiving ICI at a single tertiary-care institution, with special attention to clinical trial enrollment, adverse events, progression and survival. Methods: Patients receiving ICI for GU malignancies at Thomas Jefferson University Hospital from January 2017 to January 2019 were identified. Descriptive statistics of treatment and pathologies were performed. Progression-free survival (PFS) was calculated from start of ICI to documentation of progression or last follow-up. PFS and overall survival were assessed using Kaplan Meier log-rank test, stratified by trial enrollment. Results: 111 patients were included: 37 on ICI clinical trial, 70 received ICI “off-trial” and 4 received ICI in both settings. 11 patients (10%) underwent multiple courses of ICI throughout treatment. The number of patients initiating ICI increased annually; by 2018, the number of patients initiated on ICI “off-trial” exceeded those initiating ICI “on-trial” (79% vs 21%). Treated pathology included Urothelial Carcinoma (UC; 42%), Renal Cell Carcinoma (RCC; 28%), and Prostate Adenocarcinoma (PCa; 20%). “Off-trial” ICI was more often administered later in the disease course, compared to a more even distribution of “on-trial” ICI administration. Mean PFS and OS for both cohorts can be seen in Table. Conclusions: As seen in our single-institution referral center, the use of immune checkpoint inhibitors has significantly increased – and is now more commonly used off-trial than on-trial. As their use becomes more common, their efficacy in “off-trial” populations must be further investigated. [Table: see text]
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