Core polymer optimization of ternary siRNA nanoparticles enhances in vivo safety, pharmacokinetics, and tumor gene silencing.

Gene silencing with siRNA nanoparticles (si-NPs) is promising but still clinically unrealized for inhibition of tumor driver genes. Ternary si-NPs containing siRNA, a single block NP core-forming polymer poly[(2-(dimethylamino)ethyl methacrylate)-co-(butyl methacrylate)] (DMAEMA-co-BMA, 50B), and an NP surface-forming diblock polymer 20 kDa poly(ethylene glycol)-block-50B (20kPEG-50B) have the potential to improve silencing activity in tumors due to the participation of both 50B and 20kPEG-50B in siRNA electrostatic loading and endosome disruptive activity. Functionally, single block 50B provides more potent endosomolytic activity, while 20kPEG-50B colloidally stabilizes the si-NPs. Here, we systematically explored the role of the molecular weight (MW) of the core polymer and of the core:surface polymer ratio on ternary si-NP performance. A library of ternary si-NPs was formulated with variation in the MW of the 50B polymer and in the ratio of the core and surface forming polymeric components. Increasing 50B core polymer MW and ratio improved si-NP in vitro gene silencing potency, endosome disruptive activity, and stability, but these features also correlated with cytotoxicity. Concomitant optimization of 50B size and ratio resulted in the identification of lead ternary si-NPs 50B4-DP100, 50B8-DP100, and 50B12-DP25, with potent activity and minimal toxicity. Following intravenous treatment in vivo, all lead si-NPs displayed negligible toxicological effects and enhanced pharmacokinetics and tumor gene silencing relative to more canonical binary si-NPs. Critically, a single 1 mg/kg intravenous injection of 50B8-DP100 si-NPs silenced the tumor driver gene Rictor at the protein level by 80% in an orthotopic breast tumor model. 50B8-DP100 si-NPs delivering siRictor were assessed for therapeutic efficacy in an orthotopic HCC70 mammary tumor model. This formulation significantly inhibited tumor growth compared to siControl-NP treatment. 50B8-DP100 si-NPs were also evaluated for safety and were well-tolerated following a multi-dose treatment scheme. This work provides new insight on ternary si-NP structure-function relationships and identifies core polymer optimization strategies that can yield safe si-NP formulations with potent oncogene silencing.

Treating Vertebral Compression Fractures: Establishing the Appropriate Diagnosis, Preoperative Considerations, Treatment Techniques, Postoperative Follow-Up and General Guidelines for the Treatment of Patients With Symptomatic Vertebral Compression Fractures.

Vertebral compression fractures (VCFs) result from either trauma or a pathologic process that weakens the bone by conditions such as osteoporosis or tumor. The incidence of VCFs has been rising over the last few decades in accordance with the aging population. These fractures can result in severe pain, physical limitation and disability, as well as increased morbidity and mortality. Patients with VCFs are optimally treated by accurate and early diagnosis and treatment. An effective method to treat these fractures is percutaneous vertebral augmentation, which is a set of minimally invasive procedures that stabilizes osseous fractures, provides immediate pain relief, and improves quality of life. Vertebral augmentation procedures include vertebroplasty, kyphoplasty, and vertebral augmentation with implants. Each of these techniques is described in general terms in this article. The ideal candidate for vertebral augmentation is a patient with a symptomatic fracture seen on cross-sectional imaging in which nonsurgical management has failed and has positive signs on physical examination with no absolute contraindication. This procedure should be done with the appropriate equipment and personnel in a facility designed for this purpose. After the procedure, the patient should undergo the appropriate follow-up to ensure optimal recovery. Additionally, it is essential that the patient receives appropriate therapy for the underlying disorder that predisposed them to the vertebral fracture.