Polycations are explored as carriers to deliver therapeutic nucleic acids. Polycations are conventionally pharmacological inert with the sole function of delivering therapeutic cargo. This study reports synthesis of a self-immolative polycation (DSS-BEN) based on a polyamine analogue drug N1,N11-bisethylnorspermine (BENSpm). The polycation was designed to function dually as a gene delivery carrier and a prodrug targeting dysregulated polyamine metabolism in cancer. Using a combination of NMR and HPLC, we confirm that the self-immolative polycation undergoes intracellular degradation into the parent drug BENSpm. The released BENSpm depletes cellular levels of spermidine and spermine and upregulates polyamine catabolic enzymes spermine/spermidine N1-acetyltransferase (SSAT) and spermine oxidase (SMO). The synthesized polycations form polyplexes with DNA and facilitate efficient transfection. Taking advantage of the ability of BENSpm to sensitize cancer cells to TNFα-induced apoptosis, we show that DSS-BEN enhances the cell killing activity of TNFα gene therapy. The reported findings validate DSS-BEN as a dual-function delivery system that can deliver a therapeutic gene and improve the outcome of gene therapy as a result of the intracellular degradation of DSS-BEN to BENSpm and the subsequent beneficial effect of BENSpm on dysregulated polyamine metabolism in cancer.

Abstract. Mesoporous silica nanoparticles (MSNs) have been proposed as drug delivery devices for approximately 15 years. The history of in vitro studies has been promising, demonstrating that MSNs have the capability for stimulus-responsive controlled release, good cellular uptake, cell specific targeting, and the ability to carry a variety of cargoes from hydrophobic drug molecules to imaging agents. However, the translation of the in vitro findings to in vivo conditions has been slow. Herein, we review the current state-of-the-art in the use of MSN for systemic drug delivery in vivo and provide critical insight into the future of MSNs as systemic drug delivery devices and directions that should be undertaken to improve their practicality.

Inflammatory bowel disease is a chronic inflammation of the gastrointestinal tract with poor understanding of its pathogenesis and no effective cure. The goal of this study was to evaluate the feasibility of orally administered non-degradable polymeric chloroquine (pCQ) to locally reduce colon inflammation. The pCQ was synthesized by radical copolymerization of N-(2-hydroxypropyl)methacrylamide with methacryloylated hydroxychloroquine (HCQ). The anti-inflammatory activity of orally administered pCQ versus HCQ was tested in a mouse model of colitis induced by Citrobacter rodentium (C. rodentium). Single-dose pharmacokinetic and biodistribution studies performed in the colitis model indicated negligible systemic absorption (p ≤ 0.001) and localization of pCQ in the gastrointestinal tract. A multi-dose therapeutic study demonstrated that the localized pCQ treatment resulted in significant reduction in the colon inflammation (p ≤ 0.05). Enhanced suppression of pro-inflammatory cytokines IL-6 (p ≤ 0.01) and IL1-β and opposing upregulation of IL-2 (p ≤ 0.05) recently reported to be involved in downstream anti-inflammatory events suggested that the anti-inflammatory effects of the pCQ are mediated by altering mucosal immune homeostasis. Overall, the reported findings demonstrate a potential of pCQ as a novel polymer therapeutic option in inflammatory bowel disease with the potential of local effects and minimized systemic toxicity.

Mesoporous silica nanomaterials show great potential to deliver chemotherapeutics for cancer treatment. The key challenges in the development of injectable mesoporous silica formulations are colloidal instability, hemolysis and inefficient drug loading and release. In this study, we evaluated the effect of PEGylation of mesoporous silica nanorods (MSNR) on hemolysis, colloidal stability, mitoxantrone (MTX) loading, in vitro MTX release, and cellular MTX delivery under hypoxic conditions. We found that PEGylation prevented dose-dependent hemolysis in the concentrations studied (0–10 mg/ml) and improved colloidal stability of MSNR. A negative effect of PEGylation on MTX loading was observed but PEGylated MSNR (PMSNR) demonstrated increased MTX release compared to non-PEGylated particles. Under hypoxic conditions, a decrease in the IC50 of MTX and MTX-loaded MSNR was observed when compared to normoxic conditions. These results showed that MSNR could deliver the chemotherapeutic agent, MTX to tumor cells and induce effective cell killing. However, the effect of PEGylation needs to be carefully studied due to the observed adverse effect on drug loading.

Eicosanoids are key mediators and regulators of inflammation and oxidative stress that are often used as biomarkers for severity and therapeutic responses in various diseases. We here report a highly sensitive LC-MS/MS method for the simultaneous quantification of at least 66 key eicosanoids in a widely used murine model of colitis. Chromatographic separation was achieved with Shim-Pack XR-ODSIII, 150 × 2.00 mm, 2.2 µm. The mobile phase was operated in gradient conditions and consisted of acetonitrile and 0.1% acetic acid in water with a total flow of 0.37 mL/min. This method is sensitive, with a limit of quantification ranging from 0.01 to 1 ng/mL for the various analytes, has a large dynamic range (200 ng/mL), and a total run time of 25 min. The inter- and intraday accuracy (85–115%), precision (≥85%), and recovery (40–90%) met the acceptance criteria per the US Food and Drug Administration guidelines. This method was successfully applied to evaluate eicosanoid metabolites in mice subjected to colitis versus untreated, healthy control mice. In summary, we developed a highly sensitive and fast LC−MS/MS method that can be used to identify biomarkers for inflammation and potentially help in prognosis of the disease in inflammatory bowel disease (IBD) patients, including the response to therapy.