Targeted gene transfer to mammalian systems using liposome constructs containing cholesterol components with or without biotinylated molecular accessories.

Ph. D. University of KwaZulu-Natal 2005.Abstract available in PDF file

Hepatocellular-Targeted mRNA Delivery Using Functionalized Selenium Nanoparticles In Vitro

Selenium’s (Se) chemopreventative and therapeutic properties have attracted attention in nanomedicine. Se nanoparticles (SeNPs) retain these properties of Se while possessing lower toxicity and higher bioavailability, potentiating their use in gene delivery. This study aimed to formulate SeNPs for efficient binding and targeted delivery of FLuc-mRNA to hepatocellular carcinoma cells (HepG2) in vitro. The colorectal adenocarcinoma (Caco-2) and normal human embryonic kidney (HEK293) cells that do not have the asialoorosomucoid receptor (ASGPR) were utilized for comparison. SeNPs were functionalized with chitosan (CS), polyethylene glycol (PEG), and lactobionic acid (LA) for ASGPR targeting on HepG2 cells. Nanoparticles (NPs) and their mRNA-nanocomplexes were characterized by Fourier transform infra-red (FTIR) and UV-vis spectroscopy, transmission electron microscopy (TEM), and nanoparticle tracking analysis (NTA). Gel and fluorescence-based assays assessed the NP’s ability to bind and protect FLuc-mRNA. Cytotoxicity was determined using the -(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, while transgene expression was evaluated using the luciferase reporter gene assay. All NPs appeared spherical with sizes ranging 57.2–130.0 nm and zeta potentials 14.9–31.4 mV. NPs bound, compacted, and protected the mRNA from nuclease digestion and showed negligible cytotoxicity in vitro. Targeted gene expression was highest in the HepG2 cells using the LA targeted NPs. These NPs portend to be efficient nanocarriers of nucleic acids and warrant further investigation

Sterically Stabilised Polymeric Mesoporous Silica Nanoparticles Improve Doxorubicin Efficiency: Tailored Cancer Therapy

The fruition, commercialisation and clinical application combining nano-engineering, nanomedicine and material science for utilisation in drug delivery is becoming a reality. The successful integration of nanomaterial in nanotherapeutics requires their critical development to ensure physiological and biological compatibility. Mesoporous silica nanoparticles (MSNs) are attractive nanocarriers due to their biodegradable, biocompatible, and relative malleable porous frameworks that can be functionalized for enhanced targeting and delivery in a variety of disease models. The optimal formulation of an MSN with polyethylene glycol (2% and 5%) and chitosan was undertaken, to produce sterically stabilized, hydrophilic MSNs, capable of efficient loading and delivery of the hydrophobic anti-neoplastic drug, doxorubicin (DOX). The pH-sensitive release kinetics of DOX, together with the anticancer, apoptosis and cell-cycle activities of DOX-loaded MSNs in selected cancer cell lines were evaluated. MSNs of 36–60 nm in size, with a pore diameter of 9.8 nm, and a cumulative surface area of 710.36 m2/g were produced. The 2% pegylated MSN formulation (PCMSN) had the highest DOX loading capacity (0.98 mgdox/mgmsn), and a sustained release profile over 72 h. Pegylated-drug nanoconjugates were effective at a concentration range between 20–50 μg/mL, inducing apoptosis in cancer cells, and affirming their potential as effective drug delivery vehicles

Folate-Targeted mRNA Delivery Using Chitosan-Functionalized Selenium Nanoparticles: Potential in Cancer Immunotherapy

Systemic messenger RNA (mRNA) delivery, although still in its infancy, holds immense potential for application in cancer vaccination and immunotherapy. Its advantages over DNA transfection make it attractive in applications where transient expression is desired. However, this has proved challenging due to mRNA’s instability and susceptibility to degradation. Selenium is important for immune function and modulation, with selenium nanoparticles (SeNPs) finding a niche in biomedicine as drug delivery vehicles, owing to their biocompatibility, low toxicity, and biodegradability. In this investigation, we synthesized chitosan-coated SeNPs with a folic acid targeting moiety for Fluc mRNA delivery to cancer cells in vitro. Synthesized SeNPs were stable and well dispersed, and ranged from 59 to 102 nm in size. Nanoparticles bound and protected mRNA from RNase degradation, while exhibiting low cytotoxicity in the human embryonic kidney (HEK293), breast adenocarcinoma (MCF-7), and nasopharyngeal (KB) cells in culture. Moderate cytotoxicity evidenced in the colorectal carcinoma (Caco-2) and colon carcinoma (HT-29) cells was attributed to apoptosis induction by selenium, as confirmed by acridine orange/ethidium bromide staining. Selenium uptake studies corroborated the transfection results, where significant transgene expression was evident for the overexpressed folate receptor-positive KB cells when compared to the other cells with less or no folate receptors

Current Stimuli-Responsive Mesoporous Silica Nanoparticles for Cancer Therapy

With increasing incidence and mortality rates, cancer remains one of the most devastating global non-communicable diseases. Restricted dosages and decreased bioavailability, often results in lower therapeutic outcomes, triggering the development of resistance to conventionally used drug/gene therapeutics. The development of novel therapeutic strategies using multimodal nanotechnology to enhance specificity, increase bioavailability and biostability of therapeutics with favorable outcomes is critical. Gated vectors that respond to endogenous or exogenous stimuli, and promote targeted tumor delivery without prematurely cargo loss are ideal. Mesoporous silica nanoparticles (MSNs) are effective delivery systems for a variety of therapeutic agents in cancer therapy. MSNs possess a rigid framework and large surface area that can incorporate supramolecular constructs and varying metal species that allow for stimuli-responsive controlled release functions. Its high interior loading capacity can incorporate combination drug/gene therapeutic agents, conferring increased bioavailability and biostability of the therapeutic cargo. Significant advances in the engineering of MSNs structural and physiochemical characteristics have since seen the development of nanodevices with promising in vivo potential. In this review, current trends of multimodal MSNs being developed and their use in stimuli-responsive passive and active targeting in cancer therapy will be discussed, focusing on light, redox, pH, and temperature stimuli

Recent Advances in Lipid-Based Nanosystems for Gemcitabine and Gemcitabine–Combination Therapy

The anti-metabolite drug gemcitabine is widely used for the treatment of a variety of cancers. At present, gemcitabine is administered as a hydrochloride salt that is delivered by slow intravenous injection in cycles of three or four weeks. Although regarded as a ‘front-line’ chemotherapeutic agent, its efficacy is hampered by poor target cell specificity, sub-optimal cellular uptake, rapid clearance from circulation, the development of chemoresistance, and undesirable side-effects. The use of organic, inorganic, and metal-based nanoparticles as delivery agents presents an opportunity to overcome these limitations and safely harness optimal drug efficacy and enhance their therapeutic indices. Among the many and varied nano delivery agents explored, the greatest body of knowledge has been generated in the field of lipid-mediated delivery. We review here the liposomes, niosomes, solid lipid nanoparticles, nanostructured lipid carriers, exosomes, lipid-polymer hybrids, and other novel lipid-based agents that have been developed within the past six years for the delivery of gemcitabine and its co-drugs

The Synergism of Platinum-Gold Bimetallic Nanoconjugates Enhances 5-Fluorouracil Delivery In Vitro

Nanoparticle application has significantly impacted the field of medicine. The need to develop novel drugs with higher therapeutic potential has stimulated the development of innovative delivery strategies to mitigate the potent side effects associated with known chemotherapeutic drugs. This paper describes the synthesis of platinum-gold bimetallic nanoparticles (PtAuBNps), their functionalisation with chitosan, and entrapment of the anticancer drug 5-fluorouracil (5-FU). All PtAuBNps and their drug nanocomposites were physico-chemically characterised, displaying desirable properties with regards to shape, size (<120 nm) and colloidal stability. 5-FU binding and loading capacities in PtAuBNps were found to be 90.17% and 22.56%, respectively. In vitro cytotoxicity profiles determined using the MTT and SRB assays reflected up to 65% cell death in the MCF-7, HepG2 and Caco-2 cell lines. These nanocomposites exhibited excellent physiochemical attributes, high specificity towards cancer cells, with a pH-sensitive drug release in a simulated acidic tumour microenvironment through zero-order release kinetics. In addition, they possessed the potential to traverse the mucosal lining facilitating oral drug administration. Overall, 5-FU encapsulation improved the bioavailability of the drug in cancer cells, with the promise of enhancing its therapeutic effect, biocompatibility and safety. These positive results highlight PtAuBNps as promising in vitro delivery systems and merits future in vivo research

Polymeric Mesoporous Silica Nanoparticles for Enhanced Delivery of 5-Fluorouracil In Vitro

There is a need for the improvement of conventional cancer treatment strategies by incorporation of targeted and non-invasive procedures aimed to reduce side-effects, drug resistance, and recurrent metastases. The anti-cancer drug, 5-fluorouracil (5-FU), is linked to a variety of induced-systemic toxicities due to its lack of specificity and potent administration regimens, necessitating the development of delivery vehicles that can enhance its therapeutic potential, while minimizing associated side-effects. Polymeric mesoporous silica nanoparticles (MSNs) have gained popularity as delivery vehicles due to their high loading capacities, biocompatibility, and good pharmacokinetics. MSNs produced in this study were functionalized with the biocompatible polymers, chitosan, and poly(ethylene)glycol to produce monodisperse NPs of 36–65 nm, with a large surface area of 710.36 m2/g, large pore volume, diameter spanning 9.8 nm, and a favorable zeta potential allowing for stability and enhanced uptake of 5-FU. Significant drug loading (0.15–0.18 mg5FU/mgmsn), controlled release profiles (15–65%) over 72 hours, and cell specific cytotoxicity in cancer cells (Caco-2, MCF-7, and HeLa) with reduced cell viability (≥50%) over the non-cancer (HEK293) cells were established. Overall, these 5FU-MSN formulations have been shown to be safe and effective delivery systems in vitro, with potential for in vivo applications

Lipid Nanoparticles: Promising Treatment Approach for Parkinson’s Disease

Parkinson’s disease (PD), a neurodegenerative disorder, is a life-altering, debilitating disease exhibiting a severe physical, psychological, and financial burden on patients. Globally, approximately 7–10 million people are afflicted with this disease, with the number of cases estimated to increase to 12.9 million by 2040. PD is a progressive movement disorder with nonmotor symptoms, including insomnia, depression, anxiety, and anosmia. While current therapeutics are available to PD patients, this treatment remains palliative, necessitating alternative treatment approaches. A major hurdle in treating PD is the protective nature of the blood–brain barrier (BBB) and its ability to limit access to foreign molecules, including therapeutics. Drugs utilized presently are nonspecific and administered at dosages that result in numerous adverse side effects. Nanomedicine has emerged as a potential strategy for treating many diseases. From the array of nanomaterials available, lipid nanoparticles (LNPs) possess various advantages, including enhanced permeability to the brain via passive diffusion and specific and nonspecific transporters. Their bioavailability, nontoxic nature, ability to be conjugated to drugs, and targeting moieties catapult LNPs as a promising therapeutic nanocarriers for PD. While PD-related studies are limited, their potential as therapeutics is evident in their formulations as vaccines. This review is aimed at examining the roles and properties of LNPs that make them efficient therapeutic nanodelivery vehicles for the treatment of PD, including therapeutic advances made to date