Anti-c-myc cholesterol-based lipoplexes: development, characterisation and evaluation as Onconanotherapeutic agents in vitro.

Doctoral Degree in (Biochemistry). University of KwaZulu-Natal, Durban.Strategies aimed at inhibiting the expression of the c-myc oncogene could provide the basis for alternative cancer treatment. In this regard, silencing c-myc expression using small interfering RNA (siRNA) is an attractive option. However, the development of a clinically viable, siRNAbased, c-myc silencing system is largely dependent upon the design of an appropriate siRNA carrier that can be easily prepared. Nanostructures formed by the electrostatic association of siRNA and cationic lipid vesicles represent uncomplicated, well-recognised siRNA delivery systems. Therefore, this study has focused on traditional cationic liposomes as the foundation for the development of a simple, but effective anti-c-myc onconanotherapeutic agent. Novel liposome formulations contained equimolar quantities of the cytofectin, N,Ndimethylaminopropylamidosuccinylcholesterylformylhydrazide (MS09), and cholesterol (Chol); with or without 2 mol % pegylation. Liposomes which contained dioleoylphosphatidylethanolamine (DOPE) as the co-lipid were included for comparative purposes. Pegylated and non-pegylated MS09/Chol (1:1) suspensions were reproducibly prepared by lipid film hydration to give unilamellar vesicles that were stable for at least 10 months at 4 ˚C. Liposomes successfully bound siRNA to form lipoplexes of less than 200 nm in size, with zeta potentials between -16 and -44 mV. These assumed globular and bilamellar structures in which siRNA was partially protected. Although all formulations were well tolerated at ≤14 nM siRNA, pegylation severely inhibited siRNA delivery in cancer cell lines, MCF-7 and HT-29, which overexpress c-myc. The non-pegylated MS09/Chol (1:1) lipoplex, at the MS09:siRNA (w /w) ratio of 16:1, was most effectively taken up by MCF-7 and HT-29 cells, with negligible effect in non-transformed cells when applied at 12 nM siRNA. Lipoplexes directed against the c-myc transcript (anti-c-myc siRNA), mediated a dramatic reduction in c-myc mRNA and protein levels. This was accompanied by a loss of migratory potential and apoptotic cell death. Moreover, oncogene knockdown and anti-cancer effects were superior to that of a commercially available transfection reagent, Lipofectamine™ 3000. Although the DOPE-containing counterpart performed with iii comparable efficacy under standard in vitro conditions, it was incapable of siRNA delivery at physiological serum concentration. Hence, the anti-c-myc MS09/Chol (1:1) lipoplex reported exemplifies a straightforward anti-cancer agent that warrants further investigation in vivo

Anti-c-myc RNAi-Based Onconanotherapeutics

Overexpression of the c-myc proto-oncogene features prominently in most human cancers. Early studies established that inhibiting the expression of oncogenic c-myc, produced potent anti-cancer effects. This gave rise to the notion that an appropriate c-myc silencing agent might provide a broadly applicable and more effective form of cancer treatment than is currently available. The endogenous mechanism of RNA interference (RNAi), through which small RNA molecules induce gene silencing by binding to complementary mRNA transcripts, represents an attractive avenue for c-myc inhibition. However, the development of a clinically viable, anti-c-myc RNAi-based platform is largely dependent upon the design of an appropriate carrier of the effector nucleic acids. To date, organic and inorganic nanoparticles were assessed both in vitro and in vivo, as carriers of small interfering RNA (siRNA), DICER-substrate siRNA (DsiRNA), and short hairpin RNA (shRNA) expression plasmids, directed against the c-myc oncogene. We review here the various anti-c-myc RNAi-based nanosystems that have come to the fore, especially between 2005 and 2020

Angiopep-2-Modified Nanoparticles for Brain-Directed Delivery of Therapeutics: A Review

Nanotechnology has opened up a world of possibilities for the treatment of brain disorders. Nanosystems can be designed to encapsulate, carry, and deliver a variety of therapeutic agents, including drugs and nucleic acids. Nanoparticles may also be formulated to contain photosensitizers or, on their own, serve as photothermal conversion agents for phototherapy. Furthermore, nano-delivery agents can enhance the efficacy of contrast agents for improved brain imaging and diagnostics. However, effective nano-delivery to the brain is seriously hampered by the formidable blood–brain barrier (BBB). Advances in understanding natural transport routes across the BBB have led to receptor-mediated transcytosis being exploited as a possible means of nanoparticle uptake. In this regard, the oligopeptide Angiopep-2, which has high BBB transcytosis capacity, has been utilized as a targeting ligand. Various organic and inorganic nanostructures have been functionalized with Angiopep-2 to direct therapeutic and diagnostic agents to the brain. Not only have these shown great promise in the treatment and diagnosis of brain cancer but they have also been investigated for the treatment of brain injury, stroke, epilepsy, Parkinson’s disease, and Alzheimer’s disease. This review focuses on studies conducted from 2010 to 2021 with Angiopep-2-modified nanoparticles aimed at the treatment and diagnosis of brain disorders

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

Bimetallic nanoparticles as suitable nanocarriers in cancer therapy

Cancer is a widespread disease which has been prevalent for decades and for which a cure is yet to be discovered. Current treatments are fraught with severe side effects to patients and with no certainty of remission. This problem has been met with research innovations in the design of nanomaterials with potential to be used as nanocarriers of cancer therapeutics. In this regard, the current review focuses on the progress that has been achieved through the synthesis and functionalisation of bimetallic nanoparticles (BNPs). Metal nanoparticles have been used extensively in the design of potential cancer treatments, with BNPs showing increasing potential. The combination of two metals each with their own advantageous properties can produce a nanoparticle with favourable properties and enhanced activity. This review outlines the current advances and avenues being explored with BNPs and their applications in cancer treatment, spanning research conducted in the last ten years. These include the efficient delivery of chemotherapeutic drugs such as doxorubicin, paclitaxel and 5-fluorouracil, use of BNPs in phototherapy and theranostics, where BNPs serve as contrast agents for imaging. In each of these instances, BNPs show strong potential for further development and optimization for cancer therapy. However, most of the research to date does not extend beyond the in vitro level. There is still a vast array of functionalisations to be explored and applications to be discovered. As such, it is clear that further research into this promising platform is imperative