Cancer nanomedicine

[Abstract unavailable

Remotely triggered scaffolds for controlled release of pharmaceuticals

Fe3O4-Au hybrid nanoparticles (HNPs) have shown increasing potential for biomedical applications such as image guided stimuli responsive drug delivery. Incorporation of the unique properties of HNPs into thermally responsive scaffolds holds great potential for future biomedical applications. Here we successfully fabricated smart scaffolds based on thermo-responsive poly(N-isopropylacrylamide) (pNiPAM). Nanoparticles providing localized trigger of heating when irradiated with a short laser burst were found to give rise to remote control of bulk polymer shrinkage. Gold-coated iron oxide nanoparticles were synthesized using wet chemical precipitation methods followed by electrochemical coating. After subsequent functionalization of particles with allyl methyl sulfide, mercaptodecane, cysteamine and poly(ethylene glycol) thiol to enhance stability, detailed biological safety was determined using live/dead staining and cell membrane integrity studies through lactate dehydrogenase (LDH) quantification. The PEG coated HNPs did not show significant cytotoxic effect or adverse cellular response on exposure to 7F2 cells (p < 0.05) and were carried forward for scaffold incorporation. The pNiPAM-HNP composite scaffolds were investigated for their potential as thermally triggered systems using a Q-switched Nd:YAG laser. These studies show that incorporation of HNPs resulted in scaffold deformation after very short irradiation times (seconds) due to internal structural heating. Our data highlights the potential of these hybrid-scaffold constructs for exploitation in drug delivery, using methylene blue as a model drug being released during remote structural change of the scaffold

The use of novel poly(allylamine) based amphiphilic polymers for drug delivery.

Fourteen novel comb shaped amphiphilic polymers were successfully synthesised to determine the effect of polymer architecture on the potential of these amphiphilic polymers for hydrophobic drug delivery. Polyallylamine (PAA) was grafted with four different types of hydrophobic pendant groups (Cholesteryl (Ch), (Fmoc), (Dansyl)and (Naphth)). Some amphiphilic polymers were further reacted with methyl orange to form quaternary ammonium moieties. The polymers were characterised by elemental analysis and nuclear magnetic resonance spectroscopy (NMR). In the aqueous environment the amphiphilic polymers formed nano self assemblies with particle size from 99 to 284 nm. The critical aggregation concentration (CAC) of the self assemblies was successfully determined by surface tension measurement. The CAC ranged from the lowest value of 0.093 to the highest 1.5 mgmL-1 (Ch5 and Fmoc5 respectively). The Fmoc and Naphth grafted polymers showed the presence of two CMC values, this phenomenon was due to stacking of the planar hydrophobic ring structures resulting in excimer formation. The theory of excimer formation was confirmed by the observation of peak shifting on the emission spectra of the compounds in water over a large concentration range (0.023 “ 3 mgmL-1). The drug loading potential of the polymers was investigated using five model hydrophobic drugs, propofol, prednisolone griseofulvin, etoposide and novel anticancer agent BNIPDaoct. The Ch5 and Dansyl10 showed excellent drug solubilisation capacities. At 6 mgmL-1 the Ch5 achieved propofol solubility 70-fold greater than its aqueous solubility, prednisolone, griseofulvin and etoposide solubilitys were increased 20-fold, 30-fold and 7-fold respectively. Similarly at 6 mgmL-1 the Dansyl10 achieved a 200-fold increase on the aqueous solubility of propofol and increased the solubility of prednisolone, griseofulvin and etoposide by 100-fold and 400-fold and 12-fold respectively. The Ch5 (at 1 mgmL-1) was also used to solubilise the novel anticancer agent Bisnaphthalimidopropyl diaminooctane (BNIPDaoct) which was otherwise insoluble achieving a solubilisation of 0.3 mgmL-1. The sizes of the optimal formulations differed greatly for both modified polymers. This was possibly due to the varying architectures of both the drug and the modified polymers and their ability to expand the hydrophobic core and shield the drugs from the hostile aqueous environment. The in vitro drug release profiles, showed controlled release of the hydrophobic drugs from the core of the nano aggregates (Ch5 and Dansyl10), the time span for 100% of the drugs to be released ranged from 48- 96 h. Biological characterisation of the polymers found that most of the polymers showed negligible haemolytic activity over the concentrations tested (0.05 “ 1 mgmL-1), the IC50 values for the cytotoxicity assay ranged from 0.01740 - 0.05585 mgmL-1 on Caco-2 cells (Fmoc5 to QCh5 respectively). The quaternized polymers showed a slightly better safety profile than their unquaternized counterparts, despite exhibiting low drug solubilisation capacities. The optimal formulations of Ch5 and Dansyl10 loaded with etoposide and BNIPDaoct were tested for their cytotoxicity in vitro on Caco-2 and HEK293 cells. All formulations were capable of lowering the IC50 values when compared with the free anticancer drugs, thus increasing their therapeutic effect. The Ch5 decreased the solubility of etoposide 2.2-fold and BNIPDaoct 1.3-fold on Caco-2 cells, with Dansyl10 achieving a 14 -fold and 16“fold reduction respectively. In vivo oral administration of Ch5 and Dansyl10, griseofulvin formulations demonstrated significantly enhanced the absorption of griseofulvin absorption in rats compared with griseofulvin in water (8.89-fold and 5.20-fold increase respectively on total concentration of griseofulvin solubilised over 24 h study). A formulation of Ch5, BNIPDaoct was also shown to significantly decrease the tumour growth when treated on tumour bearing nude mice over a 4 week period. This is the first time these novel PAAs grafted with cholesteryl and dansyl have shown promising potential in hydrophobic drug delivery

Enhancement of the Cytotoxic Effect of Anticancer Agent by Cytochrome c Functionalised Hybrid Nanoparticles in Hepatocellular Cancer Cells

Treatment of hepatocellular cancer with chemotherapeutic agents has limited success in clinical practice and their efficient IC50 concentration would require extremely high doses of drug administration which could not be tolerated due to systemic side effects. In order to potentiate the efficacy of anticancer agents we explored the potential of co-treatment with pro-apoptotic Cytochrome c which activates the apoptotic pathway downstream of p53 that is frequently mutated in cancer. To this end we used hybrid iron oxide-gold nanoparticles as a drug delivery system to facilitate the internalisation of Cytochrome c into cultured HepG2 hepatocellular carcinoma cells. Our results showed that Cytochrome c can be easily conjugated to the gold shell of the nanoparticles which are readily taken up by the cells. We used Cytochrome c in concentration (0.2µgmL-1) below the threshold required to induce apoptosis on its own. When the conjugate was administered to cells treated by doxorubicin, it significantly reduced its IC50 concentration from 9µgmL-1 to 3.5µgmL-1 as detected by cell viability assay, and the efficiency of doxorubicin on decreasing viability of HepG2 cells was significantly enhanced in the lower concentration range between 0.01µgmL-1 to 5µgmL-1. The results demonstrate the potential of the application of therapeutic proteins in activating the apoptotic pathway to complement conventional chemotherapy to increase its efficacy. The application of hybrid iron oxide-gold nanoparticles can also augment the specificity of drug targeting and could serve as a model drug delivery system for pro-apoptotic protein targeting and delivery

Towards advanced wound regeneration

Wound management is a major contributor towards the economic burden placed upon the national health service (NHS), serving as an important target for the development of advanced therapeutic interventions. The economic expenditure of wound care for the NHS exceeds £5 billion per annum, thus presenting a significant opportunity for the introduction of alternative treatments in regards to their approach in tackling the ever increasing prevalence of wound management associated problems. As most wounds typically fall under the acute or chronic category, it is therefore necessary to design a therapeutic intervention capable of effectively resolving the pathologies associated with each problem. Such an intervention should be of increased economic viability and therapeutic effectiveness when compared to standardized treatments, thus helping to alleviate the financial burden imposed upon the NHS. The purpose of this review is to critically analyse the various aspects associated with wound management, detailing the fundamental concepts of dermal regeneration, whilst also providing an evaluation of the different materials and methods that can be utilised to achieve maximal wound regeneration. The primary aspects of this review revolve around the three concepts of antibacterial methodology, enhancement of dermal regeneration and the utilisation of a carrier medium to facilitate the regenerative process. Each aspect is explored, conveying its justifications as a target for dermal regeneration, whilst offering various solutions towards the fulfilment of a therapeutic design that is both effective and financially feasible

Simple calix[n]arenes and calix[4]resorcinarenes as drug solubilizing agents

Many drug molecules have low solubility in aqueous media and, hence, poor bioavailability. The formation of a host-guest complex with some other compound which has a good solubility profile can facilitate solubilization of hydrophobic drugs. Complex formation relies upon the formation of non-covalent interactions between the host molecule and the drug guest. The use of calix[n]arenes, a well-characterized class of cyclic oligomers, has been investigated for their ability to form complexes with a variety of ionic and molecular species. This review highlights those studies which have demonstrated the potential of calix[n]arenes as host molecules in novel drug delivery systems

The use of nano polymeric self-assemblies based on novel amphiphilic polymers for oral hydrophobic drug delivery.

Purpose: To investigate the use of nano self-assemblies formed by polyallylamine (PAA) modified with 5 or 10% mole fluorenylmethoxy carbonyl (Fmoc5/10), dimethylamino-1-naphthalenesulfonyl (Dansyl5/10) and 5% mole cholesteryl group (Ch5) for oral hydrophobic drug delivery. Methods: Propofol, griseofulvin and prednisolone were loaded into amphiphilic PAAs. Particle size and morphology of drug-loaded self-assemblies were determined using photon correlation spectroscopy and transmission electron microscopy. Solubilising capacity, in vitro drug release and formulation stability were analysed by HPLC, and in vitro biocompatibility studies (haemolysis and cytotoxicity) were carried out on bovine erythrocytes and Caco-2 cells, respectively. Dansyl10 and Ch5 griseofulvin formulations were administered intra-gastrically to rats, and drug plasma levels were analysed by HPLC. Results: Drug-encapsulated self-assemblies typically have hydrodynamic size of 300–400 nm. Dansyl10 exhibited universal drug solubiliser property and had significantly improved prednisolone, griseofulvin and propofol solubility by 145, 557 and 224-fold, respectively. Fmoc polymers resulted in modest drug solubility improvement. These polymers were non-haemolytic, did not enhance cytotoxicity compared to unmodified PAA, and demonstrated significant increase in griseofulvin plasma concentration compared to griseofulvin in water after oral administration. Conclusions: Ch5 and Dansyl10 showed promising potential as nano-carriers for oral hydrophobic drug delivery

A novel PAA derivative with enhanced drug efficacy in pancreatic cancer cell lines.

Nanoparticles have been shown to be effective drug carriers in cancer therapy. Pancreatic cancer forms dense tumours which are often resistant to drug molecules. In order to overcome such multidrug resistance, new drug entities, novel delivery systems and combination therapy strategies are being explored. In this paper, we report the design and synthesis of a poly(allylamine)-based amphiphile modified with hydrophobic naphthalimido pendant groups. Bisnaphthalimide compounds have been shown to possess anticancer activity. The potential of this polymer to encapsulate, solubilize and enhance drug (5-fluorouricil and bis-(naphthalimidopropyl)-diaminooctane) cytotoxicity in BxPC-3 cells was evaluated. Our studies showed that the insoluble drugs could be formulated up to 4.3 mg mL−1 and 2.4 mg mL−1 inside the amphiphiles, respectively. Additionally, the novel poly(allylamine)-naphthalimide carrier resulted in an amplification of cytotoxic effect with drug treatment after 24 h, and was capable of reduction of 50% cell population at concentrations as low as 3 μg mL−1

Current and future strategies against cutaneous parasites

Cutaneous parasites are identified by their specific cutaneous symptoms which are elicited based on the parasite's interactions with the host. Standard anti-parasitic treatments primarily focus on the use of specific drugs to disrupt the regular function of the target parasite. In cases where secondary infections are induced by the parasite itself, antibiotics may also be used in tandem with the primary treatment to deal with the infection. Whilst drug-based treatments are highly effective, the development of resistance by bacteria and parasites, is increasingly prevalent in the modern day, thus requiring the development of non-drug based anti-parasitic strategies. Cutaneous parasites vary significantly in terms of the non-systemic methods that are required to deal with them. The main factors that need to be considered are the specifically elicited cutaneous symptoms and the relative cutaneous depth in which the parasites typically reside in. Due to the various differences in their migratory nature, certain cutaneous strategies are only viable for specific parasites, which then leads to the idea of developing an all-encompassing anti-parasitic strategy that works specifically against cutaneous parasites. The main benefit of this would be the overall time saved in regards to the period that is needed for accurate diagnosis of parasite, coupled with the prescription and application of the appropriate treatment based on the diagnosis. This review will assess the currently identified cutaneous parasites, detailing their life cycles which will allow for the identification of certain areas that could be exploited for the facilitation of cutaneous anti-parasitic treatment