Hybrid iron oxide-gold nanoparticles (HNPs) are capable of drug binding onto their surface with a triggered release at elevated temperatures. The iron oxide core allows for diagnostic imaging whilst heating of the gold shell upon laser irradiation reverses drug binding. This study exploits the reversible binding of novel polyamine based drugs in order to provide specific and effective method for pancreatic cancer treatment. Here we used novel bisnaphthalamido (BNIP) based drug series. Our hybrid nanoparticles (50 nm) were capable of drug loading onto their surface (3:1:0.25, Drug:Fe:Au). By exploiting the surface-to-drug electrostatic interaction of a range of BNIP agents, heat triggered drug release was achieved.12-fold reduction in IC 50 after 24 h in vitro and 5-fold reduction of tumour retardation in vivo compared with free drug in pancreatic models after treatment with the HNP-formulation and laser irradiation. This heat activated system could provide a key platform for future therapy strategies.

cell death could be an ideal solution for controlling and reducing tumor volume [8]. Numerous proteins are involved in apoptosis and thus serve as both potential targets as well as therapeutic tools in cancer treatment. A crucial event during apoptosis is the release of intra-mitochondrial pro-apoptotic proteins into the cytosol, which marks the point of no return in the process [9]. One of the proteins translocated from the mitochondria to the cytosol is Cytochrome c (Cyt c), a 12.7 kDa protein that is also involved in the transport of electrons in the mitochondrial respiratory chain, shuttling electrons between respiratory complex III and IV [10]. Following an apoptotic stimuli, Cyt c released from the mitochondria facilitates the assembly of the apoptosome which comprises of apoptosis activating factor 1 (Apaf-1), pro-caspase 9 and dATP and initiates the activation of the caspase cascade [11]. This mechanism can be exploited in practice by introducing Cyt c into tumor cells which can trigger apoptosis and lead to cell death. However, the intracellular targeting of proteins exhibits significant challenges and it requires the application of specific drug delivery systems. There have previously been attempts to introduce Cyt c into cells using lipid-apolipoprotein particles [12], biodegradable chimeric polymersomes [13], mesoporous silica nanoparticles with a pore surface that undergoes charge conversion intracellularly [14], biodegradable polymersomes containing Abbreviations

Hybrid iron oxide-gold nanoparticles (HNPs) have shown potential in cancer therapy as agents for tumour ablation and thermal switches for targeted drug release. Heat generation occurs by exploitation of the surface plasmon resonance of the gold coating, which usually occurs at the maximum UV absorption wavelength. However, lasers at such wavelength are often expensive and highly specialised. Here, we report the heating and monitoring of heat dissipation of HNPs suspended in agar phantoms using a relatively inexpensive Ng: YAG pulsed 1064 nm laser source. The particles experience heating of up to 40°C with a total area of heat dissipation up to 132.73 mm 2 from the 1 mm diameter irradiation point after 60 seconds. This work reports the potential and possible drawbacks of these particles for translation into cancer therapy based on our findings.

Laser irradiation of hybrid nanoparticles in biological conditions for future application in pancreatic cancer therapy.

BackgroundPancreatic cancer is the 4th most aggressive cancer in the western world with less than 34% of patients surviving past 5 years. Lack of specific symptoms results in delayed diagnosis. Theranostics are new platforms, which offer simultaneous diagnosis and therapy resulting in a decrease in treatment time. Here treatments are conjugated onto diagnostics by stimuli responsive binding allowing for controlled drug release resulting in a rapid and localised clinical effect. Hybrid nanoparticles are composed of an iron oxide core surrounded by a rigid gold shell. These particles undergo manipulation due to inherent magnetism of the core whilst laser irradiation of their gold shell results in localised heating due to surface plasmon resonance. Hence, they can be utlilised as diagnostics using MRI and laser irradiation can be used as a trigger for drug release. MethodsProof of concept studies have been carried out using a novel bisnaphthalamido (BNIP) based drug series. BNIPs are a series of novel compounds, which have exhibited exciting potential as chemotherapy agents. HNPs were fabricated and characterised using PCS, TEM, MRI, SQUID and zeta potential measurement. Drug conjugation and release was quantified using reverse phase HPLC. Cellular response and cytotoxicity assays were carried out using trypan blue exclusion, MTT assay and atomic force microscopy. Results and DiscussionIn our studies, we designed hybrid nanoparticles (50 nm) capable of drug loading onto their surface (3:1:0.25, Drug:Fe:Au). By exploiting the gold surface-to-drug interaction of a range of novel Bisnaphtalamido based agents a system with heat triggered drug release was produced. In vitro studies of these formulations showed the novel formulations possess a 10-fold lower IC 50 value when compared with the free drug after only 24 h. These cytotoxicity studies combined with cellular uptake studies showed the formulations to be significantly more effective compared with gemcitabine. In vivo trials have commenced to further elucidate their viability for use as theranostics. ConclusionThese data highlight the potential of HNPs as dual imaging agents and contrast agents for pancreatic cancer therapy.