Lysosomal cysteine proteases are mediators of cell death in macrophages following exposure to amorphous silica nanoparticles.

Increasing use of nanomaterials in everyday products such as cosmetics, medicines and food packaging is of grave concern given the lack of understanding with regards the impact such materials have on biological systems. The aim of this study is to examine cell death induced by cationic amorphous silica nanoparticles and determine the involvement of lysosomal cysteine proteases in this process. We report that multiple forms of cell death including apoptosis and pyroptosis are elicited following exposure to amorphous silica nanoparticles and that lysosomal cysteine proteases are involved in both cell death pathways in macrophages.

Nanomedicine in Pancreatic Cancer: Current Status and Future Opportunities for Overcoming Therapy Resistance.

The development of drug resistance remains one of the greatest clinical oncology challenges that can radically dampen the prospect of achieving complete and durable tumour control. Efforts to mitigate drug resistance are therefore of utmost importance, and nanotechnology is rapidly emerging for its potential to overcome such issues. Studies have showcased the ability of nanomedicines to bypass drug efflux pumps, counteract immune suppression, serve as radioenhancers, correct metabolic disturbances and elicit numerous other effects that collectively alleviate various mechanisms of tumour resistance.

DR5-targeted, chemotherapeutic drug-loaded nanoparticles induce apoptosis and tumor regression in pancreatic cancer in vivo models.

Pancreatic cancer is usually advanced and drug resistant at diagnosis. A potential therapeutic approach outlined here uses nanoparticle (NP)-based drug carriers, which have unique properties that enhance intra-tumor drug exposure and reduce systemic toxicity of encapsulated drugs. Here we report that patients whose pancreatic cancers express elevated levels of Death Receptor 5 (DR5) and its downstream regulators/effectors FLIP, Caspase-8, and FADD had particularly poor prognoses.

Repurposing of Cetuximab in antibody-directed chemotherapy-loaded nanoparticles in EGFR therapy-resistant pancreatic tumours.

The anti-Epidermal Growth Factor Receptor (EGFR) antibody Cetuximab (CTX) has demonstrated limited anti-cancer efficacy in cells overexpressing EGFR due to activating mutations in RAS in solid tumours, such as pancreatic cancer. The utilisation of antibodies as targeting components of antibody-drug conjugates, such as trastuzumab emtansine (Kadcyla), demonstrates that antibodies may be repurposed to direct therapeutic agents to antibody-resistant cancers. Here we investigated the use of CTX as a targeting agent for camptothecin (CPT)-loaded polymeric nanoparticles (NPs) directed against KRAS mutant CTX-resistant cancer cells.

Development of an advanced nanoformulation for the intracellular delivery of a caspase-3 selective activity-based probe.

The ability to label active caspase-3 represents a useful pharmacodynamic strategy to determine the efficacy of anti-tumour drugs. Activity-based probes (ABPs) provide a method for the labelling of activated caspases and the recent development of hybrid combinatorial substrate libraries (HyCoSuL) has allowed for the generation of highly selective ABPs to discriminately label these proteases. Here using this approach, a novel caspase-3 selective ABP (CS1) has been developed and validated in apoptotic cells to selectively bind caspase-3 over the closely related caspase-7.

Antibody conjugated nanoparticles as a novel form of antibody drug conjugate chemotherapy.

Antibody conjugated nanoparticles (ACNPs) represent a novel strategy for the development of therapies exploiting antibodies to augment the delivery of chemotherapy payloads. Following in the footsteps of the success of antibody drug conjugates (ADCs), ACNPs are only now reaching clinical evaluation. In this review we discuss the success of ADCs and explore the opportunities ACNPs offer, such as broad chemotherapy payload selection, high drug to antibody ratios and the ability to finely tailor drug release in comparison to ADCs.