Nanopharmaceuticals: A focus on their clinical translatability.

Nanoscale materials have contributed changing the way biomedical researchers address the biological and therapeutic limitations of conventional drugs and diagnostic agents. Thanks to a plethora of different materials and synthetic routes, particulate carriers can be designed to modify the half-life of compounds, alter their biodistribution and control the drug release profile, eventually providing an overall clinical benefit to patients. While around 50 nanoformulations (excluding biologics) are already on the market, several challenges still withhold them from unlocking their full translational potential. This review discusses the advantages and current hurdles in the use of nanopharmaceuticals, and describes the most important nanotechnological approaches which have been investigated so far. A focus is given on the record of clinical success and failures and current clinical trends. In an effort to identify opportunities and problems associated with each specific nanosystem, this manuscript underlines the need of a more product-oriented research, that can foster the progress of nanomedicines to the clinic.

Dual delivery of nucleic acids and PEGylated-bisphosphonates via calcium phosphate nanoparticles.

Despite many years of research and a few success stories with gene therapeutics, efficient and safe DNA delivery remains a major bottleneck for the clinical translation of gene-based therapies. Gene transfection with calcium phosphate (CaP) nanoparticles brings the advantages of low toxicity, high DNA entrapment efficiency and good endosomal escape properties. The macroscale aggregation of CaP nanoparticles can be easily prevented through surface coating with bisphosphonate conjugates. Bisphosphonates, such as alendronate, recently showed promising anticancer effects. However, their poor cellular permeability and preferential bone accumulation hamper their full application in chemotherapy. Here, we investigated the dual delivery of plasmid DNA and alendronate using CaP nanoparticles, with the goal to facilitate cellular internalization of both compounds and potentially achieve a combined pharmacological effect on the same or different cell lines. A pH-sensitive poly(ethylene glycol)-alendronate conjugate was synthetized and used to formulate stable plasmid DNA-loaded CaP nanoparticles. These particles displayed good transfection efficiency in cancer cells and a strong cytotoxic effect on macrophages. The in vivo transfection efficiency, however, remained low, calling for an improvement of the system, possibly with respect to the extent of particle uptake and their physical stability.

Poly(ethylene glycol)-alendronate coated nanoparticles for magnetic resonance imaging of lymph nodes.

Nanoparticulate systems can passively target regional lymphatic vessels and lymph nodes (LNs) after interstitial administration. Highly sensitive non-invasive imaging techniques, such as magnetic resonance imaging (MRI), can take advantage from particles' lymphotropic properties to provide a reliable tool to monitor lymphatic function and LN morphology with high spatial resolution. In this work, we developed and characterised a bioerodible nanosystem with MRI contrast properties, based on poly(ethylene glycol)-alendronate stabilised gadolinium calcium phosphate nanoparticles (NPs). After foot paw injection in mice, the particles exhibited a distinct pattern of gradual uptake into the local lymphatics and a localised deposition in the popliteal LN. Less variability in the onset of the signal, intensity and localisation was observed compared to the commercially available tracer gadobutrol, suggesting that these NPs could be useful to monitor physiological and dysfunctional lymphatic conditions. Moreover, dissolution of the particles indicated that they would be rapidly cleared from the body after imaging. Nevertheless, our findings call for an improvement of the system that includes reduction of gadolinium leakage from the NPs, and decrease in size of the latter to increase their selective uptake by the LN.