The Theranostic Path to Personalized Nanomedicine

Advances in nanotechnology and chemical engineering have led to the development of many different drug delivery systems. These 1–100(0)-nm-sized carrier materials aim to increase drug concentrations at the pathological site, while avoiding their accumulation in healthy non-target tissues, thereby improving the balance between the efficacy and the toxicity of systemic (chemo-)therapeutic interventions. An important advantage of such nanocarrier materials is the ease of incorporating both diagnostic and therapeutic entities within a single formulation, enabling them to be used for theranostic purposes. We here describe the basic principles of using nanomaterials for targeting therapeutic and diagnostic agents to pathological sites, and we discuss how nanotheranostics and image-guided drug delivery can be used to personalize nanomedicine treatments

Bone resorption and body reorganization during maturation induce maternal transfer of toxic metals in anguillid eels

During their once-in-a-lifetime transoceanic spawning migration, anguillid eels do not feed, instead rely on energy stores to fuel the demands of locomotion and reproduction while they reorganize their bodies by depleting body reserves and building up gonadal tissue. Here we show how the European eel (Anguilla anguilla) breaks down its skeleton to redistribute phosphorus and calcium from hard to soft tissues during its sexual development. Using multiple analytical and imaging techniques, we characterize the spatial and temporal degradation of the skeletal framework from initial to final gonadal maturation and use elemental mass ratios in bone, muscle, liver, and gonadal tissue to determine the fluxes and fates of selected minerals and metals in the eels' bodies. We find that bone loss is more pronounced in females than in males and eventually may reach a point at which the mechanical stability of the skeleton is challenged. P and Ca are released and translocated from skeletal tissues to muscle and gonads, leaving both elements in constant proportion in remaining bone structures. The depletion of internal stores from hard and soft tissues during maturation-induced body reorganization is accompanied by the recirculation, translocation, and maternal transfer of potentially toxic metals from bone and muscle to the ovaries in gravid females, which may have direct deleterious effects on health and hinder the reproductive success of individuals of this critically endangered species

In vivo nanotoxicity testing using the zebrafish embryo assay

Nanoparticles are increasingly used for biomedical purposes. Many different diagnostic and therapeutic applications are envisioned for nanoparticles, but there are often also serious concerns regarding their safety. Given the fact that numerous new nanomaterials are being developed every day, and that not much is known about the long-term toxicological impact of exposure to nanoparticles, there is an urgent need to establish efficient methods for nanotoxicity testing. The zebrafish (Danio rerio) embryo assay has recently emerged as an interesting ‘intermediate’ method for in vivo nanotoxicity screening, enabling (semi-) high-throughput analyses in a system significantly more complex than cultured cells, but at the same time also less ‘invasive’ and less expensive than large-scale biocompatibility studies in mice or rats. The zebrafish embryo assay is relatively well-established in the environmental sciences, but has not yet gained wide notice in the nanomedicine field. Using prototypic polymeric drug carriers, gold-based nanodiagnostics and nanotherapeutics, and iron oxide-based nanodiagnostics, we here show that toxicity testing using zebrafish embryos is easy, efficient and informative, and faithfully reflects, yet significantly extends, cell-based toxicity testing. We therefore expect that the zebrafish embryo assay will become a popular future tool for in vivo nanotoxicity screening

Path integral Monte Carlo studies of the H5 +/D 5 + clusters using ab initio potential surfaces

We report here on classical and path integral Monte Carlo studies for the H5 + cluster and its deuterated counterpart, in order to investigate the floppy nature of its molecular structure due to anharmonic quantum effects. This method relies on the standard harmonic normal mode analysis and has been found to be effective for evaluating thermochemical/ ground-state properties of highly anharmonic systems. A full-dimensional recent analytical CCSD(T) potential surface and a novel realistic density functional theory (DFT) 'on the fly'-based potential scheme were employed. Thermal equilibrium energies for H5 + and D5 + are determined from the path integral Monte Carlo (PIMC) calculations. The H5 + and D5 + probability density distributions are also obtained from both classical Monte Carlo and fully converged PIMC calculations, and they show strong spatial delocalization with highly anharmonic character. It was found that, on average, H5 + and D5 + can be described as a proton shared between the two outer almost freely rotating H2/D2 molecules. The implementation of such a combined PIMC/DFT approach to study nuclear quantum fluctuation on the electronic properties of H5 + is discussed, and its extension to larger protonated hydrogen clusters is also proposed. © 2011 The Royal Swedish Academy of Sciences.Peer Reviewe

Application of polymersomes engineered to target p32 protein for detection of small breast tumors in mice

Triple negative breast cancer (TNBC) is the deadliest form of breast cancer and its successful treatment critically depends on early diagnosis and therapy. The multicompartment protein p32 is overexpressed and present at cell surfaces in a variety of tumors, including TNBC, specifically in the malignant cells and endothelial cells, and in macrophages localized in hypoxic areas of the tumor. Herein we used polyethylene glycol-polycaprolactone polymersomes that were affinity targeted with the p32-binding tumor penetrating peptide LinTT1 (AKRGARSTA) for imaging of TNBC lesions. A tyrosine residue was added to the peptide to allow for 124I labeling and PET imaging. In a TNBC model in mice, systemic LinTT1-targeted polymersomes accumulated in early tumor lesions more than twice as efficiently as untargeted polymersomes with up to 20% ID/ cc at 24 h after administration. The PET-imaging was very sensitive, allowing detection of tumors as small as ~20 mm3. Confocal imaging of tumor tissue sections revealed a high degree of vascular exit and stromal penetration of LinTT1-targeted polymersomes and co-localization with tumor-associated macrophages. Our studies show that systemic LinTT1-targeted polymersomes can be potentially used for precision-guided tumor imaging and treatment of TNBC