Mechanism of erosion of nanostructured porous silicon drug carriers in neoplastic tissues

Nanostructured porous ​silicon (PSi) is emerging as a promising platform for drug delivery owing to its biocompatibility, degradability and high surface area available for drug loading. The ability to control PSi structure, size and porosity enables programming its in vivo retention, providing tight control over embedded drug release kinetics. In this work, the relationship between the in vitro and in vivo degradation of PSi under (pre)clinically relevant conditions, using breast cancer mouse model, is defined. We show that PSi undergoes enhanced degradation in diseased environment compared with healthy state, owing to the upregulation of reactive oxygen species (ROS) in the tumour vicinity that oxidize the silicon scaffold and catalyse its degradation. We further show that PSi degradation in vitro and in vivo correlates in healthy and diseased states when ROS-free or ROS-containing media are used, respectively. Our work demonstrates that understanding the governing mechanisms associated with specific tissue microenvironment permits predictive material performance.Russell Berrie Nanotechnology InstituteLokey Center for Life Science and Engineerin

Mechanism of erosion of nanostructured porous silicon drug carriers in neoplastic tissues

Nanostructured porous silicon (PSi) is emerging as a promising platform for drug delivery owing to its biocompatibility, degradability and high surface area available for drug loading. The ability to control PSi structure, size and porosity enables programming its in vivo retention, providing tight control over embedded drug release kinetics. In this work, the relationship between the in vitro and in vivo degradation of PSi under (pre)clinically relevant conditions, using breast cancer mouse model, is defined. We show that PSi undergoes enhanced degradation in diseased environment compared with healthy state, owing to the upregulation of reactive oxygen species (ROS) in the tumour vicinity that oxidize the silicon scaffold and catalyse its degradation. We further show that PSi degradation in vitro and in vivo correlates in healthy and diseased states when ROS-free or ROS-containing media are used, respectively. Our work demonstrates that understanding the governing mechanisms associated with specific tissue microenvironment permits predictive material performance

Intracellular responsive dual delivery by endosomolytic polyplexes carrying DNA anchored porous silicon nanoparticles

Bioresponsive cytosolic nanobased multidelivery has been emerging as an enormously challenging novel concept due to the intrinsic protective barriers of the cells and hardly controllable performances of nanomaterials. Here, we present a new paradigm to advance nano-in-nano integration technology amenable to create multifunctional nanovehicles showing considerable promise to overcome restrictions of intracellular delivery, solve impediments of endosomal localization and aid effectual tracking of nanoparticles. A redox responsive intercalator chemistry comprised of cystine and 9-aminoacridine is designed as a cross-linker to cap carboxylated porous silicon nanoparticles with DNA. These intelligent nanocarriers are then encapsulated within novel one-pot electrostatically complexed nano-networks made of a zwitterionic amino acid (cysteine), an anionic bioadhesive polymer (poly(methyl vinyl ether-alt-maleic acid)) and a cationic endosomolytic polymer (polyethyleneimine). This combined nanocomposite is successfully tested for the co-delivery of hydrophobic (sorafenib) or hydrophilic (calcein) molecules loaded within the porous core, and an imaging agent covalently integrated into the polyplex shell by click chemistry. High loading capacity, low cyto- and hemo-toxicity, glutathione responsive on-command drug release, and superior cytosolic delivery are shown as achievable key features of the proposed formulation. Overall, formulating drug molecules, DNA and imaging agents, without any interference, in a physicochemically optimized carrier may open a path towards broad applicability of these cost-effective multivalent nanocomposites for treating different diseases. (C) 2017 Elsevier B.V. All rights reserved

Tailoring drug and gene codelivery nanosystems for glioblastoma treatment

Glioblastoma is the most common primary and aggressive brain tumour, with an increasing incidence worldwide. The prognosis of this disease is still poor, with a median survival time not exceeding two years. Standard-of-care therapy includes surgical resection, radio- and chemotherapy, but nearly all patients experience progression of the disease. This may be ascribed to the heterogeneity, invasiveness and resistance of tumour cells, along with the struggle that many chemical drugs present in effectively crossing the dual blood brain-blood brain tumour barrier. Considering the hurdles associated to traditional therapeutic approaches, there is a pressing need to improve patient care, as treatments currently available have little effect on the overall survival. Therefore, the use of adjuvant chemotherapeutics in combination with temozolomide, a first-line drug, and novel molecularly-targeted approaches against both tumor and stem cells and respective microenvironment are under investigation. This chapter addresses the development of innovative multi-target nanomedicines, comprising complementary chemo- (e.g. temozolomide) and gene therapeutic (antimiR and miRNA mimic) agents, combined with targeting ligands within a single nanostructure directed at the treatment of glioblastoma multiforme. The approach aims at providing significantly improved therapeutics, as treatments currently available have little effect on overall survival