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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - VERDI (polyValent mEsopoRous nanosystem for bone DIseases)

Teaser

Summary

Finding simple solutions to complex problems has been a challenge for human kind for decades. VERDI aims at designing a multifunctional nanosystem to heal complex bone diseases: bone infection, bone cancer and osteoporosis. The novelty of this proposal is the design of a nanosystem that may address several diseases using a unique, versatile and scalable strategy. Mesoporous silica nanoparticles (MSNs) are selected as the main component of the nanoplatform because of their biocompatibility, robustness, loading capacity and versatile surface modification. MSNs will be modified by rational selection of building blocks, with targeting and/or therapeutic abilities, to tackle either one or a combination of pathologies. These features will enable us to deliver a library of nanomedicines using a toolbox of building blocks, customizing a specific nanosystem depending on the disease to be treated.
Bone cancer including primary tumors and bone metastases is a major concern, which counts with more than 3.4 million new cases and 1.7 million cancer-related deaths each year in Europe. Moreover, it is present in 70% patients dying of cancer. Bone infection is an inflammatory process caused by an infecting microorganism accompanied by bone destruction. The annual incidence of this disease in Europe has been estimated to be 2/100,000 persons. On the other hand, in a perfect scenario, there should be equilibrium between the rates of bone gain and bone loss. However, disruption of this balance takes place in metabolic bone diseases such as osteoporosis, which is by far the most frequent metabolic disease affecting bone. This pathology is the responsible of more than 9 million fractures annually worldwide. Current treatments for these three diseases are not always effective. We propose tackling both isolated and comorbid bone diseases with a multifunctional platform. This represents a novel approach that has not been done so far: a combined solution for a complex problem.
VERDI represents an approach beyond the state of the art in the field of nanotechnology as, to our knowledge, is the first strategy focused to addressing several diseases with a unique, easy-to combine and scalable strategy, which may be marketed by the end of the project. The rational design and assembly of the building blocks in the proposed nanosystem entails numerous scientific and technical engineering challenges.

Work performed

This brief report is structured in two main sections. The first one is focused on the design of the nanoparticles set for the assembly of the different functional components, which constitutes the pivotal element for the subsequent steps in the design of the custom-made nanosystems (Section A). The second one (Section B) shows the specific design and optimization of the nanosystems to treat each one of the bone pathologies.

Section A
Diverse nanoparticles have been synthesized as components assembly platforms, which exhibit different characteristics. Figure 1 summarizes all nanoparticles sets that have been obtained in the context of VERDI so far.

Section B
1) INFECTION
To overcome the limitations of current infection treatments, different MSN sets have been designed to increase the therapeutic antimicrobial efficacy of the antibiotic loaded decreasing notably the side effects. Different approaches have been tackled which are collected in the different key task of infection. These approaches are mainly focused in achieving: (i) targeted therapy (to bacterial wall and/or biofilm), (ii) combined therapy (antibiotics inside the mesopores and antimicrobial molecules anchored to nanoparticle surfaces), (iii) stimulus-response therapy through light and magnetic external stimulus and (iv) in the design of nanosystems with furtive properties to the immune system and antibacterial activity.
2) CANCER
This includes primary tumors (osteosarcoma, etc.) and bone metastases. The administration route varies according to the cancer etiology. When dealing with bone metastases, the preferred administration route will be systemic, whereas in primary osseous tumors the administration route will be local. In this case, it is worth to highlight that nanoparticles must have the peculiarity that once accumulated in bone (guided by targeting ligands), they can be internalized by the tumor cells. In this scenario, the bonds that maintain targeting units linked to the nanosystem will have to be broken in response to an internal stimulus, which will permit internalization of the nanosystem by tumor cells. As active targeting agents, different ligands such as transferrin, folic acid, whose receptors are over-expressed on the surface of tumor vascular endothelium or the tumor cell membrane, will be used. The therapeutic action area will incorporate combinations of antitumor agents to be released within the tumor cell upon exposure to certain stimuli (pH, redox conditions, etc). In addition, the Janus structure of the nanosystem plays a key role because they are capable of selectively interacting with the tumor cell making use of its double-targeted or two-drug delivery systems using its two hemispheres.
3) OSTEOPOROSIS
Different nanoplatforms have been designed to be used as combined therapy: nanosystems that will sequentially release an anabolic agent (osteostatin) and SiRNA of an osteoporotic gene (SOST). These nanosystems are an alternative to systemic administration of drugs obtaining an optimal therapeutic efficacy to osteoporosis disease. Unfortunately, current treatments for osteoporosis have notable restrictions, including adequacy and long-term safety issues.

Final results

Regarding cancer treatment, there have been reached in vitro tests with promising results; which practically covers all the expected work planned at the beginning of the project. Now our objectives are focused on deepening on such preclinical studies to gather more information on the particularities of nanocarrier-based treatment of cancer in order to achieve a possible translation into clinical studies.
In the case of bone infection, we have developed diverse nanomedicines based on MSNs as nanocarriers of antimicrobial agents with the capability to target biofilm and/or bacteria, namely â€œnanoantibioticsâ€. They constitute promising alternatives to conventional therapies by increasing the antimicrobial efficiency and notably decreasing side effects. The acquired knowledge allows us to go a step forward towards the search of more specific targeting strategies able to distinguish between Gram-/Gram+ bacteria and their corresponding biofilms. Other of the approaches that we are dealing with is the synergistic effect of an applied external stimulus for disrupting the biofilm. In this sense we have started working with alternating magnetic fields and near infrared light to induce hyperthermia and photothermia effect in vitro, respectively.
In the case of osteoporosis, we have been able to develop an in vitro and in vivo model to test the silencing of a gene implicated in osteoporosis (SOST). Therefore, we have design a dual delivery nanosystem that improved the gene expression of osteogenic markers, and effectively knockdown SOST gene, re-establishing the BMD through the combined effect of osteostatin and SOST siRNA in vivo, being a synergy between these two molecules that never has been reported, opening a field on research to study them as a possible combine therapy.