Drug Delivery Systems in the Development of Novel Strategies for Glioblastoma Treatment.

Glioblastoma multiforme (GBM) is a grade IV glioma considered the most fatal cancer of the central nervous system (CNS), with less than a 5% survival rate after five years. The tumor heterogeneity, the high infiltrative behavior of its cells, and the blood-brain barrier (BBB) that limits the access of therapeutic drugs to the brain are the main reasons hampering the current standard treatment efficiency. Following the tumor resection, the infiltrative remaining GBM cells, which are resistant to chemotherapy and radiotherapy, can further invade the surrounding brain parenchyma. Consequently, the development of new strategies to treat parenchyma-infiltrating GBM cells, such as vaccines, nanotherapies, and tumor cells traps including drug delivery systems, is required. For example, the chemoattractant CXCL12, by binding to its CXCR4 receptor, activates signaling pathways that play a critical role in tumor progression and invasion, making it an interesting therapeutic target to properly control the direction of GBM cell migration for treatment proposes. Moreover, the interstitial fluid flow (IFF) is also implicated in increasing the GBM cell migration through the activation of the CXCL12-CXCR4 signaling pathway. However, due to its complex and variable nature, the influence of the IFF on the efficiency of drug delivery systems is not well understood yet. Therefore, this review discusses novel drug delivery strategies to overcome the GBM treatment limitations, focusing on chemokines such as CXCL12 as an innovative approach to reverse the migration of infiltrated GBM. Furthermore, recent developments regarding in vitro 3D culture systems aiming to mimic the dynamic peritumoral environment for the optimization of new drug delivery technologies are highlighted.

Erratum: Gascon S.; et al. Characterization and Mathematical Modeling of Alginate/Chitosan-Based Nanoparticles Releasing the Chemokine CXCL12 to Attract Glioblastoma Cells. Pharmaceutics 2020, 12, 356.

The authors wish to make the following correction to this paper [...].

Characterization and Mathematical Modeling of Alginate/Chitosan-Based Nanoparticles Releasing the Chemokine CXCL12 to Attract Glioblastoma Cells.

Chitosan (Chit) currently used to prepare nanoparticles (NPs) for brain application can be complexed with negatively charged polymers such as alginate (Alg) to better entrap positively charged molecules such as CXCL12. A sustained CXCL12 gradient created by a delivery system can be used, as a therapeutic approach, to control the migration of cancerous cells infiltrated in peri-tumoral tissues similar to those of glioblastoma multiforme (GBM). For this purpose, we prepared Alg/Chit NPs entrapping CXCL12 and characterized them. We demonstrated that Alg/Chit NPs, with an average size of ~250 nm, entrapped CXCL12 with ~98% efficiency for initial mass loadings varying from 0.372 to 1.490 µg/mg NPs. The release kinetic profiles of CXCL12 were dependent on the initial mass loading, and the released chemokine from NPs after seven days reached 12.6%, 32.3%, and 59.9% of cumulative release for initial contents of 0.372, 0.744, and 1.490 µg CXCL12/mg NPs, respectively. Mathematical modeling of released kinetics showed a predominant diffusive process with strong interactions between Alg and CXCL12. The CXCL12-NPs were not toxic and did not promote F98 GBM cell proliferation, while the released CXCL12 kept its chemotaxis effect. Thus, we developed an efficient and tunable CXCL12 delivery system as a promising therapeutic strategy that aims to be injected into a hydrogel used to fill the cavity after surgical tumor resection. This system will be used to attract infiltrated GBM cells prior to their elimination by conventional treatment without affecting a large zone of healthy brain tissue.

Characterization of alginate/chitosan-based nanoparticles and mathematical modeling of their SpBMP-9 release inducing neuronal differentiation of human SH-SY5Y cells.

The incidence of brain degenerative disease such as Alzheimer's disease (AD) will increase as the world population is ageing. While current AD treatments have only a transient effect, there are many evidences indicating that some growth factors, such as BMP-9, may be used to treat AD. However, growth factors cannot readily access the brain because of their size and the presence of the blood brain barrier. We have therefore developed a small peptide derived from BMP-9, SpBMP-9, which can promote the differentiation of cholinergic neurons and inactivate GSK3beta, a Tau kinase. Here, we investigated the potential of a nanoparticle-based delivery system of SpBMP-9, made of alginate and chitosan (Alg/Chit NPs), as a new therapeutic strategy against AD. The Alg/Chit NPs size distribution revealed NPs with an average diameter of ∼240nm. The encapsulation efficiency of SpBMP-9 was ∼70% of the initial peptide mass loading. Release kinetics of SpBMP-9 were performed in physiological conditions and modelled with a mechanistic framework that took into account the size distribution of Alg/Chit NPs. The release of SpBMP-9 revealed to be mostly diffusive, but there were interactions between the peptide and the alginate chains. The Alg/Chit NPs could also increase the viability of SH-SY5Y cells in comparison to the control. Finally, the SpBMP-9 released from Alg/Chit NPs promoted the SH-SY5Y differentiation into mature neurons as demonstrated by a higher neurite outgrowth and an increased expression of the neuronal markers NSE and VAchT. In conclusion, the nano-scale SpBMP-9 delivery system made of Alg/Chit may be a promising therapeutic strategy against AD.

Drying of Durum Wheat Pasta and Enriched Pasta: A Review of Modeling Approaches.

Models on drying of durum wheat pasta and enriched pasta were reviewed to identify avenues for improvement according to consumer needs, product formulation and processing conditions. This review first summarized the fundamental phenomena of pasta drying, mass transfer, heat transfer, momentum, chemical changes, shrinkage and crack formation. The basic equations of the current models were then presented, along with methods for the estimation of pasta transport and thermodynamic properties. The experimental validation of these models was also presented and highlighted the need for further model validation for drying at high temperatures (>-100°C) and for more accurate estimation of the pasta diffusion and mass transfer coefficients. This review indicates the need for the development of mechanistic models to improve our understanding of the mass and heat transfer mechanisms involved in pasta drying, and to consider the local changes in pasta transport properties and relaxation time for more accurate description of the moisture transport near glass transition conditions. The ability of current models to describe dried pasta quality according to the consumers expectations or to predict the impact of incorporating ingredients high in nutritional value on the drying of these enriched pasta was also discussed.

A Meta-Analysis of Enriched Pasta: What Are the Effects of Enrichment and Process Specifications on the Quality Attributes of Pasta?

Pasta products enriched with ingredients to improve their nutritional value or functionality have become increasingly popular, and substantial research efforts have been directed towards the development of new enriched pasta products. In this work, a meta-analysis was conducted to quantify the impact of enrichment and process specifications on the quality attributes of pasta. A literature search revealed 66 studies on enriched pasta. Process specifications and quality attributes, namely proximate composition, dough, drying, cooking, and mechanical properties, color, and sensory attributes, were extracted from the studies and compiled in a data set. Analysis of the data set revealed significant differences between pasta enriched with high-fiber ingredients and pasta enriched with pulse flour. High-fiber ingredients generally preserved the quality attributes of pasta more effectively than pulse flour. Comparisons based on the drying temperature showed that high drying temperatures generally improve the cooking properties of enriched pasta. Sensory evaluations indicated that enrichment levels below 10% generally do not affect consumer acceptance, but higher enrichment levels significantly decrease it. Pearson correlation coefficients showed that the gelatinization temperature and Farinograph properties are useful indicators of the mechanical properties and sensory attributes of pasta. The meta-analysis revealed the need to better understand the impact of the processing history of the enrichment ingredient on the quality attributes and the health benefits of enriched pasta.

Nanoparticle-mediated growth factor delivery systems: A new way to treat Alzheimer's disease.

The number of people diagnosed with Alzheimer's disease (AD) is increasing steadily as the world population ages, thus creating a huge socio-economic burden. Current treatments have only transient effects and concentrate on a single aspect of AD. There is much evidence suggesting that growth factors (GFs) have a great therapeutic potential and can play on all AD hallmarks. Because GFs are prone to denaturation and clearance, a delivery system is required to ensure protection and a sustainable delivery. This review provides information about the latest advances in the development of GF delivery systems (GFDS) targeting the brain in terms of in vitro and in vivo effects in the context of AD and discusses new strategies designed to increase the availability and the specificity of GFs to the brain. This paper also discusses, on a mechanistic level, the different delivery hurdles encountered by the carrier or the GF itself from its injection site up to the brain tissue. The major mass transport phenomena influencing the delivery systems targeting the brain are addressed and insights are given about how mechanistic mathematical frameworks can be developed to use and optimize them.

Growth factor treatment to overcome Alzheimer's dysfunctional signaling.

The number of people suffering from Alzheimer's disease (AD) will increase as the world population ages, creating a huge socio-economic burden. The three pathophysiological hallmarks of AD are the cholinergic system dysfunction, the ß-amyloid peptide deposition and the Tau protein hyperphosphorylation. Current treatments have only transient effects and each tends to concentrate on a single pathophysiological aspect of AD. This review first provides an overall view of AD in terms of its pathophysiological symptoms and signaling dysfunction. We then examine the therapeutic potential of growth factors (GFs) by showing how they can overcome the dysfunctional cell signaling that occurs in AD. Finally, we discuss new alternatives to GFs that help overcome the problem of brain uptake, such as small peptides, with evidence from some of our unpublished data on human neuronal cell line.

Identification of a growth factor mimicking the synergistic effect of fetal bovine serum on BMP-9 cell response.

The bone morphogenetic proteins (BMPs) are potent osteogenic molecules that are used for bone repair in delivery systems and in regenerative medicine. We studied the responses of murine MC3T3-E1 preosteoblasts to doses of recombinant human (rh)BMP-9 with and without fetal bovine serum (FBS). rhBMP-2 was used as a control since it is currently approved by the Food and Drug Administration for bone application. We analyzed the major cell signaling pathways and the expression of osteogenic markers. Without FBS, BMP-9 had a similar effect on MC3T3-E1 preosteoblast differentiation in comparison to BMP-2. In contrast, FBS reduced the EC50 of BMP-9 fourfold to sixfold, as determined by osterix gene expression and alkaline phosphatase (ALP) activity, while it had no influence on EC50 of BMP-2. As suggested by MAPK inhibitor assays, FBS could induce an intracellular signaling environment that favors cell response to BMP-9 by inhibiting ERK1/2 activation and increasing p38 phosphorylation. Finally, IGF-2 (100 ng/mL) could mimic the effect of FBS on BMP-9 cell response in terms of MAPK signaling and ALP activity. Thus, the action of BMP-9 on preosteoblast differentiation can be greatly improved by IGF-2. This finding may well be critical for developing optimal growth factor delivery systems and bone tissue engineering strategies.

Effect of initial pBMP-9 loading and collagen concentration on the kinetics of peptide release and a mathematical model of the delivery system.

Type I collagen is one of the most widely used materials for drug delivery in tissue repair. It is the reference carrier for delivering growth factors like bone morphogenetic proteins (BMPs such as BMP-2 and BMP-7) for bone repair. Since BMPs are expensive to produce, we have developed a peptide derived from BMP-9 (pBMP-9) that is 300 times less expensive than the entire protein while still promoting osteogenic differentiation. We have now evaluated the effects of the collagen concentration and the initial pBMP-9 load on peptide release. We then developed a model of pBMP-9 release kinetics by finite differences using a system based on Fick's second law in which the interactions between the peptide and collagen fibers are assumed to follow Langmuir adsorption kinetics. The Langmuir isotherms suggest that the structure of the collagen gel influences the strength of its electrostatic interaction with the peptide, since increasing the collagen concentration decreased the affinity of pBMP-9 for the collagen. The resulting model of the mechanism accurately reflects the experimental data and the parameters estimated indicate that the diffusivities with the different collagen concentrations are similar, whereas the mass transfer coefficient increases with the collagen concentration. The results also indicate that perfect sink conditions cannot be assumed and suggest the presence of an optimal collagen concentration. Finally, we have correlated our conclusions with the differences in collagen fiber organization observed by transmission electron microscopy.

Flaxseed-Enriched Cereal-Based Products: A Review of the Impact of Processing Conditions.

The properties of cereals products, bread, pasta, muffins, cookies, cakes, and bars, enriched with flaxseed, were reviewed to highlight suitable processing conditions for the production of high-quality flaxseed-enriched products with the desired health attributes. The review highlights the contrasting effect of flaxseed enrichment on the mechanical and physical properties of cereal products according to product type, flaxseed enrichment level, and processing history. Flaxseed lipids remain stable for most processing and storage conditions, presumably due to the significant antioxidant properties of lignans, but information is lacking on the impact of home-handling, such as bread toasting, on lipid oxidation. Cereal products enriched with flaxseed generally exhibit similar or improved shelf life compared to equivalent products with no flaxseed enrichment, suggesting that flaxseed may limit starch retrogradation, maintain moisture content, and delay microbial growth. Sensory analysis shows lower organoleptic properties of most cereal products containing flaxseed, but similar consumer acceptance for cereal products without and with flaxseed enrichment up to 15% is reported in the literature. This review indicates the need to better understand the impact of flaxseed enrichment on product microstructure and to conduct an extensive assessment of the health effects of flaxseed-enriched products, since very few studies have focused on the quantification of the bioaccessibility, bioavailability, and activity of flaxseed bioactive compounds for a variety of processing conditions and product formulation.

Bone repair: new developments in growth factor delivery systems and their mathematical modeling.

More and more of our aging populations will suffer from large bone defects in the next few years. But the growth factor (GF) delivery systems (DSs) currently under investigation will help overcome the limitations of the bone grafts presently used. Some GFDSs accredited by the Food and Drug Administration (FDA) are commercially available, but they have mechanical, structural and GF retention weaknesses. New studies focus on polymers and the composition of GFs in order to mimic as closely as possible the physiological environment of healing bone. This review first summarizes the process of endochondral bone healing and the major cytokines involved. We then review the latest GFDSs, with their combinations of organic, inorganic, natural and synthetic biomaterials, the kinetics of GF release and their biological effects. We will explore new research avenues such as the use of peptides derived from bone morphogenetic proteins, including our own results, and the sequential release of bone-inducing GFs. We then review the latest mathematical models of drug delivery systems (DDSs) for several transport phenomena that may be encountered when using GFDS. The final section discusses new improvements for GFDS modeling.