Engineering mesoporous silica nanoparticles for drug delivery: where are we after two decades?

The present review details a chronological description of the events that took place during the development of mesoporous materials, their different synthetic routes and their use as drug delivery systems. The outstanding textural properties of these materials quickly inspired their translation to the nanoscale dimension leading to mesoporous silica nanoparticles (MSNs). The different aspects of introducing pharmaceutical agents into the pores of these nanocarriers, together with their possible biodistribution and clearance routes, would be described here. The development of smart nanocarriers that are able to release a high local concentration of the therapeutic cargo on-demand after the application of certain stimuli would be reviewed here, together with their ability to deliver the therapeutic cargo to precise locations in the body. The huge progress in the design and development of MSNs for biomedical applications, including the potential treatment of different diseases, during the last 20 years will be collated here, together with the required work that still needs to be done to achieve the clinical translation of these materials. This review was conceived to stand out from past reports since it aims to tell the story of the development of mesoporous materials and their use as drug delivery systems by some of the story makers, who could be considered to be among the pioneers in this area.

Interaction of Squid (Dosidicus giga) Mantle Protein with a Mixtures of Potato and Corn Starch in an Extruded Snack, as Characterized by FTIR and DSC.

The majority of snacks expanded by extrusion (SEE) are made with vegetable sources, to improve their nutritional content; it has been proposed to incorporate squid (Dosidicus gigas), due to its high protein content, low price and high availability. However, the interaction of proteins of animal origin with starch during extrusion causes negative effects on the sensory properties of SEE, so it is necessary to know the type of protein-carbohydrate interactions and their effect on these properties. The objective of this research was to study the interaction of proteins and carbohydrates of SEE elaborated with squid mantle, potato and corn. The nutritional composition and protein digestibility were evaluated, Fourier transform infrared (FTIR) and Differential Scanning Calorimetry (DSC) were used to study the formation of protein-starch complexes and the possible regions responsible for their interactions. The SEE had a high protein content (40-85%) and biological value (>93%). The melting temperature (Tm) was found between 145 and 225 °C; the Tm values in extruded samples are directly proportional to the squid content. The extrusion process reduced the amine groups I and II responsible for the protein-protein interaction and increased the O-glucosidic bonds, so these bonds could be responsible for the protein-carbohydrate interactions.

Volatile and sensory evaluation of Mexican Fresco cheese as affected by specific wild Lactococcus lactis strains.

Lactococcus lactis is the lactic acid bacteria most frequently used for the production of cheese starter cultures, mainly because of their efficient production of aroma compounds. However, commercial cultures do not always produce the typical aroma notes of artisanal raw-milk cheeses. Thus, the objective of this study was to characterize the volatile compounds generated by wild L. lactis strains in Mexican Fresco cheese made with pasteurized milk. Four strains of wild L. lactis were evaluated for their aroma production in Mexican Fresco cheese using sensory and instrumental analysis. The aroma profiles were evaluated by descriptive sensory analysis. Volatiles were determined by solid-phase microextraction and gas chromatography-mass spectrometry. Principal component analysis was applied to interpret analytical and sensory data. Mexican Fresco cheese aroma was described as milkfat, yogurt, yeasty, barny, dirty socks, and Fresco cheese. Cheese with L. lactis strains R7 or B7 were most similar to commercial raw milk Fresco cheese in all aroma descriptors. Volatiles identified in all cheeses were esters, acids, alcohols, ketones, and aldehydes, but the main differences were found for total volatile relative abundance. Also, volatile concentrations (µg/g) in commercial raw milk Fresco cheese and cheeses made with L. lactis R7 or B7 were 4 methyl esters [C4 (4.15 vs. 5.47-13.74), C6 (0.12 vs. 1.53-15.34), C8 (1.06 vs. 0.32-6.65), and C10 (0.62 vs. 0.41-3.74)], 7 acids [C4 (1.92 vs. 0.30-9.29), C6-C10 (0.05-4.48 vs. 0.11-30.45), and C12 (0.13 vs. 0.28-0.30)], 2 alcohols [(3-methyl-1-butanol (3.48 vs. 3.4-13.13) and phenylethyl alcohol (0.10 vs. 0.63-2.04)], and 1 ketone (acetoin; 1.22 vs. 0.28-0.99). The first 3 principal components explained 78.2% of the total variation and clearly distinguished 3 main groups. Cheese made with L. lactis R7 was classified in the same group as key compounds associated with Fresco cheese aroma and show potential as a starter in Mexican Fresco cheese manufacture.

Mesoporous silica nanoparticles in nanomedicine applications.

In the last few years mesoporous silica nanoparticles (MSNs) have gained the attention of the nanomedicine research community, especially for the potential treatment of cancer. Although this topic has been reviewed before, periodic updates on such a hot topic are necessary due to the dynamic character of this field. The reasons that make MSNs so attractive for designing controlled drug delivery systems lie beneath their physico-chemical stability, easy functionalisation, low toxicity and their great loading capacity of many different types of therapeutic agents. The present brief overview tries to cover some of the recent findings on stimuli-responsive mesoporous silica nanocarriers together with the efforts to design targeted nanosystems using that platform. The versatility of those smart nanocarriers has promoted them as very promising candidates to be used in the clinic in the near future to overcome some of the pitfalls of conventional medicine.

Management of Cancer in the Older Age Person: An Approach to Complex Medical Decisions.

The management of cancer in older aged people is becoming a common problem due to the aging of the population. There are many variables determining the complex situation that are interconnected. Some of them can be assessed, such as risk of mortality and risk of treatment complications, but many others are still unknown, such as the course of disease, the host-related factors that influence cancer aggressiveness, and the phenotype heralding risk of permanent treatment-related damage.This article presents a dynamic and personalized approach to older people with cancer based on our experience on aging, cancer, and their biological interactions. Also, novel treatments and management approaches to older individuals, based on their functional age and their social and emotional needs, are thoughtfully explored here. The Oncologist 2017;22:335-342 IMPLICATIONS FOR PRACTICE: The goal of this article is to suggest a practical approach to complexity, a clinical situation becoming increasingly common with the aging of the population. Beginning with the analysis of two clinical cases, the authors offer an algorithm for approaching cancer in the older person that involves the assessment of life expectancy without cancer, the risk that cancer might compromise a patient's survival, function, or quality of life, and the potential benefits and risks of the treatments based on a clinical evaluation. The authors then review possible laboratory assessment of functional age and the importance of rapid-learning databases in the study of cancer and age.

Mesoporous Silica Nanoparticles for Drug Delivery: Current Insights.

This manuscript reviews the recent progress on mesoporous silica nanoparticles as drug delivery systems. Their intrinsic structural, textural and chemical features permit to design versatile multifunctional nanosystems with the capability to target the diseased tissue and release the cargo on demand upon exposition to internal or external stimuli. The degradation rate of these nanocarriers in diverse physiological fluids is overviewed obeying their significance for their potential translation towards clinical applications. To conclude, the balance between the benefits and downsides of this revolutionary nanotechnological tool is also discussed.

Effect of Amidated Low-Methoxyl Pectin on Physicochemical Characteristics of Jumbo Squid (Dosidicus gigas) Mantle Muscle Gels.

Jumbo squid (Dosidicus gigas) muscle proteins show low functionality with limited use in gel products. This work aims to assess the influence of adding the natural and commercially available fibre, amidated low-methoxyl pectin (at 0.5, 1.0, 1.5, 2.0 and 3.0%), on the physicochemical and functional characteristics of jumbo squid (Dosidicus gigas) mantle muscle gels. The addition of 0.5% fibre showed an immediate effect on the gel texture profile analysis, improving hardness (p<0.05) from (3.4±0.7) N of the control (no added fibre) to (5.2±0.9) N, and increasing elasticity (p≥0.05). Shear force was significant only at 3.0% fibre addition. Water holding capacity also improved (p<0.05) with fibre addition (from 75% in the control to 90-95% after the treatments). Whiteness was affected (p<0.05) when 3.0% fibre was added. Differential scanning calorimetry showed two endothermic transition peaks in the gels. The second peak (actin) increased (p<0.05) by 1-2 °C with fibre addition. Therefore, the present study demonstrates that amidated low-methoxyl pectin (0.5-3.0%) is an excellent ingredient to improve jumbo squid mantle muscle protein functionality, increasing the gel texture and water retention characteristics.

An Overview of the Use of Nanoparticles in Vaccine Development.

Vaccines represent one of the most significant advancements in public health since they prevented morbidity and mortality in millions of people every year. Conventionally, vaccine technology focused on either live attenuated or inactivated vaccines. However, the application of nanotechnology to vaccine development revolutionized the field. Nanoparticles emerged in both academia and the pharmaceutical industry as promising vectors to develop future vaccines. Regardless of the striking development of nanoparticles vaccines research and the variety of conceptually and structurally different formulations proposed, only a few of them advanced to clinical investigation and usage in the clinic so far. This review covered some of the most important developments of nanotechnology applied to vaccine technologies in the last few years, focusing on the successful race for the preparation of lipid nanoparticles employed in the successful anti-SARS-CoV-2 vaccines.

Natural Biopolymers as Smart Coating Materials of Mesoporous Silica Nanoparticles for Drug Delivery.

In recent years, the functionalization of mesoporous silica nanoparticles (MSNs) with different types of responsive pore gatekeepers have shown great potential for the formulation of drug delivery systems (DDS) with minimal premature leakage and site-specific controlled release. New nanotechnological approaches have been developed with the objective of utilizing natural biopolymers as smart materials in drug delivery applications. Natural biopolymers are sensitive to various physicochemical and biological stimuli and are endowed with intrinsic biodegradability, biocompatibility, and low immunogenicity. Their use as biocompatible smart coatings has extensively been investigated in the last few years. This review summarizes the MSNs coating procedures with natural polysaccharides and protein-based biopolymers, focusing on their application as responsive materials to endogenous stimuli. Biopolymer-coated MSNs, which conjugate the nanocarrier features of mesoporous silica with the biocompatibility and controlled delivery provided by natural coatings, have shown promising therapeutic outcomes and the potential to emerge as valuable candidates for the selective treatment of various diseases.

Bioinspired extracellular vesicle-coated silica nanoparticles as selective delivery systems.

In recent years, there has been a breakthrough in the integration of artificial nanoplatforms with natural biomaterials for the development of more efficient drug delivery systems. The formulation of bioinspired nanosystems, combining the benefits of synthetic nanoparticles with the natural features of biological materials, provides an efficient strategy to improve nanoparticle circulation time, biocompatibility and specificity toward targeted tissues. Among others biological materials, extracellular vesicles (EVs), membranous structures secreted by many types of cells composed by a protein rich lipid bilayer, have shown a great potential as drug delivery systems themselves and in combination with artificial nanoparticles. The reason for such interest relays on their natural properties, such as overcoming several biological barriers or migration towards specific tissues. Here, we propose the use of mesoporous silica nanoparticles (MSNs) as efficient and versatile nanocarriers in combination with tumor derived extracellular vesicles (EVs) for the development of selective drug delivery systems. The hybrid nanosystems demonstrated selective cellular internalization in parent cells, indicating that the EV targeting capabilities were efficiently transferred to MSNs by the developed coating strategy. As a result, EVs-coated MSNs provided an enhanced and selective intracellular accumulation of doxorubicin and a specific cytotoxic activity against targeted cancer cells, revealing these hybrid nanosystems as promising candidates for the development of targeted treatments.

Biomimetic camouflaged nanoparticles with selective cellular internalization and migration competences.

In the last few years, nanotechnology has revolutionized the potential treatment of different diseases. However, the use of nanoparticles for drug delivery might be limited by their immune clearance, poor biocompatibility and systemic immunotoxicity. Hypotheses for overcoming rejection from the body and increasing their biocompatibility include coating nanoparticles with cell membranes. Additionally, source cell-specific targeting has been reported when coating nanoparticles with tumor cells membranes. Here we show that coating mesoporous silica nanoparticles with membranes derived from preosteoblastic cells could be employed to develop potential treatments of certain bone diseases. These nanoparticles were selected because of their well-established drug delivery features. On the other hand MC3T3-E1 cells were selected because of their systemic migration capabilities towards bone defects. The coating process was here optimized ensuring their drug loading and delivery features. More importantly, our results demonstrated how camouflaged nanocarriers presented cellular selectivity and migration capability towards the preosteoblastic source cells, which might constitute the inspiration for future bone disease treatments. STATEMENT OF SIGNIFICANCE: This work presents a new nanoparticle formulation for drug delivery able to selectively target certain cells. This approach is based on Mesoporous Silica Nanoparticles coated with cell membranes to overcome the potential rejection from the body and increase their biocompatibility prolonging their circulation time. We have employed membranes derived from preosteoblastic cells for the potential treatment of certain bone diseases. Those cells have shown systemic migration capabilities towards bone defects. The coating process was optimized and their appropriate drug loading and releasing abilities were confirmed. The important novelty of this work is that the camouflaged nanocarriers presented cellular selectivity and migration capability towards the preosteoblastic source cells, which might constitute the inspiration for future bone disease treatments.

Pleiotrophin-Loaded Mesoporous Silica Nanoparticles as a Possible Treatment for Osteoporosis.

Osteoporosis is the most common type of bone disease. Conventional treatments are based on the use of antiresorptive drugs and/or anabolic agents. However, these treatments have certain limitations, such as a lack of bioavailability or toxicity in non-specific tissues. In this regard, pleiotrophin (PTN) is a protein with potent mitogenic, angiogenic, and chemotactic activity, with implications in tissue repair. On the other hand, mesoporous silica nanoparticles (MSNs) have proven to be an effective inorganic drug-delivery system for biomedical applications. In addition, the surface anchoring of cationic polymers, such as polyethylenimine (PEI), allows for greater cell internalization, increasing treatment efficacy. In order to load and release the PTN to improve its effectiveness, MSNs were successfully internalized in MC3T3-E1 mouse pre-osteoblastic cells and human mesenchymal stem cells. PTN-loaded MSNs significantly increased the viability, mineralization, and gene expression of alkaline phosphatase and Runx2 in comparison with the PTN alone in both cell lines, evidencing its positive effect on osteogenesis and osteoblast differentiation. This proof of concept demonstrates that MSN can take up and release PTN, developing a potent osteogenic and differentiating action in vitro in the absence of an osteogenic differentiation-promoting medium, presenting itself as a possible treatment to improve bone-regeneration and osteoporosis scenarios.

Characterization of a Mesoporous Silica Nanoparticle Formulation Loaded with Mitomycin C Lipidic Prodrug (MLP) and In Vitro Comparison with a Clinical-Stage Liposomal Formulation of MLP.

Nanomedicines have revolutionized the treatment of certain types of cancer, as is the case of doxil, liposomal formulation with doxorubicin encapsulated, in the treatment of certain types of ovarian cancer, AIDS-related Kaposi sarcoma, and multiple myeloma. These nanomedicines can improve the performance of conventional chemotherapeutic treatments, with fewer side effects and better efficiency against cancer. Although liposomes have been used in some formulations, different nanocarriers with better features in terms of stability and adsorption capabilities are being explored. Among the available nanoparticles in the field, mesoporous silica nanoparticles (MSNP) have attracted great attention as drug delivery platforms for the treatment of different diseases. Here, a novel formulation based on MSNP loaded with a potent antitumor prodrug that works in vitro as well as in a clinically evaluated liposomal formulation has been developed. This novel formulation shows excellent prodrug encapsulation efficiency and effective release of the anticancer drug only under certain stimuli typical of tumor environments. This behavior is of capital importance for translating this nanocarrier to the clinic in the near future.

Hydrolysates and peptide fractions from pork and chicken skin collagen as pancreatic lipase inhibitors.

The objective of this work was to obtain hydrolysates and peptide fractions from pork (PSC) and chicken (CSC) skin collagen extracts and to evaluate their ability as pancreatic lipase inhibitors. Collagen extracts were hydrolyzed with collagenase or a protease from Bacillus licheniformis (MPRO NX®) at 6, 12, and 24 h. After 24 h incubation, the highest degree of hydrolysis of PSC (p < 0.05) was obtained with collagenase (72.58%), while in CSC was obtained with MPRO NX® (64.45%). Hydrolysates obtained at 24 h had the highest inhibitory activity of lipase (p < 0.05). CSC/collagenase hydrolysates (10 mg/mL) presented the highest inhibitory activity (75.53%) (p < 0.05). Ultrafiltrated fractions >5 kDa from CSC/collagenase and PSC/MPRO NX® hydrolysates were the most bioactive fractions (IC50: 4.33 mg/mL). The highest were obtained by CSC peptides (IC50s: 6.30 and 6.08 mg/mL). These results may be considered as a novel approach to use collagen hydrolysates, or their peptide fractions, as promising natural inhibitors of pancreatic lipase.

Non-replicative antibiotic resistance-free DNA vaccine encoding S and N proteins induces full protection in mice against SARS-CoV-2.

SARS-CoV-2 vaccines currently in use have contributed to controlling the COVID-19 pandemic. Notwithstanding, the high mutation rate, fundamentally in the spike glycoprotein (S), is causing the emergence of new variants. Solely utilizing this antigen is a drawback that may reduce the efficacy of these vaccines. Herein we present a DNA vaccine candidate that contains the genes encoding the S and the nucleocapsid (N) proteins implemented into the non-replicative mammalian expression plasmid vector, pPAL. This plasmid lacks antibiotic resistance genes and contains an alternative selectable marker for production. The S gene sequence was modified to avoid furin cleavage (Sfs). Potent humoral and cellular immune responses were observed in C57BL/6J mice vaccinated with pPAL-Sfs + pPAL-N following a prime/boost regimen by the intramuscular route applying in vivo electroporation. The immunogen fully protected K18-hACE2 mice against a lethal dose (105 PFU) of SARS-CoV-2. Viral replication was completely controlled in the lungs, brain, and heart of vaccinated mice. Therefore, pPAL-Sfs + pPAL-N is a promising DNA vaccine candidate for protection from COVID-19.

Anti-osteoporotic drug release from ordered mesoporous bioceramics: experiments and modeling.

The release of a potent bone-resorption inhibitor such as zoledronate from a versatile drug delivery system such as SBA 15 has been modeled. The initial and boundary conditions have been defined, together with the system parameters, including the determination of equilibrium and transport parameters. Additionally, the experimental model of the same system has been observed to validate the prediction here developed. This approach represents a powerful tool for the designing of mesoporous implantable drug delivery systems because their release kinetics can be predicted in advance, and this leads to a considerable time and resources saving.

Chronology of Global Success: 20 Years of Prof Vallet-Regí Solving Questions.

Twenty years ago, a group of bold scientists led by Prof Vallet-Regí suggested for the first time the use of mesoporous materials as potential drug delivery systems. Without knowing it; these pioneers unleashed the beast of creativity around the world because that original idea has been the inspiration of hundreds of scientific groups for the design of many versatile delivery systems based on mesoporous materials. Because the dream is not the destination, it is the journey, the present review aims to summarise the chain of events that catapulted a small and young research team from the grassroots of academia to the elite of the Biomedical Engineering field.

Osteoporosis Remission and New Bone Formation with Mesoporous Silica Nanoparticles.

Nanotechnology changed the concept of treatment for a variety of diseases, producing a huge impact regarding drug and gene delivery. Among the different targeted diseases, osteoporosis has devastating clinical and economic consequences. Since current osteoporosis treatments present several side effects, new treatment approaches are needed. Recently, the application of small interfering RNA (siRNA) has become a promising alternative. Wnt/ß-catenin signaling pathway controls bone development and formation. This pathway is negatively regulated by sclerostin, which knock-down through siRNA application would potentially promote bone formation. However, the major bottleneck for siRNA-based treatments is the necessity of a delivery vector, bringing nanotechnology as a potential solution. Among the available nanocarriers, mesoporous silica nanoparticles (MSNs) have attracted great attention for intracellular delivery of siRNAs. The mesoporous structure of MSNs permits the delivery of siRNAs together with another biomolecule, achieving a combination therapy. Here, the effectiveness of a new potential osteoporosis treatment based on MSNs is evaluated. The proposed system is effective in delivering SOST siRNA and osteostatin through systemic injection to bone tissue. The nanoparticle administration produced an increase expression of osteogenic related genes improving the bone microarchitecture. The treated osteoporotic mice recovered values of a healthy situation approaching to osteoporosis remission.

Designing Mesoporous Silica Nanoparticles to Overcome Biological Barriers by Incorporating Targeting and Endosomal Escape.

The several biological barriers that nanoparticles might encounter when administered to a patient constitute the major bottleneck of nanoparticle-mediated tumor drug delivery, preventing their successful translation into the clinic and reducing their therapeutic profile. In this work, mesoporous silica nanoparticles have been employed as a platform to engineer a versatile nanomedicine able to address such barriers, achieving (a) excessive premature drug release control, (b) accumulation in tumor tissues, (c) selective internalization in tumoral cells, and (d) endosomal escape. The nanoparticles have been decorated with a self-immolative redox-responsive linker to prevent excessive premature release, to which a versatile and polyvalent peptide that is able to recognize tumoral cells and induce the delivery of the nanoparticles to the cytoplasm via endosomal escape has been grafted. The excellent biological performance of the carrier has been demonstrated using 2D and 3D in vitro cell cultures and a tumor-bearing chicken embryo model, demonstrating in all cases high biocompatibility and cytotoxic effect, efficient endosomal escape and tumor penetration, and accumulation in tumors grown on the chorioallantoic membrane of chicken embryos.

Protective Effect of Lacticaseibacillus casei CRL 431 Postbiotics on Mitochondrial Function and Oxidative Status in Rats with Aflatoxin B1-Induced Oxidative Stress.

Studies have shown that the intracellular content of probiotic (postbiotics) has antioxidant properties, which can improve the antioxidant status in vivo. However, its absorption and mechanisms underlying the protective effects are still unknown. The antioxidant capacity of Lacticaseibacillus casei CRL431 (IC-431) postbiotics was determined after an in vitro simulated digestive process. Permeability of antioxidant constituents of IC-431 was determined by an ex vivo everted duodenum assay. Aflatoxin B1-induced oxidative stress rat models were established and treated with IC-431; biomarkers of hepatic mitochondrial function and H2O2 levels, oxidative stress, and oxidative stress index (OSi) were examined. The antioxidant capacity of IC-431 (477 ± 45.25 µmol Trolox Equivalent/L) was reduced by exposure to the simulated digestive process. No difference (p > 0.05) was found among digested and the permeate fraction of IC-431. A protective effect was observed by significantly lower OSi and higher liver glutathione peroxidase and catalase activities. Lower H2O2 production, a higher degree of mitochondrial uncoupling, and lower mitochondrial respiration coefficient were also observed (p < 0.05). These results suggest that IC-431 antioxidant components permeate intestinal barriers to enter the bloodstream and regulate antioxidant status during AFB1-induced oxidative stress by reducing hepatic mitochondrial dysfunction, thus enhancing antioxidant enzyme response.