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This study unravels a formulation made of food-based microparticles (MPs) able to control the release of quercetin, a natural anticancer compound, which activity is only limited by its poor aqueous solubility and consequent low bioavailability. To solve this issue, a spray-dried micro delivery system was developed using a bench mini spray dryer B290 Buchi. The resulting MPs were only manufactured with foodderived ingredients such as whey proteins and milk, avoiding the use of any other synthetic material. These microparticles were characterised with a testing campaign encompassing either the physical–chemical characterisation with SEM, DSC and DLS, or the technological and biological features with in vitro, ex vivo and in vivo studies, the latter being characterised by a human colon cancer xenograft model. These studies showed as the quercetin solubility and release rate improved when tested in condition mimicking oral administration, resulting in a general improvement of its bioavailability and the consequent anticancer activity. This study shows as the whey proteins may serves as natural adjuvant able to provide valuable technological features when used to manufactures micro carriers by spray drying.

Halloysite nanotubes (HNTs) represent a versatile core structure for the design of functional nanosystems of biomedical interest. However, the development of selective methodologies for the site-controlled functionalization of the nanotubes at specific sites is not an easy task. This study aims to accomplish a procedure for the site-selective/specific, “pin-point”, functionalization of HNTs with polydopamine (HNTs@PDA). This goal was achieved, at pH 6.5, by exploiting the basicity of ZnO nanoparticles anchored on the HNTs external surface (HNTs@ZnO) to induce a punctual polydopamine polymerization and coating. The morphology and the chemical composition of the nanomaterial was demonstrated by several techniques. Turbidimetric analysis showed that PDA coating affected the aqueous stability of HNTs@PDA compared to both HNTs@ZnO and HNTs. Notably, hyperthermia studies revealed that the nanomaterial induced a local thermic rise, up to 50 °C, under near-infrared (NIR) irradiation. Furthermore, secondary functionalization of HNTs@PDA by selective grafting of biotin onto the PDA coating followed by avidin binding was also accomplished.

A coating technology based on low molecular weight hyaluronic acid (HA) and ferulic acid (FA) was applied to the coating of low generation poly(propylene imine) dendrimers through a biocompatible hexa(ethylene glycol) spacer. The ensuing HA-FA-HEG-PPID dendrimeric materials showed interesting loading capability (between 7.65% and 9.08%) regarding anticancer agent doxorubicin, and their interactions with the drug appeared to hamper the drug release in the physiological environment. Thus, the stable nanostructured loaded delivery systems were able to internalize into cells expressing the HA receptor CD44 and to demonstrate high cytotoxicity comparable to that shown by equivalent amounts of free doxorubicin. Thus, HA-FA-HEG-PPID dendrimeric materials were proposed as biocompatible drug carriers capable of transporting anticancer doxorubicin to tumor cells.

A microfibrous tubular scaffold has been designed and fabricated by electrospinning using poly (1,4-butylene succinate) as biocompatible and biodegradable material. The scaffold morphology was optimized as a small diameter and micro-porous conduit, able to foster cell integration, adhesion, and growth while avoiding cell infiltration through the graft’s wall. Scaffold morphology and mechanical properties were explored and compared to those of native conduits. Scaffolds were then seeded with adult normal human dermal fibroblasts to evaluate cytocompatibility in vitro. Haemolytic effect was evaluated upon incubation with diluted whole blood. The scaffold showed no delamination, and mechanical properties were in the physiological range for tubular conduits: elastic modulus (17.5 ± 1.6 MPa), ultimate tensile stress (3.95 ± 0.17 MPa), strain to failure (57 ± 4.5%) and suture retention force (2.65 ± 0.32 N). The shown degradation profile allows the graft to provide initial mechanical support and functionality while being colonized and then replaced by the host cells. This combination of features might represent a step toward future research on PBS as a biomaterial to produce scaffolds that provide structure and function over time and support host cell remodelling.

Regeneration and recovery of nerve tissues are a great challenge for medicine, and positively affect the quality of life of patients. The development of tissue engineering offers a new approach to the problem with the creation of multifunctional artificial scaffolds that act on various levels in the damaged tissue, providing physical and biochemical support for the growth of nerve cells. In this study, the effects of the use of a tubular scaffold made of polybutylene succinate (PBS), surgically positioned at the level of a sciatic nerve injured in rat, between the proximal stump and the distal one, was investigated. Scaffolds characterization was carried out by scanning electron microscopy and X-ray microcomputed tomography and magnetic resonance imaging, in vivo. The demonstration of the nerve regeneration was based on the evaluation of electroneurography, measuring the weight of gastrocnemius and tibialis anterior muscles, histological examination of regenerated nerves and observing the recovery of the locomotor activity of animals. The PBS tubular scaffold minimized iatrogenic trauma on the nerve, acting as a directional guide for the regenerating fibers by conveying them toward the distal stump. In this context, neurotrophic and neurotropic factors may accumulate and perform their functions, while invasion by macrophages and scar tissue is hampered.

In this work, we introduce the use of 4-dimethylamino-4'-nitrostilbene (DANS) fluorescent dye for applications in the detection and analysis of microplastics, an impendent source of pollution made of synthetic organic polymers with a size varying from less than 5 mm to nanometer scale. The use of this dye revealed itself as a versatile, fast and sensitive tool for readily discriminate microplastics in water environment. The experimental evidences herein presented demonstrate that DANS efficiently absorbs into a variety of polymers constituting microplastics, and its solvatochromic properties lead to a positive shift of the fluorescence emission spectrum according to the polarity of the polymers. Therefore, under UV illumination, microplastics glow a specific emission spectrum from blue to red that allows for a straightforward polymer identification. In addition, we show that DANS staining gives access to different detection and analysis strategies based on fluorescence microscopy, from simple epifluorescence fragments visualization, to confocal microscopy and phasor approach for plastic components quantification.

Ferritin nanoparticles play many important roles in theranostic and bioengineering applications and have been successfully used as nanovectors for the targeted delivery of drugs due to their ability to specifically bind the transferrin receptor (TfR1, or CD71). They can be either genetically or chemically modified for encapsulating therapeutics or probes in their inner cavity. Here, we analyzed a new engineered ferritin nanoparticle, made of the H chain mouse ferritin (HFt) fused with a specific lanthanide binding tag (LBT). The HFt-LBT has one high affinity lanthanide binding site per each of the 24 subunits and a tryptophane residue within the tag that acts as an antenna able to transfer the energy to the lanthanide ions via a LRET process. In this study, among lanthanides, we selected europium for its red emission that allows to reduce overlap with tissue auto-fluorescence. Steady state emission measurements and time-resolved emission spectroscopy have been employed to investigate the interaction between the HFt-LBT and the Eu

The high incidence of cancer recurrences and the frequent occurrence of multidrug resistance often stem from a poorly selective and inefficient antineoplastic therapy, responsible for the onset of undesired side effects as well. A combination of minimal-invasive approaches could thus be a useful strategy to surmount these shortcomings, achieving a safe and solid cancer therapy. Herein, a multi-therapeutic nanotool was designed by merging the photothermal properties of gold nanorods (AuNRs) with the photodynamic activity of the photosensitizer ver-teporfin. AuNRs were coated with the natural materials lipoic acid and gellan gum (AuNRs_LA,GG) and subse-quently loaded with verteporfin (AuNRs_LA,GG/Vert) producing stable colloidal dispersions. AuNRs_LA,GG/Vert were characterized in terms of stability, size and morphology. The hyperthermia exhibited after NIR excitation (810 nm) was also evaluated to highlight the effect on increasing the drug released profile in intra-tumoral mimicking media, as well as cytotoxicity on human colon cancer cell line (HCT116). In vivo studies on HCT116 murine xenograft models were carried out to prove the ability of AuNRs_LA,GG to arrest the tumor growth via NIR laser-triggered hyperthermia. Furthermore, the complete xenograft depletion was demonstrated upon AuNRs_LA,GG/Vert administration by combined photothermal (PTT) and photodynamic (PDT) effects.

HBDI-like chromophores represent a novel set of biomimetic switches mimicking the fluorophore of the green fluorescent protein that are currently studied with the hope to expand the molecular switch/motor toolbox. However, until now members capable of absorbing visible light in their neutral (i. e. non-anionic) form have not been reported. In this contribution we report the preparation of an HBDI-like chromophore based on a 3-phenylbenzofulvene scaffold capable of absorbing blue light and photoisomerizing on the picosecond timescale. More specifically, we show that double-bond photoisomerization occurs in both the E-to-Z and Z-to-E directions and that these can be controlled by irradiating with blue and UV light, respectively. Finally, as a preliminary applicative result, we report the incorporation of the chromophore in an amphiphilic molecule and demonstrate the formation of a visible-light-sensitive nanoaggregated state in water.

Halloysite nanotubes (HNTs) represent a versatile core structure for the design of functional nanosystems of biomedical interest. However, the development of selective methodologies for the site-controlled functionalization of the nanotubes at specific sites is not an easy task. This study aims to accomplish a procedure for the site-selective/specific, ''pin-point", functionalization of HNTs with polydopamine (HNTs@PDA). This goal was achieved, at pH 6.5, by exploiting the basicity of ZnO nanoparticles anchored on the HNTs external surface (HNTs@ZnO) to induce a punctual polydopamine polymerization and coating. The morphology and the chemical composition of the nanomaterial was demonstrated by several techniques. Turbidimetric analysis showed that PDA coating affected the aqueous stability of HNTs@PDA compared to both HNTs@ZnO and HNTs. Notably, hyperthermia studies revealed that the nanomaterial induced a local thermic rise, up to 50 C, under near-infrared (NIR) irradiation.

Streptomyces coelicolor is a model organism for the study of Streptomyces, a genus of Gram-positive bacteria that undergoes a complex life cycle and produces a broad repertoire of bioactive metabolites and extracellular enzymes. This study investigated the production and characterization of membrane vesicles (MVs) in liquid cultures of S. coelicolor M145 from a structural and biochemical point of view; this was achieved by combining microscopic, physical and -omics analyses. Two main populations of MVs, with different sizes and cargos, were isolated and purified. S. coelicolor MV cargo was determined to be complex, containing different kinds of proteins and metabolites. In particular, a total of 166 proteins involved in cell metabolism/differentiation, molecular processing/transport, and stress response were identified in MVs, the latter functional class also being important for bacterial morpho-physiological differentiation. A subset of these proteins was protected from degradation following treatment of MVs with proteinase K, indicating their localization inside the vesicles. Moreover, S. coelicolor MVs contained an array of metabolites, such as antibiotics, vitamins, amino acids, and components of carbon metabolism. In conclusion, this analysis provides detailed information on S. coelicolor MVs under basal conditions and on their corresponding content, which may be useful in the near future to elucidate vesicle biogenesis and functions. IMPORTANCE Streptomycetes are widely distributed in nature and characterized by a complex life cycle that involves morphological differentiation. They are very relevant in industry because they produce about half of all clinically used antibiotics, as well as other important pharmaceutical products of natural origin. Streptomyces coelicolor is a model organism for the study of bacterial differentiation and bioactive molecule production. S. coelicolor produces extracellular vesicles that carry many molecules, such as proteins and metabolites, including antibiotics. The elucidation of S. coelicolor extracellular vesicle cargo will help us to understand different aspects of streptomycete physiology, such as cell communication during differentiation and response to environmental stimuli. Moreover, the capability of these vesicles for carrying different kinds of biomolecules opens up new biotechnological possibilities related to drug delivery. Indeed, decoding the molecular mechanisms involved in cargo selection may lead to the customization of extracellular vesicle content.

As transcorneal drug delivery is still a challenge, the scope of the present study was to prepare useful nanosystems able to enhance transcorneal permeation/penetration of drugs. Moreover, this work aims to evaluate the effectiveness of inulin-based nanosystems in the specific field of ocular drug delivery and the effect of PEG chains to promote mucoadhesion, stability and transcorneal penetration/permeation enhancer effect of self-assembling nanoparticles in vitro (transwell systems and HCE) and ex vivo (Franz cells and bovine cornea). In particular, inulin was chosen as the starting natural polysaccharide polymer to design a novel amphiphilic derivative named INU-EDA-RA-PEG capable of self-assembling to form self-assembling nanoparticles and corticosteroids-loaded self-assembling nanoparticles. As observed, self-assembling nanoparticles show appropriate particle size values, mucoadhesivity and cytocompatibility. Moreover, self-assembling nanoparticles are able to act efficiently as permeation/penetration enhancer. Additionally, the presence of PEG has positive influence. Thus, the developed inulin-based nanosystems represent a promising tool to improve transcorneal delivery of corticosteroids.

Biomaterial-based-scaffolds’ functions are to replace anatomical and functional features loss of an injured tissue. They can replace native tissue after their reabsorption. Material and methods. In our experimental procedures we utilized the PHEA-PLA+PCL scaffold in 2 female pigs to assess its resistance to bile and urine. Results. Both pigs survived to surgical procedures. After a month fibres appeared unchanged in term of form and dimension at electronic microscopy. Cells and ECM factors were founded inside the scaffold in a microscopical evaluation. Conclusion. Planar and tubular scaffolds were colonized by cells and extracellular matrix elements. The study conducted on pig suggested that this type of material can resist to the action of bile and urine. This material could be proposed as a tissue substitute.

Efforts in the field of anticancer therapy are increasingly focusing on the development of localized and selective treatments. Photothermal therapy (PTT) can lead to a spatially confined death of cancer cells, exploiting an increasing in temperature generated after UV-NIR irradiation of peculiar materials. Herein, a new actively targeted gold-based drug delivery system, named PHEA-LA-Fol-AuNRs/Iri, was explored for hyperthermia and chemotherapy colon cancer treatment. Gold nanorods were stabilized using a folate-derivative of α,β-poly(N-2-hydroxyethyl)-D,L-aspartamide (PHEA-LA-PEG-FA) as coating agent and then loaded with the antineoplastic drug irinotecan (Iri). The efficacy of empty and irinotecan-bearing systems was investigated in vitro on human colon cancer (HCT116) cell line, as well as in vivo, employing a xenograft mouse model of colon cancer. After laser treatment, both nanostructures tested induced a considerable deceleration in tumor growth overtime, achieving the total eradication of the cancer when the nanosystems produced were intratumorally administered. Biodistribution data showed that the polymer coated nanorods were able to preferentially accumulate in the tumor site. Considering the excellent stability in aqueous media, the capacity to reach the tumor site and, finally, the in vivo efficacy, PHEA-LA-Fol-AuNRs/Iri might be recommended as an effective tool in the chemotherapy and PTT of colon cancer.

Poly-hydroxy-aspartamide was used as a backbone to synthesize bisphosphonate derivatives thus achieving macromolecular carriers to be potentially used as targeting agents for bone drug delivery. Molecules bearing bisphosphonate groups, such as aminobisphosphonate (ABP) and neridronate (NRD), have been conjugated to polyaspartamide (α,β-poly(N-2-hydroxyethyl)-dl-aspartamide, PHEA), with or without a spacer (succinic acid or 6-aminocaproic acid) thus obtaining PHEA-succinate-ABP and PHEA-caproylcarbamate-ABP and PHEA-ABP and PHEA-NRD, respectively. Bisphosphonate-polymer conjugates were physico-chemically characterized using size exclusion chromatography and 1H-NMR; and their in vitro and ex vivo affinity for bone tissue has been further tested using the hydroxylapatite and rabbit bone binding assays, respectively. In vivo studies were carried out using rats to evaluate the biodistribution features of bisphosphonate-polymer conjugates in comparison with the starting PHEA. In vivo findings evidenced a suitable selectivity of bisphosphonate-polymer conjugates toward the bone tissues also as a function of time.

In order to obtain new advanced functional materials capable of recognizing drug molecules, the polybenzofulvene backbone of molecular brush poly-6-MOEG-9-TM-BF3k has been functionalized with a “synthetic dynamic receptor” composed of two 1-adamantylurea moieties linked together by means of a dipropyleneamino bridge as in Meijer's bis(adamantylurea) pincer (BAUP). This functional material, bearing synthetic receptors potentially capable of recognizing/loading and then delivering drug molecules, was used to prepare colloidal drug delivery systems (by means of soft interaction with BAUP) for delivering the model anti-cancer drug doxorubicin (DOXO). The resulting nanostructured drug delivery systems containing the physically loaded drug were characterized in terms of drug loading and release, dimensions and zeta potential, and in vitro cell activity and uptake on two different cell lines (i.e. the human bronchial epithelial 16HBE and the human colon cancer HCT116). On normal cells, free DOXO was found to be more cytotoxic than DOXO-loaded nanogels at the higher tested concentration and, only on cancer cells, DOXO-loaded nanogels show similar or slightly higher cytotoxicity values than free DOXO, suggesting potential advantages in the treatment of cancer. These results were supported by fluorescence microscopy studies, which suggested that DOXO-loaded nanogels provide an extracellular reservoir of the drug, which is gradually released and internalized within the cells.

Efficient theranostic tools are today more and more frequently represented by the nano-sized systems. In this paper, polymeric micelles were produced and exploited to encapsulate both an antitumor drug (Doxorubicin) and gold core–shell quantum dots nanoparticles (Au-SiO2/QDs). α,β-poly(N-hydroxyethyl)- dl -aspartamide (PHEA) was functionalized with lipoic acid (LA), polyethylenglycol (PEG), and folic acid (FA) pendant moieties to obtain a synthetic derivative (PHEA-LA-PEG-FA) able to self assemble in aqueous medium giving rise to the formation of polymeric micelles exposing on their surface both targeting groups (FA) and hydrophilic chains (PEG). The drug carrying ability of PHEA-LA-PEG-FA micelles was here studied along with the cytotoxity of the obtained nanostructures toward breast cancer cells employing doxorubicin as a model anticancer drug. Finally, the properties of the gold-shell QDs incorporated into the micelles as cells imaging agent and photothermal anticancer treatment tool were explored.

In order to evaluate the potential of a technology platform based on hyaluronan copolymers grafted with propargylated ferulate fluorophores (HA-FA-Pg) in the development of drug delivery systems, the propargyl groups of HA-FA-Pg derivatives were employed with oleic acid (OA) or stearic acid (SA) residues across a biocompatible hexa(ethylene glycol) (HEG) spacer. The designed materials (i.e., HA-FA-HEG-OA or HA-FA-HEG-SA) showed clear-cut aggregation features in an aqueous environment, as confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM), generating nanoaggregate systems. In fact, HA-FA-HEG-OA and HA-FA-HEG-SA derivatives showed the property to create self-assembled cytocompatible nanostructured aggregates in water, thanks to the simultaneous presence of hydrophilic portions in the polymeric backbone, such as hyaluronic acid, and hydrophobic portions in the side chains. Furthermore, the designed materials interact with living cells showing a high degree of cytocompatibility. The potential ability of nanosystems to load pharmacologically active molecules was assessed by the physical entrapment of olanzapine into both polymeric systems. The drug loading evaluation demonstrated that the nanoparticles are able to incorporate a good quantity of olanzapine, as well as improve drug solubility, release profile, and cytocompatibility.

Background There is increasing interest in the development of vessel substitutes, and many studies are currently focusing on the development of biodegradable scaffolds capable of fostering vascular regeneration. We tested a new biocompatible and biodegradable material with mechanical properties similar to those of blood vessels. Methods The material used comprises a mixture of α,β-poly(N-2-hydroxyethyl)- d,l -aspartamide (PHEA) and polylactic acid (PLA), combined with polycaprolactone (PCL) by means of electrospinning technique. Low-molecular-weight heparin was also linked to the copolymer. A tubular PHEA-PLA/PCL sample was used to create an arteriovenous fistula in a pig model with the use of the external iliac vessels. The flow was assessed by means of Doppler ultrasound examination weekly, and 1 month after the implantation we removed the scaffold for histopathologic evaluation. Results The implants showed a perfect leak-proof seal and adequate elastic tension to blood pressure. About ∼3 weeks after the implantation, Doppler examination revealed thrombosis of the graft, so we proceeded to its removal. Histologic examination showed chronic inflammation, with the presence of foreign body cells and marked neovascularization. The material had been largely absorbed, leaving some isolated spot residues. Conclusions The biocompatibility of PHEA-PLA/PCL and its physical properties make it suitable for the replacement of vessels. In the future, the possibility of functionalizing the material with a variety of molecules, to modulate the inflammatory and coagulative responses, will allow obtaining devices suitable for the replacement of native vessels.

Objective: A new tumor targeted polymer-coated gold/graphene hybrid has been developed for achieving simultaneously thermoablation and chemoterapy of folate receptor-positive cancer cells. Methods: The gold/graphene hybrid was prepared by depositing gold nanospheres onto graphene oxide and coating it with an inulin-folate conjugate. Paclitaxel was loaded by sonication. The hybrid was characterized by UV-Vis spectroscopy, DSC analysis and SEM microscopy. The cytotoxicity, thermoablation and anticancer activity were evaluated in vitro on MCF-7 and 16 HBE. Results: In vitro tests showed that the paclitaxel-loaded hybrid improved the effectiveness of the drug especially after photothermal treatments. Conclusion: On the whole, while gold/graphene composite provided an excellent time-dependent photothermal effect, the loading of paclitaxel allowed a suitable chemotherapy, thus killing cancer cells both via a selective laser beam thermoablation and hyperthermia-triggered chemotherapy.

Gold nanorods (AuNRs) can combine therapeutic hyperthermia with diagnostic features, representing a smart choice to address personalized cancer treatments. In this regard, a crucial quest is the selection of the right biocompatible coating agent able to stabilize them in the physiological environment, further endowing the possibility to load bioactive molecules and/or targeting moieties. Therefore, AuNRs optical properties can be successfully merged with advantageous materials features to obtain selective photothermal therapy (PTT) systems. Here, the natural materials lipoic acid (LA) and the polysaccharide gellan gum (GG) were chosen to prepare three types of stabilized gold nanorods, using LA (AuNRs/LA), a layered coating of LA and GG (AuNRs/LA,GG) or a newly synthesized covalent derivative of LA and GG (AuNRs/GG-LA). The samples displayed diverse stability and dispersibility. Hydrodynamic diameters and surface potential analyses confirmed the nanometric size (100&ndash, 200 nm) and showed surface charges ranging from +19.5 to &minus, 25.6 mV. Particular attention was thus paid to analyze the differences between hyperthermia properties exhibited after near-infrared (NIR) laser irradiation. Furthermore, the cytocompatibility and photothermal effect were tested on HCT116 human colon cancer cell line. Collected data have finally allowed selecting AuNRs/LA,GG as the best candidate for possible use in PTT of cancer.

This study was conducted to formulate buccal films consisting of polyvinyl alcohol (PVA) and poly-N-hydroxyethyl-aspartamide (PHEA), to improve the dissolution of the drug through the oral mucosa. Ibuprofen sodium salt was used as a model drug, and the buccal film was expected to enhance its dissolution rate. Two different concentrations of PVA (5% w/v and 7.5% w/v) were used. Solvent casting was used to prepare films, where a solution consisting of drug and polymer was cast and allowed to dry. Attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM) were used to investigate the properties of films. In vitro dissolution studies were also conducted to investigate drug release. SEM studies showed that films containing a higher concentration of PVA had larger particles in microrange. FTIR studies confirmed the presence of the drug in films and indicated that ibuprofen sodium did not react with polymers. DSC studies confirmed the crystalline form of ibuprofen sodium when incorporated within films. In vitro dissolution studies found that the dissolution percentage of ibuprofen sodium alone was increased when incorporated within the film from 59 to 74%. This study led to the development of solid microcrystalline dispersion as a buccal film with a faster dissolution rate than the drug alone overcoming problem of poor solubility.

Despite eye drops generally represent the most convenient, simple and patient-friendly formulations to treat ocular diseases, they suffer from poor retention on the ocular surface and low drug bioavailability leading to the necessity of prolonged and continuous treatment over time. Therefore, ocular insert could represent an innovative way to benefit from ocular topical administration while minimizing all the relevant limitation related to this route of administration. Polymeric non-erodible mucoadhesive ocular inserts should be comfortable and should rapidly adhere on the ocular surface, remain in situ for prolonged period, assure a reproducible and controlled drug release as well as act as transcorneal absorption promoters. In this study, a well-known aliphatic polyester, poly(1,4-butylene succinate) (PBS), was used as starting material to produce hydrophobic microfibrillar scaffolds by means of electrospinning technique. Plasma-assisted chemical surface functionalization of the PBS scaffolds with appropriate biopolymers (inulin, α,β-poly(N-2-hydroxyethyl)-D,L-aspartamide, heparin) was carried out to confer to the final ocular inserts ad hoc properties as wettability, mucoadhesion and cytocompatibility on human corneal epithelial cells, by improving surface hydrophilicity without modifying the bulk properties of the material. The lipophilic drug triamcinolone acetonide was loaded into the obtained ocular insert and release studies were carried out to demonstrate the ability of drug loaded inserts to release the active until 30 days.

The term “multicomponent solid dispersion” is widely used in recent literature to describe solid formulations consisting of a special excipient's mixture and active molecules finely dispersed. However, this term has not yet been defined. In this review, we aimed to improve the definition of multicomponent solid dispersions as a new generation of solid dispersions capable to improve both formulation issues and the therapeutic effect of the final dosage form. As it is well-known the use of solid dispersions to improve drug dissolution rate and solubility, this review describes the field of solid dispersions as well as the formulation strategies available for their production. In particular, the review highlights the use of the spray-drying technique and the benefits provided by this method in the manufacturing of multicomponent solid dispersion.

Chitosan oligosaccharide (C) was functionalized with L-arginine (A) and short hydrocarbon chains (C-8) to design an amphiphilic copolymer, henceforth CAC(8), leading to microparticles (MPs) consisting of an arginine-decorated hydrophilic shell and inner hydrophobic domains allowing the encapsulation of high amount hydrophobic drugs such as sorafenib tosylate (>10% w/w). L-arginine side chains were selected in order to impart the final MPs enhanced transcorneal penetration properties, thus overcoming the typical biological barriers which hamper the absorption of drugs upon topical ocular administration. The mucoadhesive properties and drug release profile of the CAC(8) MPs (CAC(8)-MPs) were studied, showing that CAC(8)-MPs can strongly interact with mucin, and thus gradually release their payload in situ to potentially improve the bioavailability of the drug after topical administration. In vitro transcorneal studies also showed that CAC(8)-MPs are endowed with effective permeation enhancer ability combined with negligible toxicity. (c) 2019 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.

Water-soluble MBHA derivatives were found to self-assemble in a water environment to generate aggregates showing core–shell architectures. The aggregates appeared to be capable of working as nanoreactors performing a multi-functionalization of poly-histidine fragments, which after an initial interaction with the solvated oligo(ethylene glycol) shell reach the reactive core.

Human colon cancer is one of the higher aggressive solid tumors, whose high mortality, much like many other solid tumors, results from metastasis formation. To reduce this high mortality, more effective chemotherapy, allowing a specific tumor accumulation and an efficient early-stage medical imaging as well, are still needed. At this regard, stimuli-responsive nanocarriers for anticancer drug delivery are promising strategy in cancer therapy. For this purpose, a dual targeted redox-responsive drug delivery system, prepared by coating superparamagnetic nanoparticles (SPIONs) with the amphiphilic copolymer INU-LA-PEG-FA and loading doxorubicin (DOXO-SPIONs) was investigated as tool for solid tumor chemotherapy. Folic acid (FA) has been chosen as active targeting agent as its receptor is upregulated in many tumors, including colon cancer. Lipoic acid (LA) has been used to act as the redox-responsive moiety, due to the presence of the -S-S- linkage into its structure, which can undergo intracellular reductive-induced cleavage, and therefore, a modification of stability and release profile of the nanocarrier. Accumulation by magnetic attraction was used as synergistic targeting strategy. Improved anticancer activity was demonstrated in mice by evaluating tumor volume reduction, immunohistochemical analyses and imaging properties using magnetic resonance imaging (MRI).

The extremely complex tumor microenvironment (TME) in humans is the major responsible for the therapeutic failure in cancer nanomedicine. A new concept of disease-driven nanomedicine, henceforth named “Theranomics”, which attempts to target cancer cells and TME on the whole, represents an attractive alternative. Herein, a nanomedicine able to co-deliver doxorubicin and a tumor suppressive proteolytic protein such as collagenase-2 was developed. We successfully obtained superparamagnetic nanogels (SPIONs/Doco@Col) via the intermolecular azide-alkyne Huisgen cycloaddition. We demonstrated that a local ECM degradation and remodeling in solid tumors by means of collagenase-2 could enhance tumor penetration of nanomedicines and the in situ sustained release of the drug payload throughout 3-D tumor spheroids up to the core (parenchyma), thus enabling a synergistic and efficient anticancer effect toward highly invasive breast tumors. We illustrate that SPIONs/Doxo@Col is also capable of reducing the invasivity of cancer cells.

The biopharmaceutical properties of supramolecular vesicular aggregates (SVAs) were characterized with regard to their physicochemical features and compared with cationic liposomes (CLs). Neutral and cationic SVAs were synthesized using two different copolymers of poly(aspartyl hydrazide) by thin-layer evaporation and extrusion techniques. Both copolymers were self-assembled in pre-formulated liposomes and formed neutral and cationic SVAs. Gemcitabine hydrochloride (GEM) was used as an anticancer drug and loaded by a pH gradient remote loading procedure, which significantly increased drug loading inside the SVAs. The resulting average size of the SVAs was 100 nm. The anticancer activity of GEM-loaded neutral and cationic SVAs was tested in human alveolar basal epithelial (A549) and colorectal cancer (CaCo-2) cells. GEM-loaded cationic SVAs increased the anticancer activity in A549 and CaCo-2 cells relative to free drug, neutral SVAs, and CLs. In vivo biodistribution in Wistar rats showed that cationic SVAs accumulate at higher concentrations in lung tissue than neutral SVAs and CLs. Cationic SVAs may therefore serve as an innovative future therapy for pulmonary carcinoma.

Among the relevant properties of graphene derivatives, their ability of acting as an energy-converting device so as to produce heat (i.e., thermoablation and hyperthermia) was more recently taken into account for the treatment of solid tumors. In this pioneering study, for the first time, the in vitro RGO-induced hyperthermia was assessed and combined with the stimuli-sensitive anticancer effect of a biotinylated inulin-doxorubicin conjugate (CJ-PEGBT), hence, getting to a nanosystem endowed with synergic anticancer effects and high specificity. CJ-PEGBT was synthesized by linking pentynoic acid and citraconic acid to inulin. The citraconylamide pendants, used as pH reversible spacer, were exploited to further conjugate doxorubicin, whereas the alkyne moiety was orthogonally functionalized with an azido PEG-biotin derivative by copper(II) catalyzed 1,3-dipolar cycloaddition. DSC measures, AFM, and UV spectrophotometry were employed to systematically investigate adsorption of CJ-PEGBT onto RGO and its physicochemical stability in aqueous media, demonstrating that a stable π-staked nanosystem can be obtained. In vitro tests using cancer breast cells (MCF-7) showed the ability of the RGO/CJ-PEGBT of efficiently killing cancer cells both via a selective laser beam thermoablation and hyperthermia-triggered chemotherapy. If compared with the nonbiotinylated nanosystem, including virgin RGO and the free conjugate, RGO/CJ-PEGBT is endowed with a smart combination of properties which warrant potential as an anticancer nanomedicine.

In order to develop a technology platform based on two natural compounds from biorenewable resources, a short series of hyaluronan (HA) copolymers grafted with propargylated ferulic acid (HA-FA-Pg) were designed and synthesized to show different grafting degree values and their optical properties were characterized in comparison with reference compounds containing the same ferulate fluorophore. Interestingly, these studies revealed that the ferulate fluorophore was quite sensitive to the restriction of intramolecular motion and its introduction into the rigid HA backbone, as in HA-FA-Pg graft copolymers, led to higher photoluminescence quantum yield values than those obtained with the isolated fluorophore. Thus, the propargyl groups of HA-FA-Pg derivatives were exploited in the coupling with oleic acid through a biocompatible nona(ethylene glycol) spacer as an example of the possible applications of this technology platform. The resulting HA-FA-NEG-OA materials showed self-assembling capabilities in aqueous environment. Furthermore, HA-FA-NEG-OA derivatives have been shown to interact with phospholipid bilayers both in liposomes and living cells, retaining their fluorogenic properties and showing a high degree of cytocompatibility and for this reason they were proposed as potential biocompatible self-assembled aggregates forming new materials for biomedical applications.

Folate-targeted gold nanorods (GNRs) are proposed as selective theranostic agents for osteosarcoma treatment. An amphiphilic polysaccharide based graft-copolymer (INU-LA-PEG-FA) and an amino derivative of the α,β-poly(N-2-hydroxyethyl)-d,l-aspartamide functionalized with folic acid (PHEA-EDA-FA), have been synthesized to act as coating agents for GNRs. The obtained polymer-coated GNRs were characterized in terms of size, shape, zeta potential, chemical composition, and aqueous stability. They protected the anticancer drug nutlin-3 and were able to deliver it efficiently in different physiological media. The ability of the proposed systems to selectively kill tumor cells was tested on U2OS cancer cells expressing high levels of FRs and compared with human bronchial epithelial cells (16HBE) and human dermal fibroblasts (HDFa). The property of the nanosystems of efficiently controlling drug release upon NIR laser irradiation and of acting as an excellent hyperthermia agent as well as Two Photon Luminescence imaging contrast agents was demonstrated. The proposed folate-targeted GNRs have also been tested in terms of chemoterapeutic and thermoablation efficacy on tridimensional (3-D) osteosarcoma models.

This paper deal with the synthesis and characterization of PEGylated squalene-grafted-inulin amphiphile capable of self-assembling and self-organizing into nanocarriers once placed in aqueous media. It was exploited as coating agent for obtaining doxorubicin loaded superparamagnetic iron oxide nanoparticles (SPIONs) endowed with stealth like behavior and excellent physicochemical stability. Inulin was firstly modified in the side chain with primary amine groups, followed in turn by conjugation with squalenoyl derivatives through common amidic coupling agents and PEGylation by imine linkage. Polymer coated SPIONs were so obtained by spontaneous self-assembling of inulin copolymer onto magnetite surface involving hydrophobic-hydrophobic interactions between the metallic core and the squalene moieties. The system was characterized in terms of hydrodynamic radius, zeta potential, shape and drug loading capacity. On the whole, the stealth-like shell stabilized the suspension in aqueous media, though allowing the release of the doxorubicin loaded in therapeutic range. The cytotoxicity profile on cancer (HCT116) cell line and in vitro drug uptake were evaluated both with and without an external magnetic field used as targeting agent and uptake promoter, displaying that magnetic targeting implies advantageous therapeutic effects, that is amplified drug uptake and increased anticancer activity throughout the tumor mass.

Novel amphiphilic copolymers have been synthesized based on a biocompatible poly(hydroxyethylaspartamide) (PHEA) backbone, bearing both anchoring groups for gold nanoparticles, such as thiols and disulfide, and conjugable moieties, such as amino groups, the latter as points suitable for appending further functional agents. The strategy was to functionalize α,β-poly[(N-2- hydroxyethyl)-d,l-aspartamide] (PHEA) with PEG2000-NH2 and with ethylenediamine (EDA) obtaining a partially pegylated copolymer with a large number of pendant primary amino groups. A fraction of the latter was conjugated with molecules bearing terminal thiol moieties such as 12-mercaptododecanoic acid (MDA) and disulfide groups such as lipoic acid (LA), obtaining the two amphiphilic derivatives PHEA-PEG2000-EDA-MDA (PPE-MDA) and PHEA-PEG2000-EDA-LA (PPE-LA), which also proved intrinsically able to self-assemble in polymeric micelles. The two copolymers efficiently coated gold nanostars (GNSs, size ∼40 nm), wrapping around the surface increasing only slightly the hydrodynamic diameter (reaching ∼45 nm), imparting them stability and a pH-switchable surface charge, due to the unreacted amino groups. Remarkably, the poor solvation and the huge steric hindrance experienced by the amino groups lowers the observed logarithmic protonation constants to 5.6-5.7. In vitro experiments demonstrated that PPE-MDA and PPE-LA copolymers have an intrinsic excellent biocompatibility in both the human brain neuroblastoma (SH-SY5Y) and human bronchial epithelial (16-HBE) cell lines. Interaction of the same cell lines with "nude" GNS and GNS coated with PPE-LA was also studied, disclosing a completely satisfactory biocompatibility of the latter. © 2013 American Chemical Society.

In this paper the preparation of magnetic nano- carriers (MNCs), containing superparamagnetic domains, is reported, useful as potential magnetically targeted drug delivery systems. The preparation of MNCs was performed by using the PHEA-IB-p(BMA) graft copolymer as coating material through the homogenization−solvent evaporation method. Magnetic and nonmagnetic nanocarriers containing flutamide (FLU-MNCs) were prepared. The prepared nanocarriers have been exhaustively characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), and magnetic measurements. Biological evaluation was performed by in vitro cytotoxicity and cell uptake tests and in vivo biodistribution studies. Magnetic nanocarriers showed dimensions of about 300 nm with a narrow size distribution, an amount of loaded FLU of 20% (w/w), and a superparamagnetic behavior. Cell culture experiments performed on prostate cancer cell line LNCaP demonstrated the cytotoxic effect of FLU-MNCs. In vivo biodistribution studies carried out by the application of an external magnetic field in rats demonstrated the effect of the external magnet on modifying the biodistribution of FLU-MNCs. FLU-MNCs resulted efficiently internalized by tumor cells and susceptible to magnetic targeting by application of an external magnetic field. The proposed nanocarriers can represent a very promising approach to obtain an efficient magnetically targeted anticancer drug delivery system.

Tissue engineering has emerged as a new approach with the potential to overcome the limitations of traditional therapies. The objective of this study was to test whether our polymeric scaffold is able to resist the corrosive action of bile and to support a cell's infiltration and neoangiogenesis with the aim of using it as a biodegradable tissue substitute for serious bile duct injuries. In particular, a resorbable electrospun polyhydroxyethyl-aspartamide–polylactic acid (90 mol% PHEA, 10 mol% PLA)/polycaprolactone (50:50 w/w) plate scaffold was implanted into rabbit gallbladder to assess the in vivo effects of the lytic action of the bile on the scaffold structure and then as a tubular scaffold to create a biliary-digestive anastomosis as well. For the above evaluation, 5 animals were used and killed after 15 days and 5 animals after 3 months. At 15-day and 3-month follow-ups, the fibrillar structure was not digested by lytic action bile. The fibers of the scaffold were organized despite being in contact with bile action. A new epithelial tissue appeared on the scaffold surface suggesting the suitability of this scaffold for future studies of the repair of biliary tract injuries with the use of resorbable copolymer on biliary injuries.

A tri-component polymer brush (TCPB), composed of a polybenzofulvene copolymer bearing low molecular weight hyaluronic acid (HA) on the surface of its cylindrical brush-like backbone and oligo-PEG fractions, was employed in the preparation of 350Â nm nanostructured drug delivery systems capable of delivering the anticancer drug doxorubicin. The obtained drug delivery systems were characterized on the basis of drug loading and release, dimensions and zeta potential, morphology and in vitro cell activity, and uptake on three different human cell lines, namely the bronchial epithelial 16HBE, the breast adenocarcinoma MCF-7, and the colon cancer HCT116 cells. Finally, the ability of doxorubicin-loaded TCPB nanoparticles (DOXO-TCPB) to be internalized into cancer cells by CD44 receptor mediated uptake was assessed by means of uptake studies in HCT cells. These data were supported by anti-CD44-FITC staining assay. The proposed TCPB nanostructured drug delivery systems have many potential applications in nanomedicine, including cancer targeted drug delivery.

In this study, a polybenzofulvene derivative named poly-6-MOEG-9-BF3k, was evaluated as polymeric material for the production of injectable thermoresponsive nano-aggregates able to load low molecular weight peptidic drug, like the anticancer leuprolide. Thermoresponsive behavior of poly-6-MOEG-9-BF3k was studied in aqueous media by evaluating scattering intensity variations by means of DLS in function of temperature. Zeta potential measurements and SEM observations were also carried out. Moreover, critical aggregation temperature of the poly-6-MOEG-9-BF3k polymer was evaluated by pyrene fluorescence analysis. Then, the ability of prepared thermoresponsive aggregates to protect this model oligopeptide drug and regulate its release rate in function of external temperature was evaluated in vitro. Finally, biocompatibility of poly-6-MOEG-9-BF3k aggregates was tested in vitro on a healthy cell line (human bronchial epithelial cell; 16-HBE) and in vivo on rat animal model upon subcutaneous administration.