A water-soluble preparation for intravenous administration of isorhamnetin and its pharmacokinetics in rats.

Flavonoids are considered as health-protecting food constituents. The testing of their biological effects is however hampered by their low oral absorption and complex metabolism. In order to investigate the direct effect(s) of unmetabolized flavonoid, a preparation in a biologically friendly solvent for intravenous administration is needed. Isorhamnetin, a natural flavonoid and a human metabolite of the most frequently tested flavonoid quercetin, has very low water solubility (<3.5 µg/mL). The aim of this study was to improve its solubility to enable intravenous administration and to test its pharmacokinetics in an animal model. By using polyvinylpyrrolidone (PVP10) and benzalkonium chloride, we were able to improve the solubility approximately 600 times to 2.1 mg/mL. This solution was then administered intravenously at a dose of 0.5 mg/kg of isorhamnetin to rats and its pharmacokinetics was analyzed. The pharmacokinetics of isorhamnetin corresponded to two compartmental model with a rapid initial distribution phase (t1/2α: 5.7 ± 4.3 min) and a slower elimination phase (t1/2ß: 61 ± 47.5 min). Two sulfate metabolites were also identified. PVP10 and benzalkonium did not modify the properties of isorhamnetin (iron chelation and reduction, and cell penetration) substantially. In conclusion, the novel preparation reported in this study is suitable for future testing of isorhamnetin effects under in vivo conditions.

Improved pharmacokinetic and lymphatic uptake of Rose Bengal after transfersome intradermal deposition using hollow microneedles.

The lymphatic system is active in several processes that regulate human diseases, among which cancer progression stands out. Thus, various drug delivery systems have been investigated to promote lymphatic drug targeting for cancer therapy; mainly, nanosized particles in the 10-150 nm range quickly achieve lymphatic vessels after an interstitial administration. Herein, a strategy to boost the lymphotropic delivery of Rose Bengal (RB), a hydrosoluble chemotherapeutic, is proposed, and it is based on the loading into Transfersomes (RBTF) and their intradermal deposition in vivo by microneedles. RBTF of 96.27 ± 13.96 nm (PDI = 0.29 ± 0.02) were prepared by a green reverse-phase evaporation technique, and they showed an RB encapsulation efficiency of 98.54 ± 0.09%. In vitro, RBTF remained physically stable under physiological conditions and avoided the release of RB. In vivo, intravenous injection of RBTF prolonged RB half-life of 50 min in healthy rats compared to RB intravenous injection; the RB half-life in rat body was further increased after intradermal injection reaching 24 h, regardless of the formulation used. Regarding lymphatic targeting, RBTF administered intravenously provided an RB accumulation in the lymph nodes of 12.3 ± 0.14 ng/mL after 2 h, whereas no RB accumulation was observed after RB intravenous injection. Intradermally administered RBTF resulted in the highest RB amount detected in lymph nodes after 2 h from the injection (84.2 ± 25.10 ng/mL), which was even visible to the naked eye based on the pink colouration of the drug. In the case of intradermally administered RB, RB in lymph node was detected only at 24 h (13.3 ± 1.41 ng/mL). In conclusion, RBTF proved an efficient carrier for RB delivery, enhancing its pharmacokinetics and promoting lymph-targeted delivery. Thus, RBTF represents a promising nanomedicine product for potentially facing the medical need for novel strategies for cancer therapy.

Conjugation, Prodrug, and Co-Administration Strategies in Support of Nanotechnologies to Improve the Therapeutic Efficacy of Phytochemicals in the Central Nervous System.

Phytochemicals, produced as secondary plant metabolites, have shown interesting potential therapeutic activities against neurodegenerative diseases and cancer. Unfortunately, poor bioavailability and rapid metabolic processes compromise their therapeutic use, and several strategies are currently proposed for overcoming these issues. The present review summarises strategies for enhancing the central nervous system's phytochemical efficacy. Particular attention has been paid to the use of phytochemicals in combination with other drugs (co-administrations) or administration of phytochemicals as prodrugs or conjugates, particularly when these approaches are supported by nanotechnologies exploiting conjugation strategies with appropriate targeting molecules. These aspects are described for polyphenols and essential oil components, which can improve their loading as prodrugs in nanocarriers, or be part of nanocarriers designed for targeted co-delivery to achieve synergistic anti-glioma or anti-neurodegenerative effects. The use of in vitro models, able to simulate the blood-brain barrier, neurodegeneration or glioma, and useful for optimizing innovative formulations before their in vivo administration via intravenous, oral, or nasal routes, is also summarised. Among the described compounds, quercetin, curcumin, resveratrol, ferulic acid, geraniol, and cinnamaldehyde can be efficaciously formulated to attain brain-targeting characteristics, and may therefore be therapeutically useful against glioma or neurodegenerative diseases.

Association of Indocyanine Green with Chitosan Oleate Coated PLGA Nanoparticles for Photodynamic Therapy.

Indocyanine green (ICG) is a safe dye widely used in the biomedical field. Its photodynamic effect (PDT), originating from laser irradiation at 803 nm, opens interesting perspectives in theranostic applications. To overcome its low water stability, ICG can be shielded with nanoparticles (NPs). In this work, previously developed NPs based on poly lactic-co-glycolic acid (PLGA) coated with chitosan oleate (CS-OA) and loaded with resveratrol as a hydrophobic model drug have been proposed as an ICG carrier. These systems have been selected for their observed immunostimulatory properties. The possible loading of the dye by adsorption onto NP surface by electrostatic interaction was studied here in comparison with the encapsulation into the PLGA core. The ICG-chitosan (CS) interaction has been characterized by spectrophotometry, spectroscopy and in-cell in vitro assays. Fluorescence quenching was observed due to the ionic interaction between ICG and CS and was studied considering the dye:polymer stoichiometry and the effect of the NP dilution in cell culture medium (DMEM). The NP systems have been compared in vitro, assessing their behaviour in Caco-2 cell lines. A reduction in cell viability was observed after irradiation of ICG associated with NPs, evident also for the samples loaded by adsorption. These findings open the opportunity to exploit the association of PDT's effect on ICG with the properties of CS-OA coated NPs, whose immunostimulatory effect can be associated with PDT mechanism in cancer therapy.

Improving Dermal Delivery of Rose Bengal by Deformable Lipid Nanovesicles for Topical Treatment of Melanoma.

Cutaneous melanoma is one of the most aggressive and metastatic forms of skin cancer. However, current therapeutic options present several limitations, and the annual death rate due to melanoma increases every year. Dermal delivery of nanomedicines can effectively eradicate primary melanoma lesions, avoid the metastatic process, and improve survival. Rose Bengal (RB) is a sono-photosensitizer drug with intrinsic cytotoxicity toward melanoma without external stimuli but the biopharmaceutical profile limits its clinical use. Here, we propose deformable lipid nanovesicles, also known as transfersomes (TF), for the targeted dermal delivery of RB to melanoma lesions to eradicate them in the absence of external stimuli. Considering RB's poor ability to cross the stratum corneum and its photosensitizer nature, transfersomal carriers were selected simultaneously to enhance RB penetration to the deepest skin layers and protect RB from undesired photodegradation. RB-loaded TF dispersion (RB-TF), prepared by a modified reverse-phase evaporation method, were nanosized with a ζ-potential value below -30 mV. The spectrophotometric and fluorimetric analysis revealed that RB efficiently interacted with the lipid phase. The morphological investigations (transmission electron microscopy and small-angle X-ray scattering) proved that RB intercalated within the phospholipid bilayer of TF originating unilamellar and deformable vesicles, in contrast to the rigid multilamellar unloaded ones. Such outcomes agree with the results of the in vitro permeation study, where the lack of a burst RB permeation peak for RB-TF, observed instead for the free drug, suggests that a significant amount of RB interacted with lipid nanovesicles. Also, RB-TF proved to protect RB from undesired photodegradation over 24 h of direct light exposure. The ex vivo epidermis permeation study proved that RB-TF significantly increased RB's amount permeating the epidermis compared to the free drug (78.31 vs 38.31%). Finally, the antiproliferative assays on melanoma cells suggested that RB-TF effectively reduced cell growth compared to free RB at the concentrations tested (25 and 50 µM). RB-TF could potentially increase selectivity toward cancer cells. Considering the outcomes of the characterization and cytotoxicity studies performed on RB-TF, we conclude that RB-TF represents a valid potential alternative tool to fight against primary melanoma lesions via dermal delivery in the absence of light.

Electrochemotherapy of Deep-Seated Tumors: State of Art and Perspectives as Possible "EPR Effect Enhancer" to Improve Cancer Nanomedicine Efficacy.

Surgical resection is the gold standard for the treatment of many kinds of tumor, but its success depends on the early diagnosis and the absence of metastases. However, many deep-seated tumors (liver, pancreas, for example) are often unresectable at the time of diagnosis. Chemotherapies and radiotherapies are a second line for cancer treatment. The "enhanced permeability and retention" (EPR) effect is believed to play a fundamental role in the passive uptake of drug-loaded nanocarriers, for example polymeric nanoparticles, in deep-seated tumors. However, criticisms of the EPR effect were recently raised, particularly in advanced human cancers: obstructed blood vessels and suppressed blood flow determine a heterogeneity of the EPR effect, with negative consequences on nanocarrier accumulation, retention, and intratumoral distribution. Therefore, to improve the nanomedicine uptake, there is a strong need for "EPR enhancers". Electrochemotherapy represents an important tool for the treatment of deep-seated tumors, usually combined with the systemic (intravenous) administration of anticancer drugs, such as bleomycin or cisplatin. A possible new strategy, worthy of investigation, could be the use of this technique as an "EPR enhancer" of a target tumor, combined with the intratumoral administration of drug-loaded nanoparticles. This is a general overview of the rational basis for which EP could be envisaged as an "EPR enhancer" in nanomedicine.

Polymeric and Lipid Nanoparticles: Which Applications in Pediatrics?

This review aims to provide the state of the art on polymeric and lipid nanoparticles, used or suggested to approach pediatric diseases' problems and needs, and to inspire new researches in this field. Several drugs are currently not available in formulations suitable for pediatric patients. The United States Pediatric Formulation Initiative suggested applying new technologies to pediatric drug formulations, for instance, nanotechnology. The literature analysis showed that polymeric and lipid nanoparticles have been widely studied to treat pediatric diseases, and albumin nanoparticles and liposomes are already used in clinical practice. Nevertheless, these studies are focused almost exclusively on pediatric cancer treatment. Although nanomedicine may solve many needs of pediatric diseases and medicines, the unavailability of data on pharmacokinetics, safety and efficacy of both drugs and nanoparticles in pediatric patients limits the development of new pediatric medicines based on nanoparticles. Therefore, nanomedicine applied in pediatrics remains a significant challenge in the near future.

Transmucosal Solid Lipid Nanoparticles to Improve Genistein Absorption via Intestinal Lymphatic Transport.

Genistein (GEN) is a soy-derived isoflavone that exhibits several biological effects, such as neuroprotective activity and the prevention of several types of cancer and cardiovascular disease. However, due to its poor water solubility and the extensive first-pass metabolism, the oral bioavailability of GEN is limited. In this work, solid lipid nanoparticles (SLN) were developed to preferentially reach the intestinal lymphatic vessels, avoiding the first-pass metabolism of GEN. GEN-loaded SLN were obtained by a hot homogenization process, and the formulation parameters were chosen based on already formulated studies. The nanoparticles were characterized, and the preliminary in vitro chylomicron formation was evaluated. The cell uptake of selected nanocarriers was studied on the Caco-2 cell line and intestinal mucosa. The SLN, characterized by a spherical shape, showed an average diameter (about 280 nm) suitable for an intestinal lymphatic uptake, good stability during the testing time, and high drug loading capacity. Furthermore, the intestinal mucosa and Caco-2 cells were found to uptake SLN. The approximately two-fold increase in particle size suggested a possible interaction between SLN and the lipid components of chylomicrons like phospholipid; therefore, the results may support the potential for these SLN to improve oral GEN bioavailability via intestinal lymphatic absorption.

Chitosan Nanoparticles for Therapy and Theranostics of Hepatocellular Carcinoma (HCC) and Liver-Targeting.

Chitosan nanoparticles are well-known delivery systems widely used as polymeric carriers in the field of nanomedicine. Chitosan is a carbohydrate of natural origin: it is a biodegradable, biocompatible, mucoadhesive, polycationic polymer and it is endowed with penetration enhancer properties. Furthermore, it can be easily derivatized. Hepatocellular carcinoma (HCC) represents a remarkable health problem because current therapies, that include surgery, liver transplantation, trans-arterial embolization, chemoembolization and chemotherapy, present significant limitations due to the high risk of recurrence, to a lack of drug selectivity and to other serious side effects. Therefore, there is the need for new therapeutic strategies and for improving the liver-targeting to HCC. Nanomedicine consists in the use of nanoscale carriers as delivery systems to target and deliver drugs and/or diagnostic agents to specific organs or tissues. Chitosan and its derivatives can be successfully used in the preparation of nanoparticles that, for their peculiar surface-properties, can specifically interact with liver tumor, by passive and active targeting. This review concerns the use of chitosan nanoparticles for the therapy and theranostics of HCC and liver-targeting.

Indocyanine Green Loaded Polymeric Nanoparticles: Physicochemical Characterization and Interaction Studies with Caco-2 Cell Line by Light and Transmission Electron Microscopy.

Biomedical applications of nanoparticles (NPs) have reached an increasing development in recent years. Recently, we demonstrated that newly synthesized poly (ethyl 2-cyanoacrylate) nanoparticles (PECA-NPs) are possible antitumor agents due to their cytotoxicity for cancer cells. Indocyanine green (ICG), an amphiphilic tricarbocyanine fluorescent dye, is widely used for the detection of tumoral extension in different organs during clinical surgery. Moreover, this fluorescent agent is unstable and it has a rapid clearance in physiological conditions in vivo. In this study, ICG was charged in PECA-NPs to improve its aqueous stability and make easier its use for the identification of tumor cells. Microscopic and ultrastructural aspects concerning the related in vitro interactions between ICG-loaded NPs and tumor cell culture were investigated. Obtained results showed an effective stabilization of ICG; furthermore, color inclusions inside the cells treated with ICG-loaded NPs demonstrated the internalization of NPs with associated ICG. Transmission electron microscopy (TEM) analysis demonstrated the cytoplasmic presence of coated vesicles (Ø ≤ 100 nm), hypothesizing their involvement in the mechanism of endocytosis. Therefore, ICG-loaded NPs could be proposed as agents for tumor diagnosis, hypothesizing also in the future a specific therapeutic treatment.

Uptake in the Central Nervous System of Geraniol Oil Encapsulated in Chitosan Oleate Following Nasal and Oral Administration.

The pharmacological activities of geraniol include anticancer and neuroprotective properties. However, its insolubility in water easily induces separation from aqueous formulations, causing administration difficulties. Here we propose new emulsified formulations of geraniol by using the amphiphilic polymer chitosan-oleate (CS-OA) as surfactant to combine mucoadhesive and absorption enhancer properties with stabilization effects on the oil dispersion. The formulation based on CS-OA 2% (w/w) (G-CS-OA-2.0%) showed viscosity values compatible with oral and nasal administration to rats, and mean diameter of the dispersed phase of 819 ± 104 nm. G-CS-OA-2.0% oral administration sensibly increases the geraniol bioavailability with respect to coarse emulsions obtained without CS-OA (AUC values in the bloodstream were 42,713 ± 1553 µg∙mL-1∙min and 2158 ± 82 µg∙mL-1∙min following administration of 50 mg/kg or 1 mg/kg, respectively), and enhances the aptitude of geraniol to reach the central nervous system from the bloodstream (AUC values in the cerebrospinal fluid were 7293 ± 408 µg∙mL-1∙min and 399 ± 25 µg∙mL-1∙min after oral administration of 50 mg/kg or 1 mg/kg, respectively). Moreover, relevant geraniol amounts were detected in the cerebrospinal fluid following the G-CS-OA-2% nasal administration (AUC values in the cerebrospinal fluid were 10,778 ± 477 µg∙mL-1∙min and 5571 ± 290 µg∙mL-1∙min after nasal administration of 4 mg/kg or 1 mg/kg, respectively).

Poly (ethyl 2-cyanoacrylate) nanoparticles (PECA-NPs) as possible agents in tumor treatment.

Tumor eradication has many challenges due to the difficulty of selectively delivering anticancer drugs to malignant cells avoiding contact with healthy tissues/organs. The improvement of antitumor efficacy and the reduction of systemic side effects can be achieved using drug loaded nanoparticles. In this study, poly (ethyl 2-cyanoacrylate) nanoparticles (PECA-NPs) were prepared using an emulsion polymerization method and their potential for cancer treatment was investigated. The size, polydispersity index and zeta potential of prepared nanoparticles are about 80 nm, 0.08 and -39.7 mV, respectively. The stability test shows that the formulation is stable for 15 days, while an increase in particle size occurs after 30 days. TEM reveals the spherical morphology of nanoparticles; furthermore, FTIR and 1H NMR analyses confirm the structure of PECA-NPs and the complete polymerization. The nanoparticles demonstrate an in vitro concentration-dependent cytotoxicity against human epithelial colorectal adenocarcinoma cell lines (Caco-2), as assessed by MTT assay. The anticancer activity of PECA-NPs was studied on 3D tumor spheroids models of hepatocellular carcinoma (HepG2) and kidney adenocarcinoma cells (A498) to better understand how the nanoparticles could interact with a complex structure such as a tumor. The results confirm the antitumor activity of PECA-NPs. Therefore, these systems can be considered good candidates in tumor treatment.

Increasing protective activity of genistein by loading into transfersomes: A new potential adjuvant in the oxidative stress-related neurodegenerative diseases?

BACKGROUND: Genistein is a soy-derived isoflavone and phytoestrogen with antioxidant and neuroprotective activity. Genistein has intrinsically low oral bioavailability that affects its dose-response activities. PURPOSE: Nanotechnologies were used to obtain the delivery of genistein to the brain: lipid-based nanovesicles, transfersomes, loaded with the phytoestrogen were developed as potential therapeutic or preventive strategy against neurodegenerative diseases by intranasal administration. METHODS: Phosphatidylcholine from soybean and different edge activators were used to prepare transfersomes. The effect of selected nanovesicles on the oxidative damage was studied in PC12 cell line. RESULTS: Suitable nanovesicles as carrier of genistein were obtained; their composition affects deformability, drug permeation behavior and cytotoxicity. In particular, the formulation containing Span 80, GEN-TF2, showed efficiency of internalization into the cell and it was able to attenuate ROS formation and to reduce the amount of apoptotic cells generated by H2O2 treatment compared to genistein. CONCLUSION: GEN-TF2 was able to reduce the oxidative damage suggesting a possible antioxidant role of this drug delivery system. These obtained data confer to GEN-TF2 a potential antioxidant activity and then it could be used as adjuvant therapy in oxidative stress-related neurodegenerative diseases.

Nanoparticles in detection and treatment of lymph node metastases: an update from the point of view of administration routes.

INTRODUCTION: Lymphatic vessels are the preferential route of most solid tumors to spread their metastases in the body. Therefore, the individuation and elimination of cancer cells within the lymphatic system (LS) is an important goal. Nanoparticles (NPs), thanks to their small size, represent suitable carriers for imaging and for chemotherapeutic transport to the LS. An update of different nanoparticle delivery systems developed for the detection and treatment of lymphatic metastases has been made, classified from the point of view of the administration routes used. AREAS COVERED: The role of the LS in tumor progression and importance of treatment and imaging strategies of lymphatic metastases; classification, with regard the administration route, of nanoparticle delivery system used to target lymph node (LN) metastases. EXPERT OPINION: The NPs are a promising approach for the treatment and detection of lymphatic metastases. However, further studies are necessary to evaluate their efficacy in human clinical application.

Lymph node metastases: importance of detection and treatment strategies.

INTRODUCTION: Lymphatic vessels are the preferential route of most solid tumors to spread their metastases in the body. The onset of metastatic nests in draining lymph nodes (LNs) are a significant indicator of cancer progression and a dismaying sign of worsen staging. Therefore, the individuation and elimination of cancer cells within the lymphatic system (LS) are an important goal. Nevertheless, the targeting of the LS with traditional contrast agents and/or chemotherapeutics is difficult, due to its anatomical structure. For this reason, many studies on new lymphatic delivery systems have been carried out, both to improve lymphatic imaging and to selectively carry chemotherapeutics to LNs, reducing the exposure of healthy tissues to the cytotoxic substances. This is an overview of the present situation in the field of detection and treatment strategies of lymphatic metastases, taking into account the use of nano-drug delivery systems. Nanocarriers, thanks to their small size and other physicochemical characteristics, are suitable vectors for imaging and chemotherapy of the LS. AREAS COVERED: The role of the LS in tumor progression and importance of treatment and imaging strategies of lymphatic metastases. EXPERT OPINION: The nanoparticles are a promising approach for treatment and detection of lymphatic metastases. However further studies are necessary in order to evaluate their efficacy in human clinical application.

Aqueous injection of quercetin: An approach for confirmation of its direct in vivo cardiovascular effects.

Potential positive effects of flavonol quercetin on humans were suggested by many studies. However, it is not clear if these effects are mediated by quercetin or its metabolites. The in vivo confirmation of quercetin effects is largely hindered by its low water solubility and thus impossibility to test directly its impact. Therefore, a solid dispersion of quercetin with polyvinylpyrrolidone (PVP) was developed to prepare an injectable formulation of water-soluble quercetin. The optimized formulation provided a 20,000-fold increase in quercetin solubility. This formulation was tested on conventional and spontaneously hypertensive rats; it lowered their blood pressure in both short- and long-term basis. Pharmacokinetic data are also provided. This study reports for the first time an injectable water-soluble formulation of quercetin suitable for confirmation of its vascular effect in vivo.

Engineered polymeric microspheres obtained by multi-step method as potential systems for transarterial embolization and intraoperative imaging of HCC: Preliminary evaluation.

The aim of this study was the development of novel fluorescent microspheres as embolic agent for transarterial embolization (TAE) of advanced stages of hepatocellular carcinoma (HCC). TAE is a minimally invasive procedure that induces tumour regression blocking the blood flow by injection of microparticles. The microspheres currently used in clinical application cannot be visualized in vivo. Surgeon could exploit the intraoperative detection of embolic agents during resection of the malignant mass. Biocompatible indocyanine green (ICG)-loaded microspheres (CAB-CS-ICG) were prepared using a multi-step method. Chitosan (CS)-ICG particles were prepared via spray-dryer and then loaded into cellulose acetate butyrate (CAB) microspheres, fabricated by emulsion solvent extraction method. Technological parameters such as yield, size, encapsulation efficiency and morphology were studied. CAB-CS-ICG microspheres showed spherical shape and smooth surface, as well as good injectability through a 21 G×1½ needle. ICG release from CAB-CS-ICG was very low due to the strong interaction between CS and ICG. This result was also confirmed by in vitro fluorescence imaging studies, conducted using Photodynamic Eye (PDE) for the detection of particles incubated in human plasma. CAB-CS-ICG were capable to maintain the fluorescence selectivity for 4weeks. Our data suggested the potential usefulness of CAB-CS-ICG in TAE application as embolic agents and following imaging of tumour during surgical procedure.

In situ forming biodegradable poly(ε-caprolactone) microsphere systems: a challenge for transarterial embolization therapy. In vitro and preliminary ex vivo studies.

BACKGROUND: In situ forming biodegradable poly(ε-caprolactone) (PCL) microspheres (PCL-ISM) system was developed as a novel embolic agent for transarterial embolization (TAE) therapy of hepatocellular carcinoma (HCC). Ibuprofen sodium (Ibu-Na) was loaded on this platform to evaluate its potential for the treatment of post embolization syndrome. METHODS: The influence of formulation parameters on the size/shape, encapsulation efficiency and drug release was investigated using mixture experimental design. Regression models were derived and used to optimize the formulation for particle size, encapsulation efficiency and drug release profile for TAE therapy. An ex vivo model using isolated rat livers was established to assess the in situ formation of microspheres. RESULTS: All PCL-ISM components affected the studied properties and fitting indices of the regression models were high (Radj2 = 0.810 for size, 0.964 encapsulation efficiency, and 0.993 or 0.971 for drug release at 30 min or 48 h). The optimized composition was: PCL = 4%, NMP = 43.1%, oil = 48.9%, surfactant = 2% and drug = 2%. Ex vivo studies revealed that PCL-ISM was able to form microspheres in the hepatic arterial bed. CONCLUSIONS: PCL-ISM system provides a novel tool for the treatment of HCC and post-embolization syndrome. It is capable of forming microspheres with desirable size and Ibu-Na release profile after injection into blood vessels.

Natural collagenic skeleton of marine sponges in pharmaceutics: Innovative biomaterial for topical drug delivery.

The growing interest in the use of recyclable and biodegradable natural materials has become a relevant topic in pharmaceutics. In this work, we suggest the use and valorization of natural horny skeleton of marine sponges (Porifera, Dictyoceratida) as bio-based dressing for topical drug delivery. Biomaterial characterization focusing on morpho-functional traits, swelling behavior, fluid uptake performances, glycosaminoglycans content and composition and microbiological quality assessment was carried out to investigate the collagenic skeleton properties. After grinding and sieving processes, l-cysteine hydrochloride-loaded formulations were designed in form of powder or polymeric film by testing various drug concentrations and different drying parameters. Drug content, SEM analyses and in vitro permeation studies were performed to test the suitability of skeleton-based formulations. To this respect, drying time and temperature are key parameters for skeleton-mediated drug crystallization. Consequently, this behavior seems to influence drug loading and permeation profiles of formulations. The high percentages of drug are found after absorption into sponge powder and in vitro permeation studies demonstrate that cysteine is released more slowly than the pure drug within 1h. Such a system is attractive because it combines the known healing properties of cysteine with the advantageous potentials of the collagen/proteoglycan network, which can act as biocompatible carrier able to absorb the excess of the wound exudate while releasing the drug. Furthermore, due to its glycosaminoglycans content, natural sponge skeletal scaffold might act as bioactive-biomimetic carrier regulating the wound healing processes.

Indocyanine green delivery systems for tumour detection and treatments.

Indocyanine green (ICG) is a cyanine compound that displays fluorescent properties in the near infrared region. This dye is employed for numerous indications but nowadays its major application field regards tumour diagnosis and treatments. Optical imaging by near infrared fluorescence provides news opportunities for oncologic surgery. The imaging of ICG can be useful for intraoperative identification of several solid tumours and metastases, and sentinel lymph node detection. In addition, ICG can be used as an agent for the destruction of malignant tissue, by virtue of the production of reactive oxygen species and/or induction of a hyperthermia effect under irradiation. Nevertheless, ICG shows several drawbacks, which limit its clinical application. Several formulative strategies have been studied to overcome these problems. The rationale of the development of ICG containing drug delivery systems is to enhance the in vivo stability and biodistribution profile of this dye, allowing tumour accumulation and resulting in better efficacy. In this review, ICG containing nano-sized carriers are classified based on their chemical composition and structure. In addition to nanosystems, different formulations including hydrogel, microsystems and others loaded with ICG will be illustrated. In particular, this report describes the preparation, in vitro characterization and in vivo application of ICG platforms for cancer imaging and treatment. The promising results of all systems confirm their clinical utility but further studies are required prior to evaluating the formulations in human trials.