Anionic Methacrylate Copolymer Microparticles for the Delivery of Myo-Inositol Produced by Spray-Drying: In Vitro and In Vivo Bioavailability.

In this study, a new micro delivery system based on an anionic methacrylate copolymer, able to improve the biological response of myo-inositol by daily oral administration, was manufactured by spray-drying. It has an ideal dose form for oral administration, with an experimental drug loading (DL)% of 14% and a regulated particle size of less than 15 µm. The new formulation features an improvement on traditional formulations used as a chronic therapy for the treatment of polycystic ovary syndrome. The microparticles' release profile was studied and ex vivo porcine intestinal mucosa permeation experiments were performed to predict potential improvements in oral absorption. Batch n. 3, with the higher Eudragit/MI weight ratio (ratio = 6), showed the best-modified release profiles of the active ingredient, ensuring the lowest myo-inositol loss in an acidic environment. The in vivo evaluation of the myo-inositol micro delivery system was carried out in a rat animal model to demonstrate that the bioavailability of myo-inositol was increased when compared to the administration of the same dosage of the pure active ingredient. The AUC and Cmax of the loaded active molecule in the micro delivery system was improved by a minimum of 1.5 times when compared with the pure substance, administered with same dosage and route. Finally, the increase of myo-inositol levels in the ovary follicles was assessed to confirm that a daily administration of the new formulation improves myo-inositol concentration at the site of action, resulting in an improvement of about 1.25 times for the single administration and 1.66 times after 7 days of repeated administration when compared to pure MI.

Spray-Drying, Solvent-Casting and Freeze-Drying Techniques: a Comparative Study on their Suitability for the Enhancement of Drug Dissolution Rates.

PURPOSE: Solid dispersions (SDs) represent the most common formulation technique used to increase the dissolution rate of a drug. In this work, the three most common methods used to prepare SDs, namely spray-drying, solvent-casting and freeze-drying, have been compared in order to investigate their effect on increasing drug dissolution rate. METHODS: Three formulation strategies were used to prepare a polymer mixture of polyvinyl-alcohol (PVA) and maltodextrin (MDX) as SDs loaded with the following three model drugs, all of which possess a poor solubility: Olanzapine, Dexamethasone, and Triamcinolone acetonide. The SDs obtained were analysed and compared in terms of drug particle size, drug-loading capacity, surface homogeneity, and dissolution profile enhancement. Physical-chemical characterisation was conducted on pure drugs, as well as the formulations made, by way of thermal analysis and infrared spectroscopy. RESULT: The polymers used were able to increase drug saturation solubility. The formulation strategies affected the drug particle size, with the solvent-casting method resulting in more homogenous particle size and distribution when compared to the other methods. The greatest enhancement in the drug dissolution rate was seen for all the samples prepared using the solvent-casting method. CONCLUSION: All of the methods used were able to increase the dissolution rate of the pure drugs alone, however, the solvent-casting method produced SDs with a higher surface homogeneity, drug incorporation capability, and faster dissolution profile than the other techniques.

Influence of Polyvinyl Alcohol (PVA) on PVA-Poly-N-hydroxyethyl-aspartamide (PVA-PHEA) Microcrystalline Solid Dispersion Films.

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.

Combining spontaneous polymerization and click reactions for the synthesis of polymer brushes: a "grafting onto" approach.

Two novel benzofulvene monomers bearing propargyl or allyl groups have been synthesized by means of readily accessible reactions, and were found to polymerize spontaneously by solvent removal, in the apparent absence of catalysts or initiators, to give the corresponding polybenzofulvene derivatives bearing clickable propargyl or allyl moieties. The clickable propargyl and allyl groups were exploited in appropriate click reactions to develop a powerful and versatile "grafting onto" synthetic methodology for obtaining tailored polymer brushes.

Amphiphilic copolymers based on poly[(hydroxyethyl)-D,L-aspartamide]: a suitable functional coating for biocompatible gold nanostars.

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,ß-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.

Polybutylene succinate artificial scaffold for peripheral nerve regeneration.

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.

Site-specific halloysite functionalization by polydopamine: A new synthetic route for potential near infrared-activated delivery system.

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.

Identification of microplastics using 4-dimethylamino-4'-nitrostilbene solvatochromic fluorescence.

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.

Effect of actively targeted copolymer coating on solid tumors eradication by gold nanorods-induced hyperthermia.

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,ß-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.

Smart copolymer coated SPIONs for colon cancer chemotherapy.

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).

Microfibrillar polymeric ocular inserts for triamcinolone acetonide delivery.

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,ß-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.

Reversibly stable thiopolyplexes for intracellular delivery of genes.

Novel polyaspartamide non-viral carriers for gene therapy were synthesized by introducing, on the same polymer backbone, positively charged groups, for electrostatic interactions with DNA, and thiol groups for the formation of disulfide bridges between polymer chains. The introduction of thiols was aimed to have a vector with low redox potential sensitivity: disulfide crosslinking in fact, being stable in extracellular environment, allowed either to have stable complexes in plasma, that can protect DNA from metabolism, or to be reduced inside the cell, where the excess of glutathion in reduced form maintains a low redox potential. The consequent destabilization of the complex after disulfide cleavage can release DNA selectively inside the cells. Alpha,beta-poly(N-2-hydroxyethyl)-D,L-aspartamide (PHEA) was used as starting polymer being a highly water-soluble synthetic polymer, already proposed with success as therapeutic carrier by our group. In this study, PHEA was firstly functionalised with ethylendiamine, obtaining a well defined copolymer with pendant primary amine groups (PHEA-EDA), to which N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP) and 3-(carboxypropyl)trimethyl-ammonium chloride (CPTA) were linked in two subsequent steps, allowing the introduction of thiol and cationic groups respectively. Finally DTT treatment lead to the final PHEA-EDA-SH-CPTA thiopolycation, named PESC. The present work describes the synthesis and characterization of the thiopolycation PESC. 1H NMR spectroscopy detected the derivatization molar degrees in SPDP and CPTA; the formation of DNA complexes (thiopolyplexes), their stability in the presence of polyanions and the ability to release DNA under reductive conditions were studied by agarose gel electrophoresis. DNase II degradation study was carried out to detect the ability of thiopolyplex to stabilize DNA towards enzymatic metabolism. Thiopolyplexes were then characterized by Dynamic Light Scattering (DLS) and Zeta Potential analysis. Finally, in vitro toxicity profile (MTT) and gene transfer efficiency (Luciferase assay) were carried out to evaluate thiopolyplex biocompatibility, safety and efficacy to be used as gene delivery system.

Folate-mediated targeting of polymeric conjugates of gemcitabine.

The synthesis of two new macromolecular prodrugs for active tumor targeting was set up. Gemcitabine (2'-deoxy-2',2'-difluorocytidine) was conjugated to alpha,beta-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA) through succinyl or diglycolyl hydrolysable spacers. The targeting agent folic acid was attached to the macromolecular backbone through the aminocaproic spacer. The two conjugates [PHEA-(5'-succinylgemcitabine)-1'-carboxypentyl-folamide and PHEA-(5'-diglycolyl-gemcitabine)-1'-carboxypentyl-folamide], were purified and extensively characterised by spectroscopic (UV, IR and NMR) and chromatographic analyses to determine the correct chemical structure, the purity degree and the reaction yield. In vitro studies demonstrated that the drug release depends on the spacer arm (diglycolyil or succinyl) and incubation pH. After 30 h incubation at pH 7.4, mimicking the plasma and extracellular compartments, the gemcitabine release from the succinyl and diglycolyl derivatives was 28 and 31%, respectively. After 30 h incubation at pH 5.5, mimicking the lisosomial compartment, the drug released from both bioconjugates was lower than 13%. In plasma, the polymer conjugation increased the drug stability and provided for a sustained drug release. In vitro citotoxicity studies performed using human nasopharyngeal epidermal carcinoma KB cells demonstrated that PHEA-(5'-succinylgemcitabine)-1'-carboxypentyl-folamide displays an higher dose dependent cytotoxic effect with respect to PHEA-(5'-diglycolyl-gemcitabine)-1'-carboxypentyl-folamide.

Novel Lipid and Polymeric Materials as Delivery Systems for Nucleic Acid Based Drugs.

Nucleic acid based drugs (NADBs) are short DNA/RNA molecules that include among others, antisense oligonucleotides, aptamers, small interfering RNAs and micro-interfering RNAs. Despite the different mechanisms of actions, NABDs have the ability to combat the effects of pathological gene expression in many experimental systems. Thus, nowadays, NABDs are considered to have a great therapeutic potential, possibly superior to that of available drugs. Unfortunately, however, the lack of effective delivery systems limits the practical use of NABDs. Due to their hydrophilic nature, NABDs cannot efficiently cross cellular membrane; in addition, they are subjected to fast degradation by cellular and extracellular nucleases. Together these aspects make the delivery of NABDs as naked molecules almost un-effective. To optimize NABD delivery, several solutions have been investigated. From the first attempts described in the beginning of the 1980s, a burst in the number of published papers occurred in the beginning of 1990 s reaching a peak in 2012-13. The extensive amount of work performed so far clearly witnesses the interest of the scientific community in this topic. In the present review, we will concentrate on the description of the most interesting advances in the field. Particular emphasis will be put on polymeric and lipid materials used alone or in combination with a promising delivery strategy based on the use of carbon nanotubes. The data presented suggest that, although further improvements are required, we are not far from the identification of effective delivery systems for NABDs thus making the clinical use of these molecules closer to reality.

Tamoxifen-loaded polymeric micelles: preparation, physico-chemical characterization and in vitro evaluation studies.

Several samples of polymeric micelles, formed by amphiphilic derivatives of PHEA, obtained by grafting into polymeric backbone of PEGs and/or hexadecylamine groups (PHEA-PEG-C(16) and PHEA-C(16)) and containing different amount of Tamoxifen, were prepared. All Tamoxifen-loaded polymeric micelles showed to increase drug water solubility. TEM studies provided evidence of the formation of supramolecular core/shell architectures containing drug, in the nanoscopic range and with spherical shape. Samples with different amount of encapsulated Tamoxifen were subjected to in vitro cytotoxic studies in order to evaluate the effect of Tamoxifen micellization on cell growth inhibition. All samples of Tamoxifen-loaded polymeric micelles showed a significantly higher antiproliferative activity in comparison with free drug, probably attributable to fluidification of cellular membranes, caused by amphiphilic copolymers, that allows a higher penetration of the drug into tumoral cells. To gain preliminary information about the potential use of prepared micelles as Tamoxifen drug delivery systems, studies evaluating drug release ability of micelle systems in media mimicking biological fluids (buffer solutions at pH 7.4 and 5.5) and in human plasma were carried out. These studies, performed evaluating the amount of Tamoxifen that remains in solution as a function of time, showed that at pH 7.4, as well as in plasma, PHEA-C(16) polymeric micelles were able to release lower drug amounts than PHEA-PEG(5000)-C(16) ones, while at pH 5.5, the behavior difference between two kind of micelles was less pronounced.

Cell uptake enhancement of folate targeted polymer coated magnetic nanoparticles.

Dual targeted drug delivery systems represent a potential platform for developing efficient vector to tumor sites. In this study we evaluated a folate- and magnetic-targeted nanocarriers based on 10 nm iron oxide nanodomais coated with the properly synthesized and characterized folic acid (FA)-functionalized amphiphilic copolymer PHEA-PLA-PEG-FA. FA was chemically conjugated to one end of diamino-polyethylene glycol of 2000 Da, in order to ensure its exposition on the polymer coated magnetic nanoparticles (MNPs-FA). The prepared nanoparticles have been exhaustively characterized by different methods, including DLS, SEM, FT-IR and magnetic measurements. Magnetic nanoparticles showed dimension of about 37 nm with a narrow size distribution and a characteristic superparamagnetic behaviour. The lack of cytotoxicity of MNPs-FA and MNPs was assessed both on MCF7 cells, used as a model tumor cell line, and on 16HBE, used as normal human cell model, by evaluating cell viability using MTS assay, while the preferential internalization of MNPs-FA into tumor cells rather that into normal cells was confirmed by the quantization of internalized iron oxide. Uptake studies were also performed in the presence of a permanent magnet in order to verify the synergistic effect of magnetic field in enhancing the internalization of magnetic nanoparticles. Finally, real-time confocal microscopy experiments were carried out to further confirmed that FA ligand enhances the MNPs-FA accumulation into cancer cell cytoplasm.

New hyaluronic acid based brush copolymers synthesized by atom transfer radical polymerization.

In this work, an efficient method for the synthesis of hyaluronic acid based brush copolymers using atom transfer radical polymerization (ATRP) has been reported. At first, two different hyaluronic acid (HA) based macroinitiators have been prepared and then they have been used for the polymerization via ATRP of hydrophilic or hydrophobic molecules carrying vinyl portions. In particular, by linking 2-bromo-2-methylpropionic acid (BMP) to the primary hydroxyl groups of tetrabutyl ammonium salt of HA (HA-TBA) or to amino groups of the ethylenediamino derivative of HA-TBA (HA-TBA-EDA), two macroinitiators (HA-TBA-BMP and HA-TBA-EDA-BMP) have been obtained. Then they have been used for the ATRP of poly(ethylene glycol) methacrylate (PEGMA), butyl methacrylate (BUTMA) or N-isopropylacrylamide (NIPAM) using a complex of Cu(I) and 2,2'-Bipyridyl (Bpy), as a catalyst. Both macroinitiators and final copolymers, named as HA-BMP-pPEGMA, HA-BMP-pBUTMA, HA-BMP-pNIPAM, HA-EDA-BMP-pPEGMA, HA-EDA-BMP-pBUTMA and HA-EDA-BMP-pNIPAM, have been characterized by spectroscopic analysis and size exclusion chromatography to confirm the success of the polymerization process.

PHEA-graft-polymethacrylate supramolecular aggregates for protein oral delivery.

Salmon calcitonin (sCT) is characterized by a poor oral availability. A new copolymer, ß-poly(N-2-hydroxyethyl)-graft-{N-2-ethylene[2-poly(methacrylic acid sodium salt)isobutyrate]}-d,l-aspartamide (PHEA-IB-p(MANa(+))), was designed for the oral administration of sCT through the formation of supramolecular aggregates (SAs) based on electrostatic interactions. Several sCT/PHEA-IB-p(MANa(+)) weight ratios were characterized by turbidimetry, DLS, zeta potential, and microscopy analysis. After the incubation of sCT/PHEA-IB-p(MANa(+)) complex with digestive enzymes, 10% (w/w) of loaded sCT was released in the native form. In vitro investigation was carried out to determine the copolymer effect on the permeability of sCT in Caco-2 cell monolayers. sCT pharmacokinetic profile and the pharmacodynamic effect on calcium plasma level were determined following an oral administration of the lead sCT/PHEA-IB-p(MANa(+)) SA (1/5 ratio) in rats. The SA yielded a marked prolongation of the sCT lowering calcium effect. The maximum decrease, 35% with respect the basal calcium plasma level at time 0 h, was achieved after 4h post-administration, and after 7 h, a decrease of 20% was still present. Differently, sCT yielded a transient calcium decrease that was completely restored after 5h. The higher bioavailability of sCT administered as SA was confirmed by the pharmacokinetic studies. In fact, the AUC and the Cmax were about 15 times higher for the sCT formulated as SA than the free sCT. This study indicates the potentials of PHEA-IB-p(MANa(+)) as carrier of sCT for oral delivery.

Folate-targeted supramolecular vesicular aggregates as a new frontier for effective anticancer treatment in in vivo model.

Supramolecular vesicular aggregates (SVAs), made up by self-assembling liposomes and polyasparthydrazide co-polymers conjugated to folic acid molecules were extensively investigated in this manuscript as potential active targeting formulation for anticancer drug delivery. Folate-targeted systems (FT-SVAs) were used to treat breast cancer and to further proof the potential in vivo administration of these systems for the therapeutic treatment for several aggressive solid tumors. The physicochemical and technological parameters of FT-SVAs are suitable for their potential in vivo administration. The chemotherapeutic activity of GEM-loaded FT-SVAs was increased during in vivo experiments. NOD-SCID mice bearing MCF-7 human xenograft is used as breast cancer model. The measurement of the volume and weight of tumor masses decreased when animal models are treated by using GEM-loaded FT-SVAs, compared to data obtained by using GEM-loaded mPEG-SUVs and the free form of GEM. An almost complete regression of the tumor (≈ 0.2 cm(3)) was observed in NOD-SCID mice bearing MCF-7 human xenografts treated by GEM-loaded FT-SVAs due to the noticeable improvement of GEM pharmacokinetic parameters provided by FT-SVAs with respect to native anticancer drug. The obtained data showed that supramolecular systems could represent an innovative drug delivery system by self-assembling liposomes and biocompatible polymers to be potentially used for anticancer treatment.

Peculiar mechanism of solubilization of a sparingly water soluble drug into polymeric micelles. Kinetic and equilibrium studies.

Complementary kinetic and equilibrium studies on the solubilization process of the sparingly water soluble tamoxifen (TAM) drug in polymeric aqueous solutions have been performed by using the spectrophotometric method. In particular, the amphiphilic copolymers obtained by derivatization of polymeric chain of poly(N-2-hydroxyethyl)-dl-aspartamide, PHEA, with poly(ethylene glycol)s, PEG (2000 or 5000 Da), and/or hexadecylamine chain, C16, namely PHEA-PEG2000-C16, PHEA-PEG5000-C16, PHEA-C16, have been employed. Preliminary to the kinetic and equilibrium data quantitative treatment, the molar absorption coefficient of TAM in polymeric micelle aqueous solution has been determined. By these studies the solubization sites of TAM into the polymeric micelles have been determined and the solubilization mechanism has been elucidated through a nonconventional approach by considering the TAM partitioned between three pseudophases, i.e., the aqueous pseudophase, the hydrophilic corona, and the hydrophobic core. The simultaneous solution of the rate laws associated with each step of the proposed mechanism allowed the calculation of the rate constants associated with the involved processes, the values of which are independent of both the copolymer concentration and nature, with the exception of the rate of the TAM transfer from the corona to the core. This has been attributed to the steric barrier, represented by the corona, which hampers the solubilization into the core. The binding constant values of the TAM to the hydrophilic corona of the polymeric micelles, calculated through the quantitative analysis of the equilibrium data, depend on the thickness of the hydrophilic headgroup, while those of the hydrophobic core are almost independent of the copolymer type. Further confirmation to the proposed solubilization mechanism has been provided by performing the kinetic and equilibrium measurements in the presence of PHEA-PEG2000 and PHEA-PEG5000 copolymers.