Next generation of selenocyanate and diselenides with upgraded leishmanicidal activity.

Nowadays, leishmaniasis is still treated with outdated drugs that present several obstacles related to their high toxicity, long duration, parenteral administration, high costs and drug resistance. Therefore, there is an urgent demand for safer and more effective novel drugs. Previous studies indicated that selenium compounds are promising derivatives for innovative therapy in leishmaniasis treatment. With this background, a new library of 20 selenocyanate and diselenide derivatives were designed based on structural features present in the leishmanicidal drug miltefosine. Compounds were initially screened against promastigotes of L. major and L. infantum and their cytotoxicity was evaluated in THP-1 cells. Compounds B8 and B9 were the most potent and less cytotoxic and were further screened for the intracellular back transformation assay. The results obtained revealed that B8 and B9 showed EC50 values of 7.7 µM and 5.7 µM, respectively, in L. major amastigotes, while they presented values of 6.0 µM and 7.4 µM, respectively, against L. infantum amastigotes. Furthermore, they exerted high selectivity (60 < SI > 70) towards bone marrow-derived macrophages. Finally, these compounds exhibited higher TryR inhibitory activity than mepacrine (IC50 7.6 and 9.2 µM, respectively), and induced nitric oxide (NO) and reactive oxygen species (ROS) production in macrophages. These results suggest that the compounds B8 and B9 could not only exert a direct leishmanicidal activity against the parasite but also present an indirect action by activating the microbicidal arsenal of the macrophage. Overall, these new generation of diselenides could constitute promising leishmanicidal drug candidates for further studies.

Norbornene and Related Structures as Scaffolds in the Search for New Cancer Treatments.

The norbornene scaffold has arisen as a promising structure in medicinal chemistry due to its possible therapeutic application in cancer treatment. The development of norbornene-based derivatives as potential chemotherapeutic agents is attracting significant attention. Here, we report an unprecedented review on the recent advances of investigations into the antitumoral efficacy of different compounds, including the abovementioned bicyclic scaffold in their structure, in combination with chemotherapeutic agents or forming metal complexes. The impact that structural modifications to these bicyclic compounds have on the antitumoral properties and the mechanisms by which these norbornene derivatives act are discussed in this review. In addition, the use of norbornene, and its related compounds, encapsulation in nanosystems for its use in cancer therapies is here detailed.

Repurposing the Antibacterial Agents Peptide 19-4LF and Peptide 19-2.5 for Treatment of Cutaneous Leishmaniasis.

The lack of safe and cost-effective treatments against leishmaniasis highlights the urgent need to develop improved leishmanicidal agents. Antimicrobial peptides (AMPs) are an emerging category of therapeutics exerting a wide range of biological activities such as anti-bacterial, anti-fungal, anti-parasitic and anti-tumoral. In the present study, the approach of repurposing AMPs as antileishmanial drugs was applied. The leishmanicidal activity of two synthetic anti-lipopolysaccharide peptides (SALPs), so-called 19-2.5 and 19-4LF was characterized in Leishmania major. In vitro, both peptides were highly active against intracellular Leishmania major in mouse macrophages without exerting toxicity in host cells. Then, q-PCR-based gene profiling, revealed that this activity was related to the downregulation of several genes involved in drug resistance (yip1), virulence (gp63) and parasite proliferation (Cyclin 1 and Cyclin 6). Importantly, the treatment of BALB/c mice with any of the two AMPs caused a significant reduction in L. major infective burden. This effect was associated with an increase in Th1 cytokine levels (IL-12p35, TNF-α, and iNOS) in the skin lesion and spleen of the L. major infected mice while the Th2-associated genes were downregulated (IL-4 and IL-6). Lastly, we investigated the effect of both peptides in the gene expression profile of the P2X7 purinergic receptor, which has been reported as a therapeutic target in several diseases. The results showed significant repression of P2X7R by both peptides in the skin lesion of L. major infected mice to an extent comparable to that of a common anti-leishmanial drug, Paromomycin. Our in vitro and in vivo studies suggest that the synthetic AMPs 19-2.5 and 19-4LF are promising candidates for leishmaniasis treatment and present P2X7R as a potential therapeutic target in cutaneous leishmaniasis (CL).

Changes in the nanoparticle uptake and distribution caused by an intramacrophagic parasitic infection.

This study investigates if visceral leishmaniasis (VL) infection has some effects on the organ and cellular uptake and distribution of 100-200 nm near-infrared fluorescently labelled non-biodegradable polystyrene latex beads (PS NPs) or biodegradable polylactic-co-glycolic nanoparticles (PLGA NPs), as this parasitic infection produces morphological alterations in liver, spleen and bone marrow, organs highly involved in NP sequestration. The results showed that the magnitude of the effect was specific for each organ and type of NP. With the exception of the liver, the general trend was a decrease in NP organ and cellular uptake, mostly due to immune cell mobilization and/or weight organ gain, as vascular permeability was increased. Moreover, NPs redistributed among different phagocytic cells to adapt infection associated changes and cellular alterations. In the liver, it is noteworthy that only isolated Kuffer cells (KCs) captured NPs, whereas they were not taken up by KC forming granulomas. In the spleen, NPs redistributed from macrophages and dendritic cells towards B cells and inflammatory monocytes although they maintained their preferential accumulation in the marginal zone and red pulp. Comparatively, the infection rarely affected the NP cellular distribution in the bone marrow. NP cellular target changes in VL infection could affect their therapeutic efficacy and should be considered for more efficient drug delivery.

New Amides and Phosphoramidates Containing Selenium: Studies on Their Cytotoxicity and Antioxidant Activities in Breast Cancer.

Breast cancer is a multifactor disease, and many drug combination therapies are applied for its treatment. Selenium derivatives represent a promising potential anti-breast cancer treatment. This study reports the cytotoxic activity of forty-one amides and phosphoramidates containing selenium against five cancer cell lines (MCF-7, CCRF-CEM, HT-29, HTB-54 and PC-3) and two nonmalignant cell lines (184B5 and BEAS-2B). MCF-7 cells were the most sensitive and the selenoamides I.1f and I.2f and the selenium phosphoramidate II.2d, with GI50 values ranging from 0.08 to 0.93 µM, were chosen for further studies. Additionally, radical scavenging activity for all the compounds was determined using DPPH and ABTS colorimetric assays. Phosphoramidates turned out to be inactive as radical scavengers. No correlation was observed for the antioxidant activity and the cytotoxic effect, except for compounds I.1e and I.2f, which showed dual antioxidant and antitumor activity. The type of programmed cell death and cell cycle arrest were determined, and the results provided evidence that I.1f and I.2f induced cell death via autophagy, while the derivative II.2d provoked apoptosis. In addition, Western blot analysis corroborated these mechanisms with an increase in Beclin1 and LC3-IIB and reduced SQSTM1/p62 levels for I.1f and I.2f, as well as an increase in BAX, p21 and p53 accompanied by a decrease in BCL-2 levels for derivative II.2d.

Nanoparticles from Gantrez® AN-poly(ethylene glycol) conjugates as carriers for oral delivery of docetaxel.

The oral delivery of docetaxel (DTX) is challenging due to a low bioavailability, related to an important pre-systemic metabolism. With the aim of improving the bioavailability of this cytotoxic agent, nanoparticles from conjugates based on the copolymer of methyl vinyl ether and maleic anhydride (poly(anhydride)) and two different types of PEG, PEG2000 (PEG2) or methoxyPEG2000 (mPEG2), were evaluated. Nanoparticles, with a DTX loading close to 10%, were prepared by desolvation and stabilized with calcium, before purification and lyophilization. For the pharmacokinetic study, nanoparticles were orally administered to mice at a single dose of 30 mg/kg. The plasma levels of DTX were high, prolonged in time and, importantly, quantified within the therapeutic window. The relative oral bioavailability was calculated to be up to 56% when DTX was loaded in nanoparticles from poly(anhydride)-mPEG2000 conjugate (DTX-NP-mPEG2). Finally, a comparative toxicity study between equitoxic doses of free iv DTX and oral DTX-NP-mPEG2 was conducted in mice. Animals orally treated with DTX-loaded nanoparticles displayed less severe signs of hypersensitivity reactions, peripheral neurotoxicity, myelosuppression and hepatotoxicity than free iv docetaxel. In summary, poly(anhydride)-PEG conjugate nanoparticles appears to be adequate carries for the oral delivery of docetaxel.

Synthesis and Leishmanicidal Activity of Novel Urea, Thiourea, and Selenourea Derivatives of Diselenides.

A novel series of thirty-one N-substituted urea, thiourea, and selenourea derivatives containing diphenyldiselenide entities were synthesized, fully characterized by spectroscopic and analytical methods, and screened for their in vitro leishmanicidal activities. The cytotoxic activity of these derivatives was tested against Leishmania infantum axenic amastigotes, and selectivity was assessed in human THP-1 cells. Thirteen of the synthesized compounds showed a significant antileishmanial activity, with 50% effective concentration (EC50) values lower than that for the reference drug miltefosine (EC50, 2.84 µM). In addition, the derivatives 9, 11, 42, and 47, with EC50 between 1.1 and 1.95 µM, also displayed excellent selectivity (selectivity index ranged from 12.4 to 22.7) and were tested against infected macrophages. Compound 11, a derivative with a cyclohexyl chain, exhibited the highest activity against intracellular amastigotes, with EC50 values similar to those observed for the standard drug edelfosine. Structure-activity relationship analyses revealed that N-aliphatic substitution in urea and selenourea is recommended for the leishmanicidal activity of these analogs. Preliminary studies of the mechanism of action for the hit compounds was carried out by measuring their ability to inhibit trypanothione reductase. Even though the obtained results suggest that this enzyme is not the target for most of these derivatives, their activity comparable to that of the standards and lack of toxicity in THP-1 cells highlight the potential of these compounds to be optimized for leishmaniasis treatment.

Combination of paromomycin plus human anti-TNF-α antibodies to control the local inflammatory response in BALB/ mice with cutaneous leishmaniasis lesions.

BACKGROUND: Cutaneous leishmaniasis (CL) skin lesions are the result of a deregulated immune response, which is unable to eliminate Leishmania parasites. The control of both, parasites and host immune response, is critical to prevent tissue destruction. The skin ulceration has been correlated with high TNF-α level. OBJECTIVE: Because human anti-TNF-α antibodies (Ab) have been successfully assayed in several mice inflammatory diseases, we hypothesized that their anti-inflammatory effect could optimize the healing of CL lesions achieved after topical application of paromomycin (PM), the current chemotherapy against CL. METHODS AND RESULTS: We first compared the in vitro efficacy of PM and Ab alone and the drug given in combination with Ab to assess if the Ab could interfere with PM leishmanicidal activity in L. major-infected bone marrow-derived macrophages. The combination therapy had similar antileishmanial activity to the drug alone and showed no influence on NO production, which allows macrophage-mediated parasite killing. Next, we demonstrated in an in vivo model of Imiquimod®-induced inflammation that topical Ab and PM inhibit the infiltration of inflammatory cells in the skin. In the efficacy studies in L. major-infected BALB/c mice, PM combined with Ab led to a sharp infection reduction and showed a stronger anti-inflammatory activity than PM alone. This was confirmed by the down-regulation of TNF-α, IL-1ß, iNOS, IL-17, and CCL3 as well as by a decrease of the neutrophilic infiltrate during infection upon treatment with the Ab. CONCLUSIONS: In terms of parasite elimination and inflammation reduction, topical application of Ab in combination with PM was more effective than the drug alone.

Pegylated poly(anhydride) nanoparticles for oral delivery of docetaxel.

The aim of this work was to investigate the potential of pegylated poly(anhydride) nanoparticles to enhance the oral bioavailability of docetaxel (DTX). Nanoparticles were prepared after the incubation between the copolymer of methyl vinyl ether and maleic anhydride (Gantrez® AN), poly(ethylene glycol) (PEG2000 or PEG6000) and docetaxel (DTX). The oral administration of a single dose of pegylated nanoparticles to mice provided sustained and prolonged therapeutic plasma levels of docetaxel for up 48-72 h. In addition, the relative oral bioavailability of docetaxel was around 32%. The organ distribution studies revealed that docetaxel underwent a similar distribution when orally administered encapsulated in nanoparticles as when intravenously as Taxotere®. This observation, with the fact that the clearance of docetaxel when loaded into the oral pegylated nanoparticles was found to be similar to that of intravenous formulation, suggests that docetaxel would be released at the epithelium surface and then absorbed to the circulation.

Novel Heteroaryl Selenocyanates and Diselenides as Potent Antileishmanial Agents.

A series of new selenocyanates and diselenides bearing interesting bioactive scaffolds (quinoline, quinoxaline, acridine, chromene, furane, isosazole, etc.) was synthesized, and their in vitro leishmanicidal activities against Leishmania infantum amastigotes along with their cytotoxicities in human THP-1 cells were determined. Interestingly, most tested compounds were active in the low micromolar range and led us to identify four lead compounds (1h, 2d, 2e, and 2f) with 50% effective dose (ED50) values ranging from 0.45 to 1.27 µM and selectivity indexes of >25 for all of them, much higher than those observed for the reference drugs. These active derivatives were evaluated against infected macrophages, and in order to gain preliminary knowledge about their possible mechanism of action, the inhibition of trypanothione reductase (TryR) was measured. Among these novel structures, compounds 1h (3,5-dimethyl-4-isoxazolyl selenocyanate) and 2d [3,3'-(diselenodiyldimethanediyl)bis(2-bromothiophene)] exhibited good association between TryR inhibitory activity and antileishmanial potency, pointing to 1h, for its excellent theoretical ADME (absorption, distribution, metabolism, and excretion) properties, as the most promising lead molecule for leishmancidal drug design.

Oral delivery of camptothecin using cyclodextrin/poly(anhydride) nanoparticles.

Camptothecin (CPT), a molecule that shows powerful anticancer activity, is still not used in clinic due to its high hydrophobicity and poor active form's stability. In order to solve these drawbacks, the combination between poly(anhydride) nanoparticles and cyclodextrins was evaluated. CPT-loaded nanoparticles, prepared in the presence of 2-hydroxypropyl-ß-cyclodextrin, (HPCD-NP) displayed a mean size close to 170nm and a payload of 50µg per mg (25 times higher than the one of the control nanoparticles). CPT was not released from nanoparticles under gastric conditions. However, under intestinal conditions, about 50% of the drug content was released as a burst, whereas the remained drug was released following a zero-order kinetic. Pharmacokinetic studies revealed that the CPT plasma levels, from orally administered nanoparticles, were high and sustained up to 48h. The CPT oral bioavailability was 7-fold higher than the value obtained with the control, whereas its clearance was significantly lower than for the aqueous suspension. These observations may be directly related to a prolonged residence time of nanoparticles in close contact with the intestinal epithelium, the presence of the cyclodextrin that decreases the CPT transformation into its inactive form and the generation of an acidic microenvironment during the degradation of the poly(anhydride) that would prevent the transformation of the active lactone into the inactive carboxylate conformation.

Molecular descriptors calculation as a tool in the analysis of the antileishmanial activity achieved by two series of diselenide derivatives. An insight into its potential action mechanism.

A molecular modeling study has been carried out on two previously reported series of symmetric diselenide derivatives that show remarkable antileishmanial in vitro activity against Leishmania infantum intracellular amastigotes and in infected macrophages (THP-1 cells), in addition to showing favorable selectivity indices. Series 1 consists of compounds that can be considered as central scaffold constructed with a diaryl/dialkylaryl diselenide central nucleus, decorated with different substituents located on the aryl rings. Series 2 consists of compounds constructed over a diaryl diselenide central nucleus, decorated in 4 and 4' positions with an aryl or heteroaryl sulfonamide fragment, thus forming the diselenosulfonamide derivatives. With regard to the diselenosulfonamide derivatives (2 series), the activity can be related, as a first approximation, with (a) the ability to release bis(4-aminophenyl) diselenide, the common fragment which can be ultimately responsible for the activity of the compounds. (b) the anti-parasitic activity achieved by the sulfonamide pharmacophore present in the analyzed derivatives. The data that support this connection include the topography of the molecules, the conformational behavior of the compounds, which influences the bond order, as well as the accessibility of the hydrolysis point, and possibly the hydrophobicity and polarizability of the compounds.

Controlled Release, Intestinal Transport, and Oral Bioavailablity of Paclitaxel Can be Considerably Increased Using Suitably Tailored Pegylated Poly(Anhydride) Nanoparticles.

The aim of the work was to evaluate in vitro and in vivo the effect of the addition of poly(ethylene glycol) (PEG) to paclitaxel (PTX)-cyclodextrin poly(anhydride) nanoparticles. For this, PTX in poly(anhydride) nanoparticles complexed with cyclodextrins (either 2-hydroxypropyl-ß-cyclodextrin or ß-cyclodextrin) and combined with PEG 2000 were prepared by the solvent displacement method. Intestinal permeability in vitro and in vivo pharmacokinetic studies in C57BL/6J mice were performed. Nanoparticle formulations containing PTX increased its apparent permeability through rat intestine in vitro in the Ussing chambers, enhancing its permeability 10-15 times compared with commercial Taxol®. In addition, in pharmacokinetic studies, drug plasma levels were observed for at least 24 h leading to a relative oral bioavailability between 60% and 80% for PTX complexed with cyclodextrin and loaded in pegylated poly(anhydride) nanoparticles after oral gavage. In all, PTX-cyclodextrin complexes encapsulated in pegylated nanoparticles managed to promote the intestinal uptake of the drug displaying sustained plasma levels after oral administration to laboratory animals with a more prolonged plasma profile compared with the formulation with no PEG at all. Therefore, pegylated poly(anhydride) nanoparticles represent a promising carrier for the oral delivery of PTX.

Pharmacokinetics and antitumor efficacy of paclitaxel-cyclodextrin complexes loaded in mucus-penetrating nanoparticles for oral administration.

AIM: The authors report a novel approach for enhancing the oral absorption of paclitaxel (PTX) by encapsulation in poly(anhydride) nanoparticles (NPs) containing cyclodextrins and poly(ethylene glycol). MATERIALS & METHODS: Formulations were prepared using the solvent displacement method. Subsequently, pharmacokinetics and organ distribution assays were evaluated after oral administration into C57BL/6J mice. In addition, antitumor efficacy studies were performed in a subcutaneous tumor model of Lewis lung carcinoma. RESULTS: PTX-loaded NPs displayed sizes between 190-300 nm. Oral NPs achieved drug plasma levels for at least 24 h, with an oral bioavailability of 55-80%. Organ distribution studies revealed that PTX, orally administered in NPs, underwent a similar distribution to intravenous Taxol(®) (Bristol-Myers Squibb, NJ, USA). For in vivo antitumor assays, oral strategy maintained a slower tumor growth than intravenous Taxol. CONCLUSION: PTX orally administered in poly(anhydride) NPs, combined with cyclodextrins and poly(ethylene glycol), displayed sustained plasma levels and significant antitumor effect in a syngenic tumor model of carcinoma in mice.

Thermosensitive hydrogels of poly(methyl vinyl ether-co-maleic anhydride) - Pluronic(®) F127 copolymers for controlled protein release.

Thermosensitive hydrogels are of a great interest due to their many biomedical and pharmaceutical applications. In this study, we synthesized a new series of random poly (methyl vinyl ether-co-maleic anhydride) (Gantrez(®) AN, GZ) and Pluronic(®) F127 (PF127) copolymers (GZ-PF127), that formed thermosensitive hydrogels whose gelation temperature and mechanical properties could be controlled by the molar ratio of GZ and PF127 polymers and the copolymer concentration in water. Gelation temperatures tended to decrease when the GZm/PF127 ratio increased. Thus, at a fixed GZm/PF127 value, sol-gel temperatures decreased at higher copolymer concentrations. Moreover, these hydrogels controlled the release of proteins such as bovine serum albumin (BSA) and recombinant recombinant kinetoplastid membrane protein of Leishmania (rKMP-11) more than the PF127 system. Toxicity studies carried out in J774.2 macrophages showed that cell viability was higher than 80%. Finally, histopathological analysis revealed that subcutaneous administration of low volumes of these hydrogels elicited a tolerable inflammatory response that could be useful to induce immune responses against the protein cargo in the development of vaccine adjuvants.

PLGA nanoparticles loaded with KMP-11 stimulate innate immunity and induce the killing of Leishmania.

We recently demonstrated that immunization with polyester poly(lactide-co-glycolide acid) (PLGA) nanoparticles loaded with the 11-kDa Leishmania vaccine candidate kinetoplastid membrane protein 11 (KMP-11) significantly reduced parasite load in vivo. Presently, we explored the ability of the recombinant PLGA nanoparticles to stimulate innate responses in macrophages and the outcome of infection with Leishmania braziliensis in vitro. Incubation of macrophages with KMP-11-loaded PLGA nanoparticles significantly decreased parasite load. In parallel, we observed the augmented production of nitric oxide, superoxide, TNF-α and IL-6. An increased release of CCL2/MCP-1 and CXCL1/KC was also observed, resulting in macrophage and neutrophil recruitment in vitro. Lastly, the incubation of macrophages with KMP-11-loaded PLGA nanoparticles triggered the activation of caspase-1 and the secretion of IL-1ß and IL-18, suggesting inflammasome participation. Inhibition of caspase-1 significantly increased the parasite load. We conclude that KMP-11-loaded PLGA nanoparticles promote the killing of intracellular Leishmania parasites through the induction of potent innate responses. FROM THE CLINICAL EDITOR: In this novel study, KMP-11-loaded PLGA nanoparticles are demonstrated to promote the killing of intracellular Leishmania parasites through enhanced innate immune responses by multiple mechanisms. Future clinical applications would have a major effect on our efforts to address parasitic infections.

Molecular buckets: cyclodextrins for oral cancer therapy.

The oral route is preferred by patients for drug administration due to its convenience, resulting in improved compliance. Unfortunately, for a number of drugs (e.g., anticancer drugs), this route of administration remains a challenge. Oral chemotherapy may be an attractive option and especially appropriate for chronic treatment of cancer. However, this route of administration is particularly complicated for the administration of anticancer drugs ascribed to Class IV of the Biopharmaceutical Classification System. This group of compounds is characterized by low aqueous solubility and low intestinal permeability. This review focuses on the use of cyclodextrins alone or in combination with bioadhesive nanoparticles for oral delivery of drugs. The state-of-the-art technology and challenges in this area is also discussed.

Towards development of novel immunization strategies against leishmaniasis using PLGA nanoparticles loaded with kinetoplastid membrane protein-11.

BACKGROUND: Vaccine development has been a priority in the fight against leishmaniases, which are vector-borne diseases caused by Leishmania protozoa. Among the different immunization strategies employed to date is inoculation of plasmid DNA coding for parasite antigens, which has a demonstrated ability to induce humoral and cellular immune responses. In this sense, inoculation of plasmid DNA encoding Leishmania kinetoplasmid membrane protein-11 (KMP-11) was able to confer protection against visceral leishmaniasis. However, recently the use of antigen delivery systems such as poly(lactic-co-glycolic acid) (PLGA) nanoparticles has also proven effective for eliciting protective immune responses. METHODS: In the present work, we tested two immunization strategies with the goal of obtaining protection, in terms of lesion development and parasite load, against cutaneous leishmaniasis caused by L. braziliensis. One strategy involved immunization with plasmid DNA encoding L. infantum chagasi KMP-11. Alternatively, mice were primed with PLGA nanoparticles loaded with the recombinant plasmid DNA and boosted using PLGA nanoparticles loaded with recombinant KMP-11. RESULTS: Both immunization strategies elicited detectable cellular immune responses with the presence of both proinflammatory and anti-inflammatory cytokines; mice receiving the recombinant PLGA nanoparticle formulations also demonstrated anti-KMP-11 IgG1 and IgG2a. Mice were then challenged with L. braziliensis, in the presence of sand fly saliva. Lesion development was not inhibited following either immunization strategy. However, immunization with PLGA nanoparticles resulted in a more prominent reduction in parasite load at the infection site when compared with immunization using plasmid DNA alone. This effect was associated with a local increase in interferon-gamma and in tumor necrosis factor-alpha. Both immunization strategies also resulted in a lower parasite load in the draining lymph nodes, albeit not significantly. CONCLUSION: Our results encourage the pursuit of immunization strategies employing nanobased delivery systems for vaccine development against cutaneous leishmaniasis caused by L. braziliensis infection.

Nanomedicine: novel approaches in human and veterinary therapeutics.

Nanomedicine can be defined as the application of nanotechnology to the prevention and treatment of diseases as well as for diagnosis purposes. In this context, the development of various types of drug-carrier nanodevices offers new strategies for targeted drug delivery, minimising the secondary effects and the toxicity associated to drug widespread to healthy organs or cells. This review is divided in two different parts. The first one summarizes the main types of nanomedicines developed in the past few decades, including drug nanocrystals, polymer therapeutics, lipid-nanosized and polymeric-nanosized drug delivery systems. The second part of our review is devoted, more specifically, to the presentation of polymeric nanoparticles. Here, we discuss various aspects of nanoparticle formulation, characterization, behaviour in the body and some of their potential applications. More particularly we present some approaches for the treatment of cancer, treatment of infectious diseases and the potential of these nanoparticles as adjuvants for vaccination purposes.

Cyclodextrin-poly(anhydride) nanoparticles as new vehicles for oral drug delivery.

INTRODUCTION: The oral administration of drugs belonging to Class IV of the Biopharmaceutical Classification System (BCS) represents a major challenge. These drugs display poor aqueous solubility and specific permeability characteristics. Most of these compounds are substrates of the P-glycoprotein and/or the cytochrome P450. Among other types of drug, various anti-cancer drugs also suffer from these drawbacks (i.e., paclitaxel), which limits the possibilities for developing oral treatments. AREAS COVERED: This review discusses the factors that influence the bioavailability of drugs when administered by the oral route, as well as the capabilities of cyclodextrins when associated with nanoparticles. In particular, evidence is given regarding the synergistic effect between cyclodextrins and bioadhesive nanoparticles, on the oral delivery of pharmaceuticals. EXPERT OPINION: This article aims to provide an overview of the multiple gains in incorporating cyclodextrins in poly(anhydride) nanoparticles, including improvement of their bioadhesive capability, the loading of lipophilic drugs and the effect on efflux membrane proteins and cytochrome P450. The combination between bioadhesive nanoparticles and P-gp inhibitors without pharmacological activity (i.e., cyclodextrins) may be useful to promote the oral bioavailability of drugs ascribed to Class IV of the BCS.