Improving in vivo oral bioavailability of a poorly soluble drug: a case study on polymeric versus lipid nanoparticles.

Poorly soluble drugs must be appropriately formulated for clinical use to increase the solubility, dissolution rate, and permeation across the intestinal epithelium. Polymeric and lipid nanocarriers have been successfully investigated for this aim, and their physicochemical properties, and in particular, the surface chemistry, significantly affect the pharmacokinetics of the drugs after oral administration. In the present study, PLGA nanoparticles (SS13NP) and solid lipid nanoparticles (SS13SLN) loaded with SS13, a BCS IV model drug, were prepared. SS13 bioavailability following the oral administration of SS13 (free drug), SS13NP, or SS13SLN was compared. SS13NP had a suitable size for oral administration (less than 300 nm), a spherical shape and negative zeta potential, similarly to SS13SLN. On the contrary, SS13NP showed higher physical stability but lower encapsulation efficiency (54.31 ± 6.66%) than SS13SLN (100.00 ± 3.11%). When orally administered (0.6 mg of drug), SS13NP showed higher drug AUC values with respect to SS13SLN (227 ± 14 versus 147 ± 8 µg/mL min), with higher Cmax (2.47 ± 0.14 µg/mL versus 1.30 ± 0.15 µg/mL) reached in a shorter time (20 min versus 60 min). Both formulations induced, therefore, the oral bioavailability of SS13 (12.67 ± 1.43% and 4.38 ± 0.39% for SS13NP and SS12SLN, respectively) differently from the free drug. These in vivo results confirm that the chemical composition of nanoparticles significantly affects the in vivo fate of a BCS IV drug. Moreover, PLGA nanoparticles appear more efficient and rapid than SLN in allowing drug absorption and transport to systemic circulation.

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.

Crocetin as New Cross-Linker for Bioactive Sericin Nanoparticles.

The nose-to-brain delivery route is used to bypass the blood-brain barrier and deliver drugs directly into the brain. Over the years, significant signs of progress have been made in developing nano-drug delivery systems to address the very low drug transfer levels seen with conventional formulations (e.g., nasal solutions). In this paper, sericin nanoparticles were prepared using crocetin as a new bioactive natural cross-linker (NPc) and compared to sericin nanoparticles prepared with glutaraldehyde (NPg). The mean diameter of NPc and NPg was about 248 and 225 nm, respectively, and suitable for nose-to-brain delivery. The morphological investigation revealed that NPc are spherical-like particles with a smooth surface, whereas NPg seem small and rough. NPc remained stable at 4 °C for 28 days, and when freeze-dried with 0.1% w/v of trehalose, the aggregation was prevented. The use of crocetin as a natural cross-linker significantly improved the in vitro ROS-scavenging ability of NPc with respect to NPg. Both formulations were cytocompatible at all the concentrations tested on human fibroblasts and Caco-2 cells and protected them against oxidative stress damage. In detail, for NPc, the concentration of 400 µg/mL resulted in the most promising to maintain the cell metabolic activity of fibroblasts higher than 90%. Overall, the results reported in this paper support the employment of NPc as a nose-to-brain drug delivery system, as the brain targeting of antioxidants is a potential tool for the therapy of neurological diseases.

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.

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.

Solid Lipid Nanoparticles as Formulative Strategy to Increase Oral Permeation of a Molecule Active in Multidrug-Resistant Tuberculosis Management.

The role of mycobacterial efflux pumps in drug-resistant tuberculosis has been widely reported. Recently, a new compound, named SS13, has been synthesized, and its activity as a potential efflux inhibitor has been demonstrated. In this work, the chemical-physical properties of the SS13 were investigated; furthermore, a formulative study aimed to develop a formulation suitable for oral administration was performed. SS13 shows nonintrinsic antitubercular activity, but it increases the antitubercular activity of all the tested drugs on several strains. SS13 is insoluble in different simulated gastrointestinal media; thus, its oral absorption could be limited. Solid lipid nanoparticles (SLNs) were, therefore, developed by using two different lipids, Witepsol and/or Gelucire. Nanoparticles, having a particle size (range of 200-450 nm with regards to the formulation composition) suitable for intestinal absorption, are able to load SS13 and to improve its permeation through the intestinal mucosa compared to the pure compound. The cytotoxicity is influenced by the concentration of nanoparticles administered. These promising results support the potential application of these nanocarriers for increasing the oral permeation of SS13 in multidrug-resistant tuberculosis management.

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.

Biodegradable Microspheres as Intravitreal Delivery Systems for Prolonged Drug Release. What is their Eminence in the Nanoparticle Era?

Drug administration to the posterior segment of the eye has many challenges due to the natural barriers and consequent problems of low and unpredictable bioavailability. There is an increasing need for managing severe posterior eye diseases, such as age-related macular degeneration, diabetic retinopathy, etc. Most of these diseases, if left untreated, lead to blindness. Traditional ocular formulations and topical administrations are almost inefficient and the drug delivery to the back of the eye requires direct administrations through intravitreal injections of innovative drug delivery systems. These systems must be easily injectable, able to release the drug for a prolonged period of time (to overcome the problem of repeated administrations) and made of biodegradable/biocompatible polymers. Among these delivery systems, microspheres still have an important role. This overview wants to highlight the use of microspheres as intravitreal systems to overcome the challenges of back of the eye diseases. Studies have shown that microspheres are able to enhance the intravitreal half-life and thus bioavailability of many drugs, protecting them from degradation. Furthermore, personalized therapies can be made by changing the amount of administered microspheres. This review focuses on the materials (polymers) used for the preparation of the microparticulate systems and comparative remarks are made with respect to the use of nanoparticles.

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.

Intranasal Delivery of Genistein-Loaded Nanoparticles as a Potential Preventive System against Neurodegenerative Disorders.

Genistein has been reported to have antioxidant and neuroprotective activity. Despite encouraging in vitro and in vivo results, several disadvantages such as poor water solubility, rapid metabolism, and low oral bioavailability limit the clinical application of genistein. The aim of this study was to design and characterize genistein-loaded chitosan nanoparticles for intranasal drug delivery, prepared by the ionic gelation technique by using sodium hexametaphosphate. Nanoparticles were characterized in vitro and their cytotoxicity was tested on PC12 cells. Genistein-loaded nanoparticles were prepared, and sodium hexametaphosphate was used as a valid alternative to well-known cross-linkers. Nanoparticle characteristics as well as their physical stability were affected by formulation composition and manufacturing. Small (mean diameters of 200⁻300 nm) and homogeneous nanoparticles were obtained and were able to improve genistein penetration through the nasal mucosa as compared to pure genistein. Nanoparticle dispersions showed a pH consistent with the nasal fluid and preserved PC12 cell vitality.