Susana Simões

Polymeric micelles for oral drug administration enabling locoregional and systemic treatments

Introduction: Amphiphilic block copolymers are recognized components of parenteral drug nanocarriers. However, their performance in oral administration has barely been evaluated to any great extent. Areas covered: This review provides an overview of the methods used to prepare drug-loaded polymeric micelles and to evaluate their stability in gastrointestinal (GI) fluids, and then analyzes in detail recent in vitro and in vivo results about their performance in oral drug delivery. Oral administration of polymeric micelles has been tested for a variety of therapeutic purposes, namely, to increase apparent drug solubility in the GI fluids and facilitate absorption, to penetrate in pathological regions of the GI tract for locoregional treatment, to carry the drug directly toward the blood stream minimizing presystemic loses, and to target the drug after oral absorption to specific tissue or cells in the body. Expert opinion: Each therapeutic purpose demands micelles with different performance regarding stability in the GI tract, ability to overcome physiological barriers and drug release patterns. Depending on the block copolymer composition and structure, a wealth of self-assembled micelles with different morphologies and stability can be prepared. Moreover, copolymer unimers can play a role in improving drug absorption through the GI mucosa, either by increasing membrane permeability to the drug and/or the carrier or by inhibiting drug efflux transporters or first-pass metabolism. Therefore, polymeric micelles can be pointed out as versatile vehicles to increase oral bioavailability of drugs that exhibit poor solubility or permeability and may even be an alternative to parenteral carriers when targeting is pursued.

Poloxamine-cyclodextrin-simvastatin supramolecular systems promote osteoblast differentiation of mesenchymal stem cells.

Osteogenic/osteoinductive systems combine simvastatin, poloxamine Tetronic 908 (T908) and α-cyclodextrins (αCDs) in a supramolecular network that enhances the solubility/stability of the simvastatin hydroxy acid form and synergistically promotes osteoblast differentiation. Incorporation of 5% αCD transforms dilute T908 solutions (as low as 2% copolymer) into gels, enhances the osteoinductive activity of T908, and provides simvastatin sustained release for more than one week, which results in higher and more prolonged alkaline phosphatase (ALP) activity. The performance of the intrinsically osteoinductive polypseudorotaxane scaffold can be easily tuned by modifying the concentrations of T908, αCD, and simvastatin in a certain range of values. Moreover, the use of affordable, stable materials that can be sterilized applying a conventional method make the supramolecular gels advantageous candidates as scaffolds to be applied in the critical defect using minimally invasive techniques.

Supramolecular gels of poly-α-cyclodextrin and PEO-based copolymers for controlled drug release.

The aim of this work was to prepare syringeable supramolecular gels of α-cyclodextrin-polymer (poly-αCD) with various poly(ethylene oxide) (PEO)-based copolymers, which can be suitable to form depots for controlled drug release. A series of water-soluble poly-αCDs was synthesized from αCD by crosslinking with epichlorohydrin in alkaline medium. The chemical composition of the polymers was characterized by NMR (αCD content>53%) and the molecular weight was evaluated using static light scattering (SLS). Supramolecular assemblies occurred by mixing poly-αCD (20-40% w/v) with a PEO-based polymer (i.e., PEG, Pluronic® F127 or Tetronic® 908) (10-15% w/v). Phase separation was observed and the αCD content in each phase was determined by means of the phenol-sulfuric acid colorimetric method. Formation of poly-αCD/PEO-based polymer 3D-supramolecular complexes was confirmed by diffusion-ordered NMR spectroscopy (DOSY) and X-ray diffractometry. The supramolecular assemblies showed good cytocompatibility against SAOS-2 cells and in the HET-CAM test. The supramolecular gels were able to sustain the release of vancomycin for at least 5 days at 37 °C, more efficiently than dispersions of each polymer component in separate. These results open new possibilities in the design of novel controlled delivery systems for the treatment of bone infections.

Syringeable Self-Assembled Cyclodextrin Gels for Drug Delivery

The design of syringeable cyclodextrin (CD) gels is a developing area in the drug delivery and tissue engineering fields, since they offer the possibility of being administered with minimally invasive maneuvers to form depots that can remain for prolonged time in the implantation site. Two different supramolecular systems can be obtained exploiting the capability of CDs to form inclusion complexes. (i) The threading of free CDs on certain blocks or side chains of copolymers leads to polypseudorotaxanes, which can assembly via regular stacking of the threaded CDs. The resultant assemblies can be reversible broken under a certain shear stress and reformed at rest, exhibiting thixotropy that enables the flow through the syringe and the gel recovery in the implantation site. (ii) CDs grafted to polymer chains can develop their ability to form inclusion complexes with complementary guest moieties in other polymeric structures. The result is a ladder- or zipper-like arrangement, which can be also broken and reformed under certain stress conditions. Both types of CDsupramolecular gels can load and stabilize a variety of drugs via interaction with available polymer functional groups or with the CDs that are not participating in other complexes. Moreover, since the complex formation depends on various external and internal variables of the body, the syringeable CD gels can also provide stimuli-responsive drug release. This review focuses on the two main types of syringeable CD gels, prepared via self-aggregation of poly(pseudo)rotaxanes and via zipper-like assembly of CD-functionalized and guest-functionalized macromolecules, and analyzes the mechanisms and variables involved in the gelling processes and the most recent applications in the drug delivery field.

Bone critical defect repair with poloxamine-cyclodextrin supramolecular gels.

The aim of this study was to evaluate the osteoinductive capacity of a poloxamine (Tetronic(®) 908, T) and α-cyclodextrin (αCD) supramolecular gel (T-CD) as scaffold in a critical size defect in rat calvaria. The T-CD gel was evaluated solely and after being loaded with simvastatin (SV) and bone morphogenetic protein (BMP-2) separately and in combinations in order to reduce the doses of the active substances. Three doses of SV (7.5, 75, 750 μg) and two doses of BMP-2 (3 and 6 μg) were tested. The histology and histomorphometrical analysis showed improved bone repair with T-CD compared to T, probably due to better release control of both SV and BMP-2. In addition, as T-CD eroded more slowly than poloxamine alone, it remained longer in the defect site. Although synergism was not obtained with BMP-2 and SV, according to the observed regeneration of the defect, the dose of BMP-2 and SV can be reduced to 3 μg and 7.5 μg, respectively.

Why most oral insulin formulations do not reach clinical trials.

Oral insulin able to induce an efficient antihyperglycemic effect either to replace or complement diabetes mellitus therapy is the major goal of health providers, governments and diabetic patients. Oral therapy is associated not only with the desire to exclude needles from the daily routine of diabetic patient but also with the physiological provision of insulin they would get. Despite numerous efforts over the past few decades to develop insulin delivery systems, there is still no commercially available oral insulin. The reasons why the formulations developed to administer insulin orally fail to reach clinical trials are critically discussed in this review. The principal features of nanoformulations used so far are also addressed as well as the undergoing clinical trials.

Molecular interaction governing solubility and release profiles in supramolecular systems containing fenbufen, pluronics and cyclodextrins

In this work, the combination of two solubilizing agents, methyl-beta-cyclodextrin and Pluronic F68, is proposed and analyzed for a sparingly water soluble drug, fenbufen. Despite the large solubility enhancement achieved, ca. 70-fold, the synergistic effect promoted by the combination of these agents, is only effective over a narrow concentration range, being replaced by a competition between the drug and hydrophobic blocks of the copolymer when the concentration of the latter increases. Moreover, the detailed analysis of the release profiles, resorting to a model dependent approach, shows that the combination of these agents is a strong modulator of the overall profile and also of the total amount of drug that is released. Molecular dynamics simulation indicates a significant change in the cyclodextrin behavior, when alone in solution, situation in which the collapse of the conical structure is relatively frequent, or in the presence of each of the other components, and also shows that copolymer extension is decreased upon introduction of the drug, while there is an increase in extension when the cyclodextrin is added. Inclusion complexes are detected for both drug and copolymer. These play a definite role in solubilization by cyclodextrins, but are also responsible for the competitive behavior observed when polymeric micelles are present. Hydrophobic block copolymers compete with the drug for the cyclodextrin cavity through the formation of polypseudorotaxanes, which in turn modulates drug release. From the fundamental point of view, this work presents an in depth analysis of the molecular behavior in these systems, focusing on the cyclodextrin, inclusion complexes, polymeric micelles and supramolecular systems.

In vivo biodistribution of antihyperglycemic biopolymer-based nanoparticles for the treatment of type 1 and type 2 diabetes

Graphical abstract Biodistribution of insulin‐loaded alginate/dextran sulfate‐based nanoparticles dual coated with chitosan and 99mTc‐albumin after oral administration. The comparison of the oral antihyperglycemic effect between type 1 and type 2 diabetic models after the intraperitoneal glucose tolerance test revealed that the effect lasted longer in the type 1 model and that the glycemia increased to a greater extend in the type 2 model. No caption available. Abstract This study aimed to assess the biodistribution of antihyperglycemic insulin‐loaded alginate/dextran sulfate‐based nanoparticles dual coated with chitosan and technetium‐99m‐albumin (99mTc‐BSA) after oral administration. The oral administration of 50 IU/kg insulin‐loaded nanoparticles to type 1 diabetic rats showed prolonged antihyperglycemic effects up to 12 h and relative pharmacological availability of 5.04% comparing to the subcutaneous administration. The oral antihyperglycemic effect was further compared between type 1 and type 2 diabetic models by the intraperitoneal glucose tolerance test, revealing that the effect lasted longer in the type 1 diabetic model. 99mTc‐BSA revealed to be a good nanoparticles’ tracer since there was no systemic absorption and 99mTc‐BSA‐nanoparticles were capable of increasing their residence time in the intestinal epithelium of balb‐c mice when compared with 99mTc‐BSA biodistribution. Thus, this biopolymeric‐based delivery nanoparticulate system is a promising tool for the therapy of type 1 and type 2 diabetic individuals and prevention of T1D.

Mucoadhesive Buccal Systems as a Novel Strategy for Anti-Inflammatory Drugs Administration

This is a review article that intends to emphasize the advantages of buccal delivery as an alternative route of administration of anti-inflammatory drugs. The oral cavity has a number of features that make it desirable for drug administration: a rich blood supply that drains directly into the jugular vein, thus bypassing the liver and sparing the drug from first pass metabolism. To understand this point of view, some considerations are done relatively to the oral mucosal structural characteristics with relevance to drug administration, oral mucosal permeability, as well as drug absorption mechanisms through oral cavity. However, to design a buccal delivery system, it is necessary to take in account the residence time of drug formulation in the buccal mucosa. Mucoadhesion mechanism can be a solution to overcome this limitation. For this reason the main buccoadhesive pharmaceutical forms are approached, as well as the importance of oral mucosal in buccal anti-inflammatory drug delivery systems in terms of future perspectives.

Modulation of Angiogenic Activity by Light-Activatable miRNA-Loaded Nanocarriers

The combinatorial delivery of miRNAs holds great promise to modulate cell activity in the context of angiogenesis. Yet, the delivery of multiple miRNAs with spatiotemporal control remains elusive. Here, we report a plasmonic nanocarrier to control the release of two microRNAs. The nanocarrier consists of gold nanorods modified with single-stranded DNA for hybridization with complementary DNA-conjugated microRNAs. DNA strands with distinct melting temperatures enable the independent release of each microRNA with a near-infrared laser using the same wavelength but different powers. Tests in human outgrowth endothelial cells (OECs) indicate that this system can be used to silence different targets sequentially and, by doing so, to modulate cell activity with spatiotemporal resolution. Finally, using an in vivo acute wound healing animal model, it is demonstrated that the order by which each miRNA was released in transplanted OECs significantly impacted the wound healing kinetics.