In this work, the capability of two polymeric drugdeliverysystems (DDS) containing racemic ibuprofen (IBU) for controlled release of IBU in different media was studied carrying out assays in-vitro. To quantitatively monitor the release of R(2)- and S(1)-IBU, a fast, sensitive and inexpensive capillary electrophoresis (CE) method was developed. To do this, different chiral selectors, temperatures, buffer compositions and pHs were tested. This new CE method uses bare silica columns together with a buffer containing 6% Dextrin in a 150 mM sodium tetraborate buffer at pH 9. Baseline separations of R(2)- and S(1)-IBU were achieved in less than 5 min at 208C. By using this method, both enantiomers can be determined at concentrations as low as 1 mg / ml, allowing the detection of enantiomeric percentages of 0.5% of R(2)-IBU in the presence of 99.5% of the optical antipode. Moreover, the method shows a high reproducibility for the same day and different days. The usefulness of this method to quantitatively monitor the release of R(2)- and S(1)-IBU from two different polymeric DDS is demonstrated. It is shown that the release rate of IBU depends on the spacer of the side residue used in the polymeric device. Also, it is demonstrated that the release of both enantiomers is enzymatically activated in rat plasma. 2002 Elsevier Science B.V. All rights reserved.
Water confined in molecular size domains, i.e. pores, channels, and cavities, is different to bulk water. 176 In pure liquid water and ice, the sp 3 oxygen creates a tetrahedral coordination geometry with each water molecule, H-bonded to four others. In confined spaces, water structure is disturbed due to the partial loss of hydrogen bonding within water molecules, and the interactions of water molecules with surface molecular components of the confinement system. Disturbed hydrogen bond clusters and networks of water molecules are ubiquitous in nature, where they are involved in cell organization and water transport through pores and channels that regulate water homeostasis. 177 The physicochemical properties of confined water are also of extremely important for emerging water purification technologies. 178 Therefore, there is a widespread interest in understanding the factors that control the structure and dynamic properties of confined water at a supramolecular scale. 179 Molecular entrapment of water in synthetic porous or channel systems offer a way to explore the properties of confined water; self-assembly of molecular crystals is, among others, a successful strategy for organizing well-defined solid structures having voids or pores with controlled dimensions. 180
As the traditional drugdeliverysystems (DDSs) often as- sociated with many side effects, there as an always require- ment of approaches to develop new formulations for trans- porting medicine at required level when it needed. This type of on demand basis drugdelivery also called smart drugdelivery or intelligent drugdelivery. These novel techniques enhance the therapeutic values and also reduce various side effects. In comparison to the conventional DDSs, the smart controlled DDSs can effectively reduce the dosage frequency, while maintaining the drug concentra- tion in targeted organs/tissues for a longer period of time. In this sense, the controlled DDSs provide broad insights and fascinating properties for decreasing drug concentra- tion fluctuation, reducing drug toxicities and improving therapeutic efficacy. 1
This work focus on two alternatives of controlleddrugdeliverysystems, dendrimers and liposomes, with potential use as carriers of highly active drugs like pristimerin. We reported the synthesis, purification strategies, and characterization of several compounds as key building blocks for the synthesis of site-‐specific dendrimers formed by 2,2-‐bis (hydroxymethyl) propanoic acid (bis-‐MPA) as a branching molecule, pristimerin as an anticancer drug model; folic acid (FA) to provide selectivity to folate receptors overexpressed in cancer cells; and fluorescein isothiocyanate (FITC), as a fluorescent dye, for future evaluation as cancer treatment.. They represent the most important molecules in the synthetic pathway, since the dendritic architecture comes from the condensation in the next steps. In this way, this work contributes to the advancement in the obtention of the final conjugates.
Abstract: Controlleddelivery of gene transfer vectors is a powerful strategy to enhance the temporal and spatial presentation of therapeutic agents in a defined target. Hydrogels are adapted biomaterials for gene delivery capable of acting as a localized depot of genes while maintaining the long term local availability of DNA vectors at a specific location. Supramolecular hydrogels based on cyclodextrins (CDs) have attracted considerable attention as potential biomaterials in a broad range of drugdelivery applications. Their unique characteristics of thixotropicity and low cytotoxicity due to their production under mild conditions make them potential candidates to form injectable deliverysystems. This work aims to provide an overview of the use of CD-based polypseudorotaxane hydrogels as controlled gene deliverysystems for different applications in regenerative medicine.
Abstract—Controlled release systems for drugs, hormones and growth factors can be particularly useful in tissue repair processes. These systems act as a biodegradable support containing the substance to be delivered, allowing their gradual release. In the past years, the local application of growth factors has acquired special relevance as a therapeutic option for use in subjects who show de cient tissue scarring, the hormone dose being the limiting factor for its success. In this study, the in vitro biocompatibility of a copolymer formed by vinylpyrrolidone and 2-hydroxyethyl methacrylate, used as an administration vehicle for hGH, was evaluated. The system was then tested in vivo in terms of its capacity for healing incisional wounds in healthy and diabetic rats. For the in vitro studies, polymer and hormone degradation rates were determined, and polymer biocompatibility was evaluated in broblast cultures. In the in vivo experiments, an incision was made in the back of the animals, and polymers discs with/ without hGH, were introduced in the aperture. Morphological, immunohistochemical and morphometric evaluations were performed on wound tissue specimens 3– 10 days after surgery. In vitro, the polymer was found to be biodegradable and showed no toxic effects on broblasts, the hormone being slowly released to the culture medium. In untreated diabetic rats, a delayed skin scarring and cell response were observed, compared to that noted in healthy animals. Skin closure, keratinisation and brosis occurred earlier in the presence of the polymer-hGH system. The use of this co-polymer as an administration vehicle for hGH improves the wound scarring process in the pathological setting of diabetes.
SMEDDS are a promising approach for the formulation of drugs with poor aqueous solubility. The oral delivery of hydrophobic drugs can be made possible by SMEDDS, which have been shown to substantially improve oral Bio- availability. As mentioned above, numerous studies have confirmed that SMEDDS substantially improved solubil- ity/dissolution, absorption and bioavailability of poorly water-soluble drugs; some of such drugs are listed in Table 3. As improvements or alternatives of conventional liquid SMEDDS, S-SMEDDS are superior in reducing production cost, simplifying industrial manufacture, and improving stability as well as patient compliance. Most importantly, S- SMEDDS are very flexible to develop various solid dosage forms for oral and parenteral administration. Moreover, GI irritation is avoidable and controlled/sustained release of drug is achievable. There is still a long way to go, however, before more solid SME dosage forms (except for SME cap- sules) appear on the market. Because there exist some fields of S-SMEDDS to be further exploited, such as studies about human bioavailability and correlation of in vitro/in vivo.
Depot-based PCL systems have been also proposed for cancer treatment with very promising results. As an example, a bleomycin depot based on PCL microparticles was evaluated in vivo in tumor-bearing mice. Interestingly, upon subcutaneous injection, the biodegradable depot-forming PCL microspheres controlleddrug release and significantly suppressed the tumor growth kinetics compared to control 41 . An injectable PTX-polymer paste formulation based on a random copolymer of PLA and PCL with PEG, blended with MePEG was proposed for the treatment of prostate tumors. This PTX-loaded copolymer was administered intratumoraly into non-metastatic human prostate LNCaP tumor-bearing mice. The administration of this PTX-loaded paste induced a decrease in the serum prostate-specific antigen (PSA) levels and in the tumor volume in comparison to the blank paste. No significant toxicity but minor ulceration at the injection site was observed 42 . Finally, an injectable and in situ forming drugdelivery system based on photocrosslinked poly(ε-caprolactone fumarate) networks loaded with tamoxifen citrate (TC) were evaluated against MCF-7 breast cancer cell line. The cytotoxicity assay showed that while this photocrosslinked network exhibited no significant cytotoxicity against MCF-7 cells, ≈ 60 % of the MCF-7 cells were killed after incubation with TC-loaded devices 43 .
The fibronectin type III domain (Fn3), which binds the integrin αvβ3, has also been fused to ELR diblocks . The self-assembly behaviour of the resulting constructs was studied through the bioproduction of ELRs with different hydrophilic and hydrophobic block lengths. The result was an increase in the uptake of ELR with Fn3 in comparison with the unimers in a transfected human leukaemia cell line overexpressing the integrin αvβ3 (K562/αvβ3). In a later study, a qualitative breakthrough in the design of ELR diblocks fused to functional peptides was accomplished. Thus, Chilkoti’s group constructed an ELR-based drug carrier termed nanopeptifier, that was able to improve cellular uptake by controlled exposure of CPPs, which toggled in response to the application of external mild hyperthermia (Figure 3) . The construct (Arg8-ELRBC- cBH3) was genetically engineered to possess a CPP (Arg8) at the N-terminus and the therapeutic payload peptide cBH3 (derived from the proapoptotic Bak protein) located at the C- terminus. The therapeutic cBH3 peptide was separated by an RVRR peptide linker cleavable by furin and cathepsin B proteases. The nanopeptifiers are soluble at physiological temperature (37 °C), whereas under of mild hyperthermia conditions (42 °C) they self-assemble into spherical micelles displaying a high density of CPP on their corona and with cBH3 located in the micelle core. Although some uptake of the nanopeptifier occurs at 37 °C, when the temperature is increased to 42 °C this cell uptake increases dramatically. Once the complex is internalized, the action of either furin (localized in the trans-Golgi) or cathepsin B (early and late endosomes and lysosomes) favours release of the cBH3 load. Increases of up to 130 arbitrary cell fluorescence units were found to induce the therapeutic effect of cBH3. Its therapeutic action was assessed by activation of caspase-3, which is involved in apoptotic processes. Thus, the nanopeptifier was able to create a cytotoxic switch that induces apoptosis only when it is in the micelle conformation.
therapeutic agent at a predetermined, zero order delivery rate based on the principle of Osmosis, which is movement of a solvent from lower concentration of solute towards higher concentration of solute across a semi-permeable membrane. After administration of osmotic system, water is imbibed into the core osmotically through semi-permeable membrane resulting in development of hydrostatic pressure that pumps drug containing solution or suspensions out of the core through one or more delivery ports. The delivery from the system is controlled by the water influx through semi-permeable membrane. 3 one of the most rate
SUMMARY . The self-microemulsifying drugdelivery system (SMEDDS) was employed to improve the bioavailability of sulpiride, a drug which is poorly soluble. The mean droplet size and emulsification time of the test formulation used for in vivo study were 9.27 ± 2.02 nm and 87 ± 5 s, respectively. When com- pared with Reference (Dogmatil®), the test formulation exhibited faster in-vitro drug release rate. The C max and AUC values of the test formulation were significantly higher than those of Reference, with an
Results. Many of the drugs employed for the treatment of neurodegenerative diseases are not capable of going through the blood-brain-barrier (BBB) and reach the brain with enough concentration, being unable to apply their therapeutic effect. That is why the idea of developing polymeric nanoparticles to be delivered through nasal delivery come out. Thanks to the use of this system, many researches have shown an improvement in the clinical utility of the drug, reducing the dose and the frequency of dosing as well as the side effects.
A main strategy of regenerative medicine is the construction of a biocompatible scaffold that, in combination with living cells and/or bioactive molecules, replaces, regenerates or repairs damaged cells or tissue. Numerous studies, using nanostructured materials, have demonstrated the validity of this approach for a variety of cell types and the application in regenerating different tissues (such as cardiac, bone, cartilage, skin, bladder, nervous and vascular) by enhancing the biological properties of the cells such as cell adhesion, cell mobility and cell differentiation [3,39–42]. In the in vivo condition the cells are located in three-dimensional (3D) microenvironments, where they are surrounded by other cells and by the extracellular matrix (ECM), whose components, such as collagen, elastin, and laminin, are organized in nanostructures (i.e., fibers, triple helixes, etc.) with specific bioactive motifs that regulate the cell homeostasis. It is therefore essential to develop scaffolds that create synthetic microenvironments providing 3D support, so as to control and direct the cellular behavior and to promote specific cell interactions [43,44]. The goal of nanomaterial-directed stem cell culture is to mimic the properties, both physical and biochemical, of the physiological stem cell niche. Electrospinning is a widely used technique for the production of nanofibers that offers great flexibility in terms of the choice of scaffold material, as well as finer control over the scaffold geometry [45–47]. In the electrospinning process, nanofibres are created as polymeric jets from the surface of a polymeric solution in a high intensity electrostatic field when the electric field overcomes the polymer surface tension. Modulation of spinning parameters such as flow rate and collecting distance, and polymer solution properties such as solvent, concentration, conductivity, and surface tension, properties of the resultant nanofibrous meshes, such as fibre diameter, porosity, mechanical properties and surface topography can be easily controlled [48,49]. Moreover, additional functionalities can be incorporated via protein coatings, or chemical conjugation of specific signalling molecules with great utility in SCs-based therapy . The development of these nanoscaffold-based therapy methods in combination with SCs is an important tool for tissue engineering and regenerative medicine.
DOPE-Rho. Specific pRBC targeting was achieved as previously described 23 through functionalization of the liposomes with the monoclonal antibody BM1234 raised against the P. falcipar- um-expressed membrane-associated histidine-rich protein 1. 8 The results obtained with P. falciparum cultures containing RBCs and 5% pRBCs (Figure 2) showed that targeted liposome-administered lipids were specifically delivered to pRBCs and after 90 min of incubation colocalized with intracellular parasites. The observation of diffuse fluorescence and the lack of punctate patterns characteristic of whole intact liposomes 8 suggests that upon contact with the pRBC plasma membrane, liposomes fused with the cell and their constituent lipids were incorporated by the growing parasites. Whole liposome entry into pRBCs might theoretically occur through the reported tubulovesicular network induced by Plasmodium during its intraerythrocytic growth, 30 which extends from the parasitophorous vacuole membrane and connects the intracellu- lar parasite with the host RBC surface. However, this confers to the pRBC the capacity of internalizing a wide range of particles up to diameters of only 70 nm, 30,31 well below the mean size of the liposomes used here (N140 nm, Figure S1). Higher resolution images of cells prepared at earlier stages in the drugdelivery process revealed phenomena consistent with the interaction of liposomes with pRBCs immediately before or just after their constituent lipids are incorporated into the cell plasma membrane (Figure 3).
In the light of the chronobiologic and chronopathologic findings, this study attempts to design and evaluate chronomodulated pul- satile drugdelivery system consisting of imper- meable capsule body, which contains the drug and is closed by an erodible tablet plug. It was aimed to have a lag time of five h i.e., the sys- tem is taken at bed time and expected to release the drug after a period of 5 h (around 2.00 am) when the asthma attacks are more prevalent. The lag time (t 10 ) was defined as intersection
Deep brain stimulation (DBS) is a surgical procedure approved for the treatment of select patients with movement disorders, such as Parkinson’s disease, essential tremors, and dystonia. DBS uses electricity to neuromodulate abnormal brain circuits found on these disorders to improve patient’s symptomatology. In almost 30 years, DBS has shown to be an effective therapy, however, it is not free of side effects. New technological advances have been aimed to improve clinical benefits and at the same time, minimize side effects. In this review, we discuss recent technological innovations in DBS along with the future direction of the field. We describe new DBS systems labeled “smart” devices, promising electrode designs, and newly defined methods to deliver electrical stimulation to the brain.
of TB cases were of pulmonary TB unaided and soaring drug dose has essential to be managed since merely little slice of the entire dose reaches the lungs. Anti Tubercular drugs delivery system which could be delivered using the respiratory route alongside with canister evade the daily dosing since they can help out in: (i) Express drug deliv- ery to the unhealthy person; (ii) The targeting of alveolar macrophages which have uses via the mycobacteria while a secure place for their extended survival; (iii) reduced sys- temic toxicity of the drugs; and (iv) improved patient com- pliance .Furthermore in distinction the oral route of admin- istration and inhaled drugs were not subjected to first pass metabolism.It is not gratified for the reason that could not steadily reside in the lung. 10-12 Silk fibroin show advanced