As the traditional drugdelivery systems (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
Equation 6 describes the drugdelivery kinetics and it is only valid for the first 60% of the fractional release. For thin disks when n is equal to 0.5 the drug is said to diffuse with Fickian behavior. For n = 1 the behavior is called Case II diffusion, controlled by the relaxation of the macromolecular chains. Finally, anomalous transport behavior, which is intermediate between Fickian and Case II, is known as non-Fickian diffusion  . In our case the n value of 0.67 points
Chemotherapy agents have little or no specificity over cancer cells, resulting in low therapeutic concentrations at the tumor site (a consequence of a broad systemic distribution), and severe side effects. With the aim of avoiding cancer therapy failure, several approaches such as design of new anticancer drugs, chemical engineering of conventional drugs and development of drugdelivery systems have been proposed. The objective is to enhance drug localization at the tumor region (by controlling its biodistribution profile) and, therefore, to increase the anti-tumor efficacy (even in multi-drug resistant tumors), while reducing systemic side effects. One of the most promising approaches to the problem is the development of drug nanocarriers based on the polymer poly( ε -caprolactone). In this review we will focus our attention on these polymeric colloids, particularly on the most significant characteristics and formulation procedures, and on their use as nanoplatforms for the delivery of chemotherapy agents to the tumor site. Furthermore, the most recent in vitro and in vivo investigations on the subject are extensively reviewed.
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).
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
After evaluating the plug material and the capsule content separately, the complete pul- satile drugdelivery system was investigated next. It consisted of formaldehyde treated cap- sule body containing theophylline, lactose the filler mixed with 15% of effervescent agents and erodible tablet plug having different composi- tion. The effect of different plug composition on theophylline release is shown in Figure 3. The release profiles revealed pulsatile characteristics. The lag time (t10) for the formulations contain- ing 4, 8, 12, 16 and 20% of HPMC K100LV in tablet plug was 0.2 h, 2 h, 3.2 h, 5.1 h and 6.35 h, respectively. Increasing the concentration of HPMC K100LV in tablet plug resulted in increase in lag time. In accordance with the chronomod- ulated therapy of asthma, the lag time criterion of 5 h was satisfied by formulation containing 16% of HPMC K100LV.
Chemical cross-linking can be used as another method for the development of thermo-responsive microgel capsules (MCs) with potential applications in drugdelivery. This approach permits shape-stable microspheres, the pore size of which can be reversibly tuned by increasing or lowering the temperature, thereby modifying the permeability to drugs, to be obtained. In a first example of this technology, a mixture of ELR and albumin at different ratios was cross-linked, with the resulting system showing shape stability and changes in the surface structure of the MCs depending on whether the temperature was above or below the Tt. In the first case, the release of BSA and prednisone acetate, both used as model drugs, was faster than in the latter. Optimal release was found in the temperature range 20-40 °C . ELR/BSA MCs were subsequently produced by a two-step cross- linking method. The ability of these microcapsules to release a drug was evaluated using two similar fluorophores, namely rhodamine B (red) and FITC (green), this latter possessing a negative charge, thus showing a charge-independent release of both molecules from the MCs. Similarly to the previous work, release of the cargo molecules was faster when the temperature was raised above Tt, and vice versa . Dual microparticles consisting of two different biomaterials, namely ELR-chitosan or alginate-chitosan, have also been designed as a proof-of-concept methodology following a layer-by-layer approach and found to have potential as drug- delivery systems . Further studies with the ELR-chitosan microparticles involved recombinant functionalization of the ELR with the RGD cell-adhesion sequence for integrins. These particles, with a size of 3-4 μm, were loaded with fluorescently labelled DQ-ovoalbumin as a model protein and used to supplement the medium in human mesenchymal stem cells (hMSCs) culture for 72 h. The findings of this study showed them to be non-cytotoxic, with improved internalization of the protein to the cytoplasm than in the case of the non-functionalized (non-RGD) ELR-chitosan microparticles, as evidenced by DQ-ovoalbumin degradation, which results in a shift in fluorescence emission. Thus, this strategy suggests the utilization of microparticles formed by different biocompatible macromolecules as carriers for drugdelivery .
Methods: To that aim, from the web sites of PubMed, HCAplus, Thomson, and Registry were used as the main sources to perform the search for the most significant research articles published on the subject. The information was then carefully analyzed, highlighting the most important results in the formulation and development of self-micro emulsifying drugdelivery systems as well as its therapeutic activity. Results: Self-emulsifying drugdelivery system (SMEDDS) has gained more attention due to enhanced oral bio-availability enabling reduction in dose, more consistent temporal profiles of drug absorption, selective targeting of drug(s) toward specific absorption window in GIT, and protection of drug(s) from the unreceptive environment in gut.
Silk-like proteins (SLPs) are another type of recombinant material with demonstrated success in biomedical applications [124, 125]. These biopolymers are designed taking into account the repetitive peptide sequences found in silkworm and spider silk. The most common of all silk variants is probably the hexapeptide GAGAGS from Bombyx mori fibroin, although recombinant spider silk has also been used in nanoparticles for gene and drugdelivery [126, 127]. In aqueous solution, these silk-derived polymers undergo an essentially irreversible conformation transition from random coil to beta sheet and a subsequent beta sheet aggregation growth accelerated by an increase in temperature. The good biocompatibility and biodegradability shown by these materials, and particularly the mechanical strength of the resulting aggregation products, stimulated the design of chimeric materials such as silk-elastin like recombinamers (SELR). There are many examples of the use of SELRs in drugdelivery and these have been extensively reviewed in the last few years [9, 128, 129]. However, very few studies reporting the synthesis of SELR-derived nanoparticles have been published [130-133]. These studies demonstrated that the self-assembly of SELR into spherical nanoparticles is a process in which the length of the silk block determines both the kinetics and the size of the aggregates. Thus, an initial temperature-driven aggregation mediated by the elastin block forms nanoparticles (around 40 nm in diameter) that then self-assemble into a nanofibrillar morphology in an annealing time-dependent manner (Figure 5). This coordinated and concomitant dual-gelation mechanism leads to the final maturation into a resistant hydrogel made of the fibrous structures when the concentration of the material and annealing time are appropriate [131, 133]. Consequently, the use of SELRs in nanocarrier synthesis for drugdelivery has excellent potential but requires more in-depth studies of the production procedures and choice of the final target.
The results obtained in this study clearly show that the anhydride groups of the alternating vinylpyrrolidone- maleic anhydride copolymer reacts efficiently with ali- phatic amines to give a hemiamide. The conversion does not change with the length of the alkyl chain. Therefore, this reaction provides a way to obtain hydrophobically modified polyelectrolytes by adding an alkyl side chain with no change in the number of carboxylic groups. More- over, the PMAVP-R-n copolymers provide a hydrophobic environment in aqueous solution, in which the drug model shows a spontaneous tendency to remain associated with the polymeric aggregates. Thus, these intrapolymer mi- celles may be used as potential reservoirs of pharmacologi- cal agents, such as nitroimidazoles.
method incorporating HPMC K4M, xanthan gum, guar gum, sodium bicarbonate and tartaric acid as gas generating agent. The influence of independent variables like, polymer: polymer ratio, polymer type and tartaric acid on floating lag time and cephalexin release profile were studied. The diffusion exponent (n) of Krosmeyer Peppas for optimized formulation was found to be 0.635 which indicates the mechanism of drug release was anomalous transport. Floating lag time of optimized formulation was 1.50 min and remained buoyant for 24 hrs. Optimized formulation was checked for stability at 40ºC / 75% RH which was found to be stable. Scanning electron microscopy study revealed gel formation. FT-IR studies revealed that there was no chemical interaction between cephalexin and other excipients.
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
We showed that the cisplatin-induced toxicity was clearly reduced using AuNPs-cisplatin. It is known that pharmacokinetic properties depend on physicochemical properties of the carrier rather than on the ones of the drug. Thus, instead of the widespread distribution observed for free cisplatin, AuNPs-cisplatin showed the typical accumulation in the organs of the mononuclear phagocytic system (i.e. liver and spleen) largely reported in the literature. Interestingly conjugated cisplatin was diverted from the kidneys, which contributed to the absence of histopathological damage, namely absence of proximal tubular degeneration and nephrosis, as observed in treatment with free cisplatin. Moreover, toxicity in the spleen and liver was also discarded by histology analysis as well as by normal levels of several biomarkers. Also body weight, which is indicative of systemic toxicity, was maintained in normal values along the treatment, except for a temporal decrease after injection. All the data indicates that cumulative toxic effect of cisplatin is avoided, which would allow to continue the treatment for longer times or to change the strategy of administration. Thus, we demonstrated a reduction of toxicity of a very effective drug that is still limited by its side effects without affecting its efficacy. This would help to improve the efficiency of the treatment with cisplatin since classic treatment has to be often stopped before the full benefits of the treatment are reached due to toxicity issues.
Hence, methylation on the terminal amino group on our SIL should lead to an increase of the reaction rate in comparison with the non-methylated analogue (Scheme 5.3, R”). Conversely, squaramate ester 14b successfully evolved to the release of an ethanol molecule after the reduction of the disulfide bond. The Intracellular disulfide reshuffling is an extensively used strategy for intracellular drug release. 206 Despite the overall redox potential in the human blood is oxidative, there are some reductive cellular environments. 207 Thus, the presence of reductive species bearing free thiolates such as glutathione, 208 dithiothreitol 209 or cysteine 208b may promote the thiol-disulfide exchange. The redox process is spontaneous and fast, and undergo efficient intracellular decomposition of the disulfide SIL. Figure 5.2 shows a general structure of a disulfide SIL (a). When the disulfide disassembles through shuffling, the resulting free thiolate attacks the electrophilic moiety which normally is a carbonyl group. Such linkage
mechanical properties and tunable degradation rates rang- ing from weeks to months in vivo due to control of excellent biocompatibility, crystallinity with low inflammatory and immunogenic response, and all aqueous material process- ing alternative to form films, gels, fibers, microspheres and sponges . For drugdelivery, particularly protein drugs, silk materials exhibit controllable drug release kinetics and high encapsulation efficiency due to the crystalline beta-sheet formation. 13-16 There are several techniques available for the
Moreover, use of NPs, as delivery system, could be the best choice for bone regeneration, as there is no need for long-term overexpression of bone morphogenetic proteins (BMP) to induce valid bone formation. Transient overexpression of protein for a few weeks is sufficient to initiate the regeneration process. Indeed, many studies have shown the potential for MSCs that transiently overexpress BMP to induce bone formation on nanofibres  and chitosan-coated BMP-2 NPs . Furthermore, several types of NPs were used as a delivery system to induce cartilage regeneration. Thus, for the safe and stable delivery of genes and to induce chondrogenesis, biodegradable PLGA NPs were used to mediate SOX9 gene delivery in hMSCs . In addition, Park et al.  employed polycationic polymer, PEI polyplexed with a combination of SOX5, 6, and 9 fused to fluorescent protein coated onto PLGA NPs. SOX trio complexed with PEI-modified PLGA NPs led to a dramatic increase of hMSCs chondrogenesis in vitro culture systems. Recently, in the field of adipogenesis a systematic study in rat mesenchymal stem cells (RMSC) demonstrated that the biocompatible silica NP-insulin (SiNP) conjugates induce in vitro adipogenic differentiation . Moreover, the biological activity of insulin conjugated to the SiNPs was not affected and the SiNPs could be used as biocompatible carriers of insulin for RMSC adipogenic differentiation, which would help to expand the new potential application of SiNPs in stem cell research. In addition, Yang et al.  achieved an efficient adipogenic differentiation of hMSC, in vitro as well of in vivo transplanted cells, using the adipogenic transcription factors C/EBP-α and C/EBP-β complexed with PEI coupled with biodegradable PLGA nanospheres. The expression of specific adipogenic genes and proteins in hMSCs was significantly elevated compared to the controls.
Schatzlein and colleagues (2005) studied the transfection activity of polypropy- lenimine dendrimers and the effect of the strength of the electrostatic interaction between carrier and DNA on gene transfer. They evaluated the in vivo gene transfer activity of low molecular weight, non-amphiphilic plain and quaternary ammonium gene carriers and concluded that the polypropylenimine dendrimers were promising systems, which may be used in gene targeting. Recently Namazi and Adeli (2005) applied citric acid–polyethylene glycol–citric acid triblock dendrimers as biocom- patible compounds for drug-delivery. They investigated the controlled release of molecules and drugs in vitro conditions and reported that the drug/dendrimer complexes were stable while the drugs were not released after storage at room temperature for about 10 months. Marano and co-workers (2004) described the synthesis of lipid–lysine dendrimers and their ability to deliver sense oligonu- cleotide ODN-1 to its target. It is important to mediate the reduction in VEGF concentration both in vitro and in vivo during ocular neovascularisation. They demonstrated that lipophilic, charged dendrimer mediated delivery of ODN-1 resulted in the down-regulation of in vitro VEGF expression. Time course studies showed that the dendrimer/ODN-1 complexes remained active for up to two months indicating the dendrimer compounds provided protection against the nucleases. Ooya and colleagues (2003) developed systems to increase the aqueous solubility of paclitaxel (PTX), a poorly water-soluble drug. They reported that graft and star-shaped graft polymers consisting of poly (ethylene glycol) (PEG 400) graft chains increased the PTX solubility in water by three orders of magnitude. Polyg- lycerol dendrimers dissolved in water at high concentrations without significantly increasing the viscosity and by increasing the solubility of PTX while the release rate was found as a function of the star shape and the dendrimer generation. Rittner and co-workers (2002) studied the design of basic amphiphilic peptides, ppTG1 and ppTG20 (20 amino acids), and evaluated their efficiencies in vitro and in vivo as single-component gene transfer vectors. Based on the structure–function studies, and sequence variants, they suggested that the high gene transfer activity of these peptides was correlated with their propensity to exist in -helical conformation, which seems to be strongly influenced by the nature of the hydrophobic amino acids.
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.