Triggered Drug Delivery Systems Research Articles

Near-infrared light remote-controlled intracellular anti-cancer drug delivery using thermo/pH sensitive nanovehicle

Stimuli-responsive drug delivery systems have been developed to enhance the tumor-targeting drug transportation and minimize the severe side effects along with the chemotherapy. In this study, a near-infrared (NIR) light triggered drug delivery system was developed based on the amphiphilic chitosan derivative-coated single-wall carbon nanotubes (CNT) encapsulated in the thermo/pH sensitive nanogel (CS/PNIPAAm@CNT). The PEG diacrylate (Mw=250Da) was applied in the present work to tune the nanoparticles with the phase transition temperature at ∼38°C, which was an attempt to match the prerequisite for the in vivo applications. Owing to the π–π stacking, hydrophobic interaction and the opportunity of Schiff-base formation between chitosan and doxorubicin (DOX), the nanoparticles possessed a relative high drug loading capacity (∼43%). The DOX loaded CS/PNIPAAm@CNT released DOX faster at 40°C than at 25°C, meanwhile faster at pH 5.0 in comparison with that at pH 7.4. Moreover, the rapid and repetitive release of DOX was observed when the DOX-loaded CS/PNIPAAm@CNT was irradiated under NIR light. Furthermore, DOX-loaded CS/PNIPAAm@CNT upon NIR irradiation showed significantly greater cytotoxicity in HeLa cells owing to NIR-triggered increase in temperature and enhanced DOX release. Confocal laser scanning microscopy (CLSM) was utilized to demonstrate the enhanced cell uptake of the as prepared nanoparticles and the faster drug release under the NIR irradiation and lower pH. All the results suggest that multifunctional DOX-loaded CS/PNIPAAm@CNT nanocomposite is a promising therapeutic nanocarrier for intracellular drug delivery with great potential for targeted cancer therapy.

Hydrazone-bearing PMMA-functionalized magnetic nanocubes as pH-responsive drug carriers for remotely targeted cancer therapy in vitro and in vivo.

To develop vehicles for efficient chemotherapeutic cancer therapy, we report a remotely triggered drug delivery system based on magnetic nanocubes. The synthesized magnetic nanocubes with average edge length of around 30 nm acted as cores, whereas poly(methyl methacrylate) (PMMA) was employed as an intermediate coating layer. Hydrazide was then tailored onto PMMA both for doxorubicin (DOX) loading and pH responsive drug delivery via the breakage of hydrazine bonds. The successful fabrication of the pH responsive drug carrier was confirmed by transmission electron microscopy, Fourier transform infrared spectroscopy, thermogravimetric analysis, and magnetic hysteresis loops, respectively. The carrier was stable at neutral environment and doxorubicin released at pH of 5.0. Cell viability assay and confocal laser scanning microscopy observations demonstrated that the loaded DOX could be efficiently released after cellular endocytosis and induced cancer cells apoptosis thereby. More importantly, the carrier could be guided to the tumor tissue site with an external magnetic field and led to efficient tumor inhibition with low side effects, which were reflected by magnetic resonance imaging (MRI), change of tumor size, TUNEL staining, and H&E staining assays, respectively. All results suggest that hydrazide-tailoring PMMA-coated magnetic nanocube would be a promising pH-responsive drug carrier for remotely targeted cancer therapy in vitro and in vivo.

A Magnetic Nanoparticle Stabilized Gas Containing Emulsion for Multimodal Imaging and Triggered Drug Release

To develop a multimodal imaging guided and triggered drug delivery system based on a novel emulsion formulation composed of iron oxide nanoparticles, nanoscopic bubbles, and oil containing drugs. Iron oxide paramagnetic nanoparticles were synthesized and modified with surface conjugation of polyethylenimide (PEI) or Bovine Serum Albumin (BSA). Both particles were used to disperse and stabilize oil in water emulsions containing coumarin-6 as the model drug. Sulfur hexafluoride was introduced into the oil phase to form nanoscopic bubbles inside the emulsions. The resulted gas containing emulsions were evaluated for their magnetic resonance (MR) and ultrasound (US) imaging properties. The drug release profile triggered by ultrasound was also examined. We have successfully prepared the highly integrated multi-component emulsion system using the surface modified iron oxide nanoparticles to stabilize the interfaces. The resulted structure had distinctive MR and US imaging properties. Upon application of ultrasound waves, the gas containing emulsion would burst and encapsulated drug could be released. The integrated emulsion formulation was multifunctional with paramagnetic, sono-responsive and drug-carrying characteristics, which may have potential applications for disease diagnosis and imaging guided drug release.

Stimuli-responsive biodegradable poly(methacrylic acid) based nanocapsules for ultrasound traced and triggered drug delivery system

Ultrasound contrast agents (UCAs) have been investigated for echogenic intravenous drug delivery system. Due to the traditional UCAs with overlarge size (micro-scale), their reluctant accumulation in target organs and the instability have presented severe obstacles to the accurate response to the ultrasound and severely limited their further clinical application. Furthermore, elimination of drug carriers from the biologic system after their carrying out the diagnostic or therapeutic functions is one important aspect to be considered. The drug carriers with large sizes, avoiding renal filtration, will lead to increasing toxicity. In this present paper, we design and develop a new type of triple-stimuli responsive (ultrasound/pH/GSH) biodegradable nanocapsules, in which fill up with perfluorohexane, and the DOX-loaded PMAA with disulfide crosslinking forms the wall. These soft nanocapsules with uniform size of 300 nm can easily enter the tumor tissues via EPR effects. The PMAA shell has high DOX-loading content (36 wt%) and great drug loading efficiency (93.5%), the PFH filled can effectively enhance US imaging signal through acoustic droplet vaporization (ADV), ensuring diagnostic and image-guided therapeutic applications. What is more, the disulfide-crosslinked PMAA shell is biodegradable and thus safe for normal organisms. These merits enabled us optimize the balance of diagnostic, therapeutic and biodegradable functionalities in a multifunctional theranostic nanoplatform.

Development and characterization of size controlled polymeric microcapsules loaded with superparamagnetic nanoparticles

AbstractBiocompatible polymeric microcapsules encapsulated Fe3O4 nanoparticles were fabricated by double emulsion solvent evaporation method. Magnetic nanoparticles were synthesized by coprecipitation of iron oxide. scanning electron microscopy, transmission electron microscope, fourier transform infrared spectroscopy, X‐ray diffraction spectroscopy, and vibrating sample magnetometer were used to determine the morphology, structure, crystallinity, and saturation magnetization of the microcapsules, respectively. The results indicate that the composite microcapsules have nitrogen gas in the core, Fe3O4 in the internal cavity with mean diameter of 3.6 μm. Thus, the alcohol as additive was applied to control the average size and size distribution of the microcapsules. Laser particle analyzer measurements indicate that the average size and size distribution decrease with the increasing of alcohol concentration, additionally the size and size distribution increase at higher alcohol concentration. Moreover, the prepared magnetic microcapsules with the coating of polymer have superparamagnetic behavior. Furthermore, the size controlled polymeric composite microcapsules have potential to act as ultrasound contrast agents and magnetic triggered drug delivery system. POLYM. COMPOS., 2013. © 2013 Society of Plastics Engineers

Magnetic Heating of Iron Oxide Nanoparticles and Magnetic Micelles for Cancer Therapy

The inclusion of magnetic nanoparticles into block copolymer micelles was studied towards the development of a targeted, magnetically triggered drug delivery system for cancer therapy. Herein, we report the synthesis of magnetic nanoparticles and poly(ethylene glycol-b-caprolactone) block copolymers, and experimental verification of magnetic heating of the nanoparticles, self-assembly of the block copolymers to form magnetic micelles, and thermally-enhanced drug release. The semicrystalline core of the micelles melted at temperatures just above physiological conditions, indicating that they could be used to release a chemotherapy agent from a thermo-responsive polymer system. The magnetic nanoparticles were shown to heat effectively in high frequency magnetic fields ranging from 30-70 kA/m. Magnetic micelles also showed heating properties, that when combined with a chemotherapeutic agent and a targeting ligand could be developed for localized, triggered drug delivery. During the magnetic heating experiments, a time lag was observed in the temperature profile for magnetic micelles, likely due to the heat of fusion of melting of polycaprolactone micelle cores before bulk solution temperatures increased. Doxorubicin, incorporated into the micelles, released faster when the micelles were heated above the core melting point.

Smart nanocarriers for pH-triggered targeting and release of hydrophobic drugs

The use of hybrid pH-sensitive micelles based mainly on the (PEO)129(P2VP)43(PCL)17 ABC miktoarm star copolymer as potential triggered drug delivery systems was investigated. Co-micellization of this star copolymer with a second copolymer labeled by a targeting ligand, i.e. biotin, on the pH sensitive block (poly-2-vinylpyridine) is considered here in order to impart possible active targeting of the tumor cells. Two architectures were studied for these labeled copolymers, i.e. a miktoarm star or a linear ABC terpolymer, and the respective hybrid micelles are compared in terms of cytotoxicity (cells viability) and cellular uptake (using fluorescent dye loaded micelles). Finally, the triggered drug release in the cytosol of tumor cells was investigated by studying, on the one hand, the lysosomal integrity after internalization and, on the other hand, the release profile in function of the pH.

Ultrasound triggered drug release from 10-hydroxycamptothecin-loaded phospholipid microbubbles for targeted tumor therapy in mice

Ultrasound targeted microbubble destruction (UTMD) was one of the most promising strategies to enhance drug delivery in cancer therapy. Microbubbles (MBs) serve as a vehicle to carry anti-tumor drugs and locally release them when exposed to therapeutic ultrasound, resulting in drug accumulation in tumor tissues and enhanced anti-tumor effect. However the ultrasound triggered drug delivery system has been seriously limited due to the poor loading capacity of MBs. Here we present a new strategy to overcome the low drug payload of MBs for ultrasound guided drug delivery. In this study, we developed a novel microbubble carrying 10-HCPT which only needs a particularly low single dose of injection (4–6mg) for tumor therapy in clinical application, therefore, the required high dosing of drug loaded MBs for ultrasound mediated drug delivery is not necessary. We subsequently investigated the combination of ultrasound application with HLMs to achieve therapeutic effect on tumor at a feasible dose of MBs. HLMs were manufactured with a high drug encapsulation and loading content and simultaneously maintained the acoustic properties as an ultrasound contrast agent. After that, tumor-bearing mice were routinely and non-invasively administered with HLMs through the tail vein and were then exposed to ultrasound, resulting in a remarkable drug accumulation in tumor tissues and a significant increase in tumor inhibition rate (70.6%) compared with HLMs alone (47.8%) as well as commercial HCPT injection (49.4). In conclusion, HLMs are expected to improve the therapeutic efficacy of MBs and are worthy of further study for UTMD mediated drug delivery.

Polymer Micelles with Crystalline Cores for Thermally Triggered Release

Interest in the use of poly(ethylene glycol)-b-polycaprolactone diblock copolymers in a targeted, magnetically triggered drug delivery system has led to this study of the phase behavior of the polycaprolactone core. Four different diblock copolymers were prepared by the ring-opening polymerization of caprolactone from the alcohol terminus of poly(ethylene glycol) monomethylether, M(n) ≈ 2000. The critical micelle concentration depended on the degree of polymerization for the polycaprolactone block and was in the range of 2.9 to 41 mg/L. Differential scanning calorimetry curves for polymer solutions with a concentration above the critical micelle concentration showed a melting endotherm in the range of 40 to 45 °C, indicating the polycaprolactone core was semicrystalline. Pyrene was entrapped in the micelle core without interfering with the ability of the polycaprolactone to crystallize. When the polymer solution was heated above the melting point of the micelle core, the pyrene was free to leave the core. Temperature-dependent measurements of the critical micelle concentration and temperature-dependent dynamic light scattering showed that the micelles remain intact at temperatures above the melting point of the polycaprolactone core.

Optical characterization of inidividual liposome-loaded microbubbles

Newly developed liposome-loaded (LPS) microbubbles [1] were characterized by comparing their oscillating response with standard phospholipid-shelled (BARE) microbubbles using the ultra-high speed imaging camera (Brandaris 128). 73 LPS bubbles and 41 BARE bubbles of diameters ranging from 3 μm to 10 μm were insonified by narrow band pulses with a driving frequency ranging from 0.5 MHz to 4 MHz and an acoustic pressure from 5 kPa to 100 kPa. Shell elasticity of LPS bubbles (0.17±0.1 N/m) was nearly the same as that of BARE bubbles (0.19±0.1 N/m) for all investigated bubble sizes. Clear difference of shell viscosity was found for bubbles larger than 6 μm. Averaged viscosity of LPS bubbles (2.5×10-8 kg/s) was almost twice of that of BARE bubbles (1.4×10-8 kg/s). A second finding for LPS bubbles was the dominant “expansion-only” behavior (70% of LPS bubbles), while this was only 13% for BARE bubbles. Results from this study will facilitate future preclinical studies and clinical applications of LPS bubbles for ultrasound triggered drug delivery system. Reference 1. Geers, B., et al., J Control Release, 2011. 152(2): p. 249-56.

Improving matrix metalloproteinase-2 specific response of a hydrogel system using electrophoresis

Matrix metalloproteinases (MMPs) overexpression plays a critical role in cancer invasion and metastasis. We utilized this key feature of tumor microenvironment to develop a disease-stimuli triggered drug delivery system. Poly(acrylic acid) hydrogels were synthesized by UV polymerization and pendant MMP-2 sensitive peptides (Gly-Pro-Leu-Gly-Val-Arg-Gly-Lys) conjugated throughout using EDC/sulfo-NHS chemistry. There were significantly more peptides released in the presence of MMP-2 compared with the control groups. The released peptide fragments were analyzed by HPLC and MALDI-MS and confirmed to be the expected fragments. In order to avoid nonspecific release of nonconjugated (i.e. unreacted) peptides, a novel method of electrophoretic washing was developed disrupting the strong electrostatic interactions between the peptides and the pendant groups of the hydrogel. After electrophoresis, the nonspecific peptide release in the absence of MMP-2 was minimized. This newly developed purification system significantly improved the control of release to be in response of the magnitude of the stimuli, i.e. MMP. Specifically, peptides were released proportionally to the concentration of MMP-2 present. Now that many of the design parameters have been examined, anticancer drugs will be conjugated to the MMP sensitive peptide linkers with the goal of implantation in a tumor void releasing anticancer reagent in response to elevated level of MMPs.

Remotely Triggerable Drug Delivery Systems

Triggerable drug delivery systems enable on-demand controlled release profiles that may enhance therapeutic effectiveness and reduce systemic toxicity. Recently, a number of new materials have been developed that exhibit sensitivity to visible light, near-infrared (NIR) light, ultrasound, or magnetic fields. This responsiveness can be triggered remotely to provide flexible control of dose magnitude and timing. Here we review triggerable materials that range in scale from nano to macro, and are activated by a range of stimuli.

Primary and novel approaches for colon targeted drug delivery – A review

The colon is a site where both local and systemic delivery of drugs can take place. Local delivery could, for example, allow topical treatment of inflammatory bowel disease. Treatment could be made more effective if it were possible for drugs to be targeted directly on the colon. Systemic side effects could also be reduced. Colon specific systems might also allow oral administration of peptide and protein drugs, which are normally inactivated in the upper parts of the gastrointestinal tract. Primary approaches for CDDS (Colon Specific Drug Delivery), which includes prodrugs, pH and time dependent systems and microbially triggered drug delivery system achieved limited success and having limitations. Newly developed CDDS, which includes pressure controlled colonic delivery capsules (PCDCS), CODESTM and osmotic controlled drug delivery are unique in terms of achieving in vivo site specificity and feasibility of manufacturing process. This review also focuses on evaluations of CDDS in general. Keywords: Colon drug delivery systems; Primary approaches; Newly developed approaches; evaluation of colon targeted drug delivery systems

Interplay Between Intestinal pH, Transit Time and Feed Status on the In Vivo Performance of pH Responsive Ileo-Colonic Release Systems

Oral pH triggered drug delivery systems, for targeting to the lower gastrointestinal tract, show erratic behaviour in vivo. This study aimed to establish correlations between in situ gastrointestinal pH, transit time or feed status and the disintegration of pH-responsive dosage forms designed to dissolve above pH 7. Tablets (radiolabelled with Technetium 99m) coated with Eudragit S were administered to eight healthy subjects in a three-way crossover study after an overnight fast. Food was administered either 30 min after (pre-feed) or 4 h after (fasted) tablet ingestion. Concurrently, a Bravo pH monitoring capsule (radiolabelled with Indium 111) was administered in a "freefall manner". In a third arm of the study tablets were given immediately after breakfast (fed). Transit was followed by gamma scintigraphy. Gastrointestinal pH showed variability between and within individuals but no differences were seen between pre-feed and fasted states. Three tablets failed to disintegrate in pre-feed and fed regimens and one in the fasted state; this has been tentatively linked to ileocaecal pH and ileoceacal junction residence time. In vivo performance of "pH-responsive" dosage forms is complex and influenced by a multitude of factors other than just in situ pH.

Development of enzymatically degradable protective coatings for use in triggered drug delivery systems: derivatized starch hydrogels

Starch is a common polysaccharide which consists of glucopyranose residues in an α-D-(1–4) linkage that yields D-glucose upon hydrolysis. Saturated aqueous solutions of soluble starch are easily reacted in the presence of glycidyl methacrylate to produce methacrylate grafted starch. Grafted starch solutions were polymerized to produce hydrogels, with and without the addition of an unsaturated acid. The grafted starch solutions and the resulting hydrogels are both shown to be degraded by the enzyme α-amylase. These acidic hydrogels are potentially useful as enzymatically degradable protective coatings in self-regulated drug delivery system applications. The pH of an acidic starch hydrogel required by this self-regulated drug delivery system does indicate that an adequately acidic hydrogel can be produced.

Triggered drug delivery systems

Previous approaches to the development of self-regulated drug delivery systems are briefly reviewed. The few systems which have been studied are based on either changes in the permeability or the rate of surface erosion of polymers in response to changes in the local environment. External stimuli have included light and pH and, in some systems, an enzymatic reaction has been used to induce the pH change. The use of antibodies bound to surface haptens is now being studied as a means of suppressing the permeability and the enzymatic biodegradation of polymeric delivery systems. The appearance of haptens in the circulatory system reverses the antibody binding and triggers drug release from the polymer matrix. The linkage of this mechanism to natural biochemistry as a means of creating reversible systems is considered. Methods of binding haptens to the surface and bulk of two different polymers are described, as are the syntheses of new polymers designed to undergo enzymatic surface erosion. A self-regulated method of delivery of metal chelating agents is proposed. It is intended that delivery be triggered by the metal, be specific for the metal, and proportionalto the metal concentration. Preliminary results demonstrating metal selectivity, and the synthesis of new polyionophores, are presented.