The role of the alliance and techniques in predicting outcome of supportive-expressive dynamic therapy for cocaine dependence.

We examine the complex relations among therapeutic alliance, adherence to Supportive-Expressive Therapy (SET), therapist competence, and their interactions in predicting change in drug use. Experts rated early therapy sessions of cocaine dependent patients (n = 108) randomized to SET as part of the Collaborative Cocaine Treatment Study. Moderate adherence to SET and competent delivery of SET were separately associated with poorer outcome. Further, strong alliance combined with low levels of SET adherence was associated with a better outcome than moderate or high levels. Moreover, the usage of nonprescribed techniques (i.e., Individual Drug Counseling [IDC]) by SET therapists predicted better outcome in a subsample (n = 36), and SET patients receiving high levels of IDC adherence had less predicted drug use compared with those with high levels of SET techniques. Overall results may suggest that decreasing cocaine use through straightforward drug counseling techniques instead of trying to help patients understand the reasons for their use is a better initial road to recovery. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mu/kappa opioid interactions in rhesus monkeys: Implications for analgesia and abuse liability.

Mu opioid receptor agonists are clinically valuable as analgesics; however, their use is limited by high abuse liability. Kappa opioid agonists also produce antinociception, but they do not produce mu agonist-like abuse-related effects, suggesting that they may enhance the antinociceptive effects and/or attenuate the abuse-related effects of mu agonists. To evaluate this hypothesis, the present study examined interactions between the mu agonist fentanyl and the kappa agonist U69,593 in three behavioral assays in rhesus monkeys. In an assay of schedule-controlled responding, monkeys responded under a fixed-ratio 30 (FR 30) schedule of food presentation. Fentanyl and U69,593 each produced rate-decreasing effects when administered alone, and mixtures of 0.22:1, 0.65:1, and 1.96:1 U69,593/fentanyl usually produced subadditive effects. In an assay of thermal nociception, tail withdrawal latencies were measured from water heated to 50 °C. Fentanyl and U69,593 each produced dose-dependent antinociception, and effects were additive for all mixtures. In an assay of drug self-administration, rhesus monkeys responded for intravenous drug injection, and both dose and FR values were manipulated. Fentanyl maintained self-administration, whereas U69,593 did not. Addition of U69,593 to fentanyl produced a proportion-dependent decrease in rates of fentanyl self-administration. Moreover, addition of U69,593 increased the sensitivity of fentanyl self-administration to increases in the FR value. Taken together, these results suggest that simultaneous activation of mu and kappa receptors, either with a mixture of selective drugs or with a single drug that targets both receptors, may reduce abuse liability without reducing analgesic effects relative to selective mu agonists administered alone. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

All‐in‐One Theranostic Nanoplatform Based on Hollow TaOx for Chelator‐Free Labeling Imaging,Drug Delivery,and Synergistically Enhanced Radiotherapy

Despite extensive use of radiotherapy in cancer treatment, there has been huge demand to improve its efficacy and accuracy in tumor destruction. To this end, nanoparticle‐based radiosensitizers, particularly those with high‐Z elements, have been explored to enhance radiotherapy. Meanwhile, imaging is an essential tool prior to the individual planning of precise radiotherapy. Here, hollow tantalum oxide (H‐TaOx) nanoshells are prepared using a one‐pot template‐free method and then modified with polyethylene glycol (PEG), yielding H‐TaOx‐PEG nanoshells for imaging‐guided synergistically enhanced radiotherapy. H‐TaOx‐PEG nanoshells show strong intrinsic binding with metal ions such as Fe³⁺ and ^99mTc⁴⁺ upon simple mixing, enabling magnetic resonance imaging and single photon emission computed tomography imaging, respectively, which are able to track in vivo distribution of those nanoshells and locate the tumor. With mesoporous shells and large cavities, those H‐TaOx‐PEG nanoshells show efficient loading of 7‐ethyl‐10‐hydroxycamptothecin (SN‐38), a hydrophobic chemotherapeutic drug. By means of the radiosensitization effect of Ta to deposit X‐ray energy inside tumors, as well as SN‐38‐induced cell cycle arrest into radiation‐sensitive phases, H‐TaOx‐PEG@SN‐38 can offer remarkable synergistic therapeutic outcome in the combined chemoradiotherapy. Without appreciable systemic toxicity, such hollow‐TaOx nanostructure may therefore find promising applications in multimodal imaging and enhanced cancer radiotherapy.     

Nanocarrier‐Mediated Codelivery of Small Molecular Drugs and siRNA to Enhance Chondrogenic Differentiation and Suppress Hypertrophy of Human Mesenchymal Stem Cells

Cartilage loss is a leading cause of disability among adults, and effective therapy remains elusive. Human mesenchymal stem cells (hMSCs), which have demonstrated self‐renewal and multipotential differentiation, are a promising cell source for cartilage repair. However, the hypertrophic differentiation of the chondrogenically induced MSCs and resulting tissue calcification hinders the clinical translation of MSCs for cartilage repair. Here, a multifunctional nanocarrier based on quantum dots (QDs) is developed to enhance chondrogenic differentiation and suppress hypertrophy of hMSCs simultaneously. Briefly, the QDs are modified with β‐cyclodextrin (β‐CD) and RGD peptide. The resulting nanocarrier is capable of carrying hydrophobic small molecules such as kartogenin in the hydrophobic pockets of conjugated β‐CD to induce chondrogenic differentiation of hMSCs. Meanwhile, via electrostatic interaction the conjugated RGD peptides bind the cargo siRNA targeting Runx2, which is a key regulator of hMSC hypertrophy. Furthermore, due to the excellent photostability of QDs, hMSCs labeled with the nanocarrier can be tracked for up to 14 d after implantation in nude mice. Overall, this work demonstrates the potential of our nanocarrier for inducing and maintaining the chondrogenic phenotype and tracking hMSCs in vivo.     

Smart Ferrofluid with Quick Gel Transformation in Tumors for MRI‐Guided Local Magnetic Thermochemotherapy

Improved techniques for local administration of anticancer drugs are needed to reduce the side effects of chemotherapy owing to leakage of anticancer drugs from tumors and to enhance therapeutic efficacy. This study presents the development of smart ferrofluid that transforms immediately into a gel in tumors and generates heat in response to an alternating magnetic field (AMF), simultaneously releasing the anticancer drug. The smart ferrofluid, which is synthesized using less toxic magnetic materials (Fe₃O₄ nanoparticles), natural polysaccharides (alginate), and amino acids (cysteine), can also act as a contrast agent for magnetic resonance imaging (MRI). The ferrofluid also incorporates an anticancer drug (i.e., doxorubicin, DOX) via hydrogen bonds. AMF causes heating of gels prepared from the DOX‐containing ferrofluid, resulting in gel shrinkage and DOX release. In vivo experiments demonstrated that the ferrofluid transforms into a gel in the tumor, with the gel remaining in the tumor. Furthermore, magnetic thermochemotherapy using this ferrofluid inhibited tumor growth, while magnetic hyperthermia alone had only a marginal effect. Thus, the combination of magnetic hyperthermia and chemotherapy may be important for suppressing tumor growth. In summary, the ferrofluid presented here has the potential to facilitate MRI‐guided magnetic thermochemotherapy through a combination of endoscopic technologies in the future.     

Dual‐Targeted Photopenetrative Delivery of Multiple Micelles/Hydrophobic Drugs by a Nanopea for Enhanced Tumor Therapy

A photoresponsive pea‐like capsule (nanopea) that also represents a photothermal agent is constructed by wrapping multiple polymer micelles (polyvinyl alcohol, PVA) in reduced graphene oxide nanoshells through a double emulsion approach. Resulting nanopeas can transport multiple PVA micelles containing the fully concealed hydrophobic drug docetaxel (DTX) which can be later released by a near‐infrared photoactuation trigger. Through integrating the rod‐shaped adhesion and lactoferrin (Lf) targeting, the nanopea enhances both uptake by cancer cellc in vitro and particle accumulation at tumor in vivo. A photopenetrative delivery of micelles/DTX to the tumor site is actuated by NIR irradiation which ruptures the nanopeas as well as releases nanosized micelles/DTX. This trigger also results in thermal damage to the tumor and increases the micelles/DTX permeability, facilitating drug penetration into the deep tumor far from blood vessels for thermal chemotherapy. This nanopea with the capability of imaging, enhanced tumor accumulation, NIR‐triggered tumor penetration, and hyperthermia ablation for photothermal chemotherapy boosts tumor treatment and shows potential for use in other biological applications.     

Treatment of Malignant Brain Tumor by Tumor‐Triggered Programmed Wormlike Micelles with Precise Targeting and Deep Penetration

The efficient and specific drug delivery to brain tumor is a crucial challenge for successful systemic chemotherapy. To overcome these limitations, here a tumor‐triggered programmed wormlike micelle is reported with precise targeting and deep penetration to treat malignant gliomas, which is composed of pH‐responsive mPEG‐b‐PDPA copolymer and bioreducible cyclic RGD peptide targeted cytotoxic emtansine (DM1) conjugates (RGD‐DM1). The RGD‐DM1 loaded nanoscaled wormlike micelles (RNW) exhibit nanometer‐sized wormlike assemblies with the transverse diameter of 21.3±1.8 nm and length within 60–600 nm, and the RGD targeting peptide in RNW is 4.2% in weight. RNW can be dissociated at intracellular acidic environments to release RGD‐DM1, and be further degraded into DM1 by cleavage of disulfide bonds in the reductive milieu. In particular, by exploiting the unique wormlike structure and the RGD targeting peptide modification, RNW can be endowed with obviously enhanced drug delivery to brain, precise targeting to brain tumor, deep penetration into tumor mass, and efficient internalization into glioma cells in a programmed manner, thereby surprisingly leading to an 88.9% inhibition on tumor progression in an orthotopic brain tumor model. Therefore, the properly designed RNW can provide a promising delivery platform for systemic chemotherapy of brain tumor.     

New Drug‐Structure‐Directing Agent Concept: Inherent Pharmacological Activity Combined with Templating Solid and Hollow‐Shell Mesostructured Silica Nanoparticles

One of the major challenges in medicine is the delivery and control of drug release over time. Current approaches take advantage of mesostructured silica nanoparticles (MSNs) as carriers but suffer several problems including complex synthesis that requires sequential steps for (1) removal of surfactants and (2) functionalization of MSNs to allow upload of the drugs. Here, a novel solution is presented to these restrictions: the design of drug‐structure‐directing agents (DSDAs) with dual inherent pharmacological activity and ability to direct the formation of solid and hollow‐shell MSNs. Pharmacologically active DSDAs obtained by amidation of drugs with fatty acids are allowed to form micelles, around which the inorganic species self‐assembled to form MSNs. Since the DSDAs direct the formation of MSNs, the steps to remove surfactants, functionalization, and drug upload are not required. The MSNs thus prepared provide sustained release of the drug over more than six months, as well as rapid cellular internalization by both physiological and tumoral human colon cells without affecting cell viability. Moreover, the gradual intracellular release of both, the active drug and lipid moiety with potential nutraceutical properties is proved. MSN particles designed with this approach are promising vehicles for controlled and sustained intra‐or extracellular drug‐delivery.     

In vitro and in vivo performance of a multiparticulate pulsatile drug delivery system

The objective of this study was to investigate the in vitro and in vivo drug release performance of a rupturable multiparticulate pulsatile system, coated with aqueous polymer dispersion Aquacoat® ECD. Acetaminophen was used as a model drug, because in vivo performance can be monitored by measuring its concentration in saliva. Drug release was typical pulsatile, characterized by lag time, followed by fast drug release. Increasing the coating level of outer membrane lag time was clearly delayed. In vitro the lag time in 0.1 N HCl was longer, compared to phosphate buffer pH 7.4 because of ionisable ingredients present in the formulation (crosscarmelose sodium and sodium dodecyl sulphate). In vitro release was also longer in medium with higher ion concentration (0.9% NaCl solution compared to purified water); but independent of paddle rotation speed (50 vs.100 rpm). Macroscopically observation of the pellets during release experiment confirms that the rupturing of outer membrane was the main trigger for the onset of release. At the end of release outer membrane of all pellets was destructed and the content completely released.

However, pellets with higher coating level and correspondingly longer lag time showed decreased bioavailability of acetaminophen. This phenomenon was described previously and explained by decreased liquid flow in the lower part of intestine. This disadvantage can be considered as a limitation for drugs (like acetaminophen) with high dose and moderate solubility; however, it should not diminish performance of the investigated system in principle.     

Oral bioavailability enhancement of acyclovir by self-microemulsifying drug delivery systems (SMEDDS)

Acyclovir is a potent anti-viral agent useful in the treatment of Herpes Simplex Virus (HSV) infections. Acyclovir exerts its antiviral activity by competitive inhibition of viral DNA through selective binding of acyclovir to HSV-thymidine kinase. The main purpose of this work was to develop self-microemulsifying drug delivery system (SMEDDS) for oral bioavailability enhancement of acyclovir. Solubility of acyclovir was determined in various vehicles. SMEDDS is mixture of oils, surfactants, and co-surfactants, which are emulsified in aqueous media under conditions of gentle agitation and digestive motility that would be encountered in the gastro-intestinal (GI) tract. Pseudoternary phase diagrams were constructed to identify the efficient self-emulsifying region dilution study was also performed for optimization of formulation. SMEDDS was evaluated for its percentage transmittance, Assay of SMEDDS, phase separation study, droplet size analysis, zeta potential, electrophoretic mobility, and viscosity. The developed SMEDDS formulation contained acyclovir (50 mg), Tween 60 (60%), glycerol (30%) and sunflower oil (9%) was compared with the pure drug solution by oral administrating to male albino rats. The absorption of acyclovir from SMEDDS form resulted about 3.5 fold increase in bioavailability compared with the pure drug solution. Our studies illustrated the potential use of SMEDDS for the delivery of hydrophobic compounds such as acyclovir by oral route.