Monitoring Of Drug Release Research Articles

Polymer nanoassemblies with solvato- and halo-fluorochromism for drug release monitoring and metastasis imaging.

Theranostics, an emerging technique that combines therapeutic and diagnostic modalities for various diseases, holds promise to detect cancer in early stages, eradicate metastatic tumors and ultimately reduce cancer mortality. This study reports unique polymer nanoassemblies that increase fluorescence intensity upon addition of hydrophobic drugs and either increase or decrease fluorescence intensity in acidic environments, depending on nanoparticle core environment properties. Extensive spectroscopic analyses were performed to determine optimal excitation and emission wavelengths, which enabled real time measurement of drugs releasing from the nanoassemblies and ex vivo imaging of acidic liver metastatic tumors from mice. Polymer nanoassemblies with solvato- and halo-fluorochromic properties are promising platforms to develop novel theranostic tools for the detection and treatment of metastatic tumors.

A Prussian Blue-Based Core-Shell Hollow-Structured Mesoporous Nanoparticle as a Smart Theranostic Agent with Ultrahigh pH-Responsive Longitudinal Relaxivity.

Novel core-shell hollow mesoporous Prussian blue @ Mn-containing Prussian blue analogue (HMPB@MnPBA) nanoparticles, designated as HMPB-Mn) as an intelligent theranostic nanoagent, are successfully constructed by coating a similarly crystal-structured MnPBA onto HMPB. This can be used as a pH-responsive T1 -weighted magnetic resonance imaging contrast agent with ultrahigh longitudinal relaxivity (r1 = 7.43 m m(-1) s(-1) ), and achieves the real-time monitoring of drug release.

Lab-on-fiber optofluidic platform for in situ monitoring of drug release from therapeutic eluting polyelectrolyte multilayers.

A lab-on-fiber (LOF) optofluidic platform that provides physiologically relevant microenvironment was developed by integrating a long period grating (LPG) coupled with high order cladding mode to achieve high index sensitivity and a liquid-tight capillary tube assembly as a microfluidic chamber for LPG to mimic physiologically relevant microenvironment. We demonstrate the utility of LOF for in situ monitoring the construction of the [chitosan (CHI)/poly (acrylic acid) (PAA)/gentamicin sulfate (GS)/PAA]n multilayers at monolayer resolution as well as evaluating the rate of GS release at a flow rate of 0.127 mL/min at 37 °C in real time. We reveal that GS is released at a faster rate under the dynamic flow condition than in a static medium. Our findings underscore the importance of conducting drug release studies in physiologically relevant conditions.

Fluorescein-containing theranostics based on the pseudo-poly(amino acid)s for monitoring of drug delivery and release

Fluorescein-containing theranostics based on the pseudo-poly(amino acid)s for monitoring of drug delivery and release

A sustained intravitreal drug delivery system with remote real time monitoring capability

Many chorioretinal diseases are chronic and need sustained drug delivery systems to keep therapeutic drug level at the disease site. Many intravitreal drug delivery systems under developing do not have mechanism incorporated for a non-invasive monitoring of drug release. The current study prepared rugate porous silicon (pSi) particles by electrochemical etching with the current frequency (K value) of 2.17 and 2.45. Two model drugs (rapamycin and dexamethasone) and two drug-loading strategies were tested for the feasibility to monitor drug release from the pSi particles through a color fundus camera. The pSi particles (k=2.45) with infiltration loading of rapamycin demonstrated progressively more violet color reflection which was negatively associated with the rapamycin released into the vitreous (r=−0.4, p<0.001, pairwise). In contrast, pSi with K value of 2.17 demonstrated progressive color change toward green and a weak association between rapamycin released into vitreous and green color abundance was identified (r=−0.23, p=0.002, pairwise). Dexamethasone was covalently loaded on to the fully oxidized pSi particles that appeared in vitreous as yellow color and fading over time. The yellow color decrease over time was strongly associated with the dexamethasone detected from the vitreous samples (r=0.7, p<0.0001, pairwise). These results suggest that engineered porous silicon particles may be used as a self-reporting drug delivery system for a non-invasive real time remote monitoring. Statement of SignificanceThe current study, for the first time, demonstrated proof of concept that engineered porous silicon photonic crystal may deliver therapeutics in a controlled fashion while at the same time might offer a noninvasive remote monitoring of its payload release in a living eye. Porous silicon photonic crystal changes color which is in association with its payload release into vitreous. With further optimization, the color change may be harnessed to inform eye care professionals of real time drug concentration in the eye and allow them to make informed decision to re-dose the patients.

Ratiometric Monitoring of Intracellular Drug Release by an Upconversion Drug Delivery Nanosystem.

Nanoscale drug delivery systems have been widely investigated due to their well-recognized advantages including controlled delivery of chemotherapeutic agents, enhanced therapeutic effectiveness, and reduced adverse effects compared to conventional chemotherapy with small molecules. However, further progress in the use of nanoscale delivery systems in clinical applications has been hampered by pharmacokinetic studies in biological samples which were associated with significant experimental challenges. Here, we report a rational ratiometric approach to monitor drug release kinetics by quantitatively investigating luminescence resonance energy transfer (LRET) from upconversion nanoparticles to the antitumor drug doxorubicin (DOX). Specifically, DOX molecules within the shell of mesoporous silica-coated upconversion nanoparticles selectively quenched the green emission of upconversion nanoparticles, while the intensity of red emission was essentially unaltered. Consequently, when DOX was gradually released, a steady recovery of green emission was observed. The ability to monitor the intensity ratio of green-to-red luminescence enabled a rational design for real-time investigation of drug delivery release kinetics. Importantly, the internal standard effect of red emission made this ratiometric approach suitable for complex biological microenvironments.

In situ monitoring of doxorubicin release from biohybrid nanoparticles modified with antibody and cell-penetrating peptides in breast cancer cells using surface-enhanced Raman spectroscopy

In situ monitoring of drug release in cancer cells is very important for real-time assessment of drug release dynamics in chemotherapy. In this study, we report label-free in situ monitoring and control of intracellular anti-cancer drug delivery process using biohybrid nanoparticles based on surface-enhanced Raman spectroscopy (SERS) for the first time. Each biohybrid nanoparticle consisted of gold nanoparticle, cell-penetrating peptide (Tat peptide), and cancer-targeting antibody to increase the efficacy of the anti-cancer drug delivery with specific targeting and increased uptake rate. The doxorubicin (Dox)-loaded biohybrid nanoparticles were showed specific SERS spectra of Dox, specifically immobilized on the target cell membrane and quickly penetrated into the cells when treated on the mixed cell culture condition. The intracellular release of Dox from the biohybrid nanoparticle was continuously monitored with time-dependent change of intracellular SERS signals of Dox. The releasing rate of Dox was successfully controlled with the addition of glutathione on the cells. The anti-cancer effect of intracellular released Dox was confirmed with cell viability assay. With the proposed monitoring system, specific cancer cell targeting and improved uptake of the anti-cancer drug were detected and time-dependent intracellular release of the anti-cancer drug was monitored successfully. The proposed novel in situ monitoring system can be used as a spectroscopic analysis tool for label-free monitoring of the time-dependent release of various kinds of anti-cancer drugs inside cells.

Real-Time Monitoring of ATP-Responsive Drug Release Using Mesoporous-Silica-Coated Multicolor Upconversion Nanoparticles.

Stimuli-responsive drug delivery vehicles have garnered immense interest in recent years due to unparalleled progress made in material science and nanomedicine. However, the development of stimuli-responsive devices with integrated real-time monitoring capabilities is still in its nascent stage because of the limitations of imaging modalities. In this paper, we describe the development of a polypeptide-wrapped mesoporous-silica-coated multicolor upconversion nanoparticle (UCNP@MSN) as an adenosine triphosphate (ATP)-responsive drug delivery system (DDS) for long-term tracking and real-time monitoring of drug release. Our UCNP@MSN with multiple emission peaks in UV-NIR wavelength range was functionalized with zinc-dipicolylamine analogue (TDPA-Zn(2+)) on its exterior surface and loaded with small-molecule drugs like chemotherapeutics in interior mesopores. The drugs remained entrapped within the UCNP-MSNs when the nanoparticles were wrapped with a compact branched polypeptide, poly(Asp-Lys)-b-Asp, because of multivalent interactions between Asp moieties present in the polypeptide and the TDPA-Zn(2+) complex present on the surface of UCNP-MSNs. This led to luminescence resonance energy transfer (LRET) from the UCNPs to the entrapped drugs, which typically have absorption in UV-visible range, ultimately resulting in quenching of UCNP emission in UV-visible range while retaining their strong NIR emission. Addition of ATP led to a competitive displacement of the surface bound polypeptide by ATP due to its higher affinity to TDPA-Zn(2+), which led to the release of the entrapped drugs and subsequent elimination of LRET. Monitoring of such ATP-triggered ratiometric changes in LRET allowed us to monitor the release of the entrapped drugs in real-time. Given these results, we envision that our proposed UCNP@MSN-polypeptide hybrid nanoparticle has great potential for stimuli-responsive drug delivery as well as for monitoring biochemical changes taking place in live cancer and stem cells.

A miniaturized in vitro release method for investigating drug-release mechanisms

We have evaluated a miniaturized in vitro method, based on the μDISS Profiler™ technique that enables on-line monitoring of drug release from a 21μl sample with 10ml of release medium. Four model drugs in eight clinically used formulations, including both solid and non-solid drug delivery systems, were investigated. The acquired data were compared with historical in vitro release data from the same formulations. Use of the Weibull function to describe the in vitro drug-release profiles allowed discrimination between the selected formulations with respect to the drug-release mechanisms. Comparison of the release data from the same formulation in different in vitro set-ups showed that the methodology used can affect the mechanism of in vitro release. We also evaluated the ability of the in vitro methods to predict in vivo activity by comparing simulated plasma concentration-time profiles acquired from the application of the biopharmaceutical software GI-Sim to the in vitro observations. In summary, the simulations based on the miniaturized-method release data predicted the plasma profiles as well as or more accurately than simulations based on the historical release data in 71% of the cases and this miniaturized in vitro method appears to be applicable for both solid and non-solid formulations.

NIR Fluorogenic Dye as a Modular Platform for Prodrug Assembly: Real‐Time in vivo Monitoring of Drug Release

The ability to monitor drug release in vivo provides essential pharmacological information. We developed a new modular approach for the preparation of theranostic prodrugs with a turn-ON near-infrared (NIR) fluorescence mode of action. The prodrugs release their chemotherapeutic cargo and an active cyanine fluorophore upon reaction with a specific analyte. The prodrug platform is based on the fluorogenic dye QCy7; upon removal of a triggering substrate, the dye fluoresces, and the free drug is released. The evaluated camptothecin prodrug was activated by endogenous hydrogen peroxide produced in tumor cells in vitro and in vivo. Drug release and in vitro cytotoxicity were correlated with the emitted fluorescence. The prodrug activation was effectively imaged in real time in mice bearing tumors. The modular design of the QCy7 fluorogenic platform should allow the preparation of numerous other prodrugs with various triggering substrates and chemotherapeutic agents. We anticipate that the development of real-time in vivo monitoring tools such as that described herein will pave the way for personalized therapy.

Non-invasive, real-time reporting drug release in vitro and in vivo.

We developed a real-time drug-reporting conjugate (CPT-SS-CyN) composed of a near-infrared (NIR) fluorescent cyanine-amine dye (CyN), a disulfide linker, and a model therapeutic drug (camptothecin, CPT). Treatment with dithiothreitol (DTT) induces cleavage of the disulfide bond, followed by two simultaneous intramolecular cyclization reactions with identical kinetics, one to cleave the urethane linkage to release the NIR dye and the other to cleave the carbonate linkage to release CPT. The released CyN has an emission wavelength (760 nm) that is significantly different from CPT-SS-CyN (820 nm), enabling easy detection and monitoring of drug release. A linear relationship between the NIR fluorescence intensity at 760 nm and the amount of CPT released was observed, substantiating the use of this drug-reporting conjugate to enable precise, real-time, and non-invasive quantitative monitoring of drug release in live cells and semi-quantitative monitoring in live animals.

A DT-diaphorase responsive theranostic prodrug for diagnosis, drug release monitoring and therapy.

A DT-diaphorase-activatable theranostic prodrug, which contains camptothecin, a self-immolative linker and a trigger group, has been developed for the detection of DT-diaphorase, tracking of drug release and selectively killing cancer cells over-expressed with DT-diaphorase. This strategy may offer a new approach for the development of enzyme-catalyzed theranostic anticancer therapeutics.

Self-carried curcumin nanoparticles for in vitro and in vivo cancer therapy with real-time monitoring of drug release.

The use of different nanocarriers for delivering hydrophobic pharmaceutical agents to tumor sites has garnered major attention. Despite the merits of these nanocarriers, further studies are needed to improve their drug loading capacities (which are typically <10%) and reduce their potential systemic toxicity. Therefore, the development of alternative self-carried nanodrug delivery strategies without using inert carriers is highly desirable. In this study, we developed a self-carried curcumin (Cur) nanodrug for highly effective cancer therapy in vitro and in vivo with real-time monitoring of drug release. With a biocompatible C18PMH-PEG functionalization, the Cur nanoparticles (NPs) showed excellent dispersibility and outstanding stability in physiological environments with drug loading capacities >78 wt%. Both confocal microscopy and flow cytometry confirmed the cellular fluorescence "OFF-ON" activation and real-time monitoring of the Cur molecule release. In vitro and in vivo experiments clearly show that the therapeutic efficacy of the PEGylated Cur NPs is considerably better than that of free Cur. This self-carried strategy with real-time monitoring of drug release may open a new way for simultaneous cancer therapy and monitoring.

Near-infrared luminescent CaTiO3:Nd3+ nanofibers with tunable and trackable drug release kinetics.

750-850 nm (NIR I) and 1000-1400 nm (NIR II) in the near infrared (NIR) spectra are two windows of optical transparency for biological tissues with the latter capable of penetrating tissue deeper. Monitoring drug release from the drug carrier is still a daunting challenge in the field of nanomedicine. To overcome such a challenge, we propose to use porous Nd3+-doped CaTiO3 nanofibers, which can be excited by NIR I to emit NIR II light, to carry drugs to test the concept of monitoring drug release from the nanofibers by detecting the NIR II emission intensity. Towards this end, we first used electrospinning to prepare porous Nd3+-doped CaTiO3 nanofibers by adding micelle-forming surfactant Pluronic F127, followed by annealing to remove the organic component. After a model drug, ibuprofen, was loaded into the porous nanofibers, the drug release from the nanofibers into the phosphate buffered saline (PBS) solution was monitored by detecting the NIR II emission from the nanofibers. We found that the release of the drug molecules from the nanofibers into the PBS solution triggers the quenching of NIR II emission by the hydroxyl groups in the surrounding media. Consequently, more drug release corresponded to more reduction in the intensity of the NIR II emission, allowing us to monitor the drug release by simply detecting the intensity of NIR II from the nanofibers. In addition, we demonstrated that tuning the amount of micelle-forming surfactant Pluronic F127 enabled us to tune the porosity of the nanofibers and thus the drug release kinetics. This study suggests that Nd3+ doped CaTiO3 nanostructures can serve as a promising drug delivery platform with the potential to monitor drug release kinetics by detecting the tissue-penetrating NIR emission.

A pH-responsive prodrug for real-time drug release monitoring and targeted cancer therapy.

A novel cancer targeting and pH-responsive prodrug was successfully designed and synthesized. This M-prodrug was demonstrated to have real-time drug release monitoring capability based on the concept of contact-mediated quenching between doxorubicin and a coumarin derivative.

In vivo mouse fluorescence imaging for folate-targeted delivery and release kinetics.

Many cancer cells over-express folate receptors, and this provides an opportunity for both folate-targeted fluorescence imaging and the development of targeted anti-cancer drugs. We present an optical imaging modality that allows for the monitoring and evaluation of drug delivery and release through disulfide bond reduction inside a tumor in vivo for the first time. A near-infrared folate-targeting fluorophore pair was synthesized and used to image a xenograft tumor grown from KB cells in a live mouse. The in vivo results are shown to be in agreement with previous in vitro studies, confirming the validity and feasibility of our method as an effective tool for preclinical studies in drug development.

Perylene-derived single-component organic nanoparticles with tunable emission: efficient anticancer drug carriers with real-time monitoring of drug release.

An organic nanoparticle-based drug delivery system with high drug loading efficacy (∼79 wt %) was developed using a perylene-derived photoremovable protecting group, namely, perylene-3,4,9,10-tetrayltetramethanol (Pe(OH)4). The anticancer drug chlorambucil was protected by coupling with Pe(OH)4 to form photocaged nanoparticles (Pe(Cbl)4). The photorelease mechanism of chlorambucil from the Pe(Cbl)4 conjugate was investigated experimentally by high-resolution mass spectrometry and theoretically by density functional theory calculations. The Pe(Cbl)4 nanoparticles perform four important roles: (i) a nanocarrier for drug delivery, (ii) a phototrigger for drug release, (iii) a fluorescent chromophore for cell imaging, and (iv) a photoswitchable fluorophore for real-time monitoring of drug release. Tunable emission of the perylene-derived nanoparticles was demonstrated by comparing the emission properties of the Pe(OH)4 and Pe(Cbl)4 nanoparticles with perylene-3-ylmethanol. These nanoparticles were subsequently employed in cell imaging for investigating their intracellular localization. Furthermore, the in vivo toxicity of the Pe(OH)4 nanoparticles was investigated using the mouse model. Histological tissue analysis of five major organs, i.e., heart, kidney, spleen, liver, and lung, indicates that the nanoparticles did not show any obvious damage to these major organs under the experimental conditions. The current research presents a successful example of integrating multiple functions into single-component organic nanoparticles for drug delivery.

Combined use of luminescence imaging and MRI for real-time, in vivo, quantitative monitoring of drug release

Combined use of luminescence imaging and MRI for real-time, in vivo, quantitative monitoring of drug release

Lanthanide-Containing Polycations for Monitoring Polyplex Dynamics via Lanthanide Resonance Energy Transfer

Theranostic nanomaterials have emerged in the past decade that combine therapeutic delivery and diagnostic imaging into one package. Such materials offer the opportunity to aid diagnosis, track therapeutic biodistribution, and monitor drug release. We have developed a series of nucleic acid delivery polymers containing oligoethylene amines that are able to be protonated at physiological pH (for binding/compacting pDNA) and a lanthanide-chelating domain, which imparts diagnostic functionality. Diamine monomers (containing between 3 and 6 Boc-protected ethyleneamines) were prepared via a multistep procedure involving the selective protection and deprotection of primary and secondary amines. The polymer structures were then synthesized by step-growth polymerization of the oligoethylene diamines with a bisanhydride of diethylenetriamine pentaacetic acid (DTPA-BA), yielding degrees of polymerization between 18 and 24. Chelation of the polymers with gadolinium and terbium was performed to offer MRI contrast agent and luminescence properties, respectively. All of the polymer chelates were found to house approximately one water coordination site, as calculated by the Horrock's equation and possess longitudinal relaxivities (r1, on a per Gd basis) at least twice that of Magnevist, a clinical contrast agent. All the structures formed polyplexes with pDNA with highly positive zeta potentials and hydrodynamic diameters around 50-80 nm. Lanthanide resonance energy transfer (LRET) was used to monitor polyplex association and dissociation. Polyplexes were formed using the donor-acceptor pair comprising of terbium-chelated polymer with five ethyleneamines within the repeat unit (6c-Tb) and tetramethyl rhodamine (TMR)-labeled pDNA. Association/dissociation in the presence of heparin and NaCl was monitored. The effect of amine number along the polymer backbone on transfection efficiency and cytotoxicity was also investigated. None of the polymers revealed cytotoxic effects with cultured cells; however, the polymer with six ethyleneamines clearly offered the highest transfection efficiency. This preliminary study offers insight into the development of materials with the ability to monitor polyplex unpackaging over time within the cellular environment.

Real‐Time In Vivo Quantitative Monitoring of Drug Release by Dual‐Mode Magnetic Resonance and Upconverted Luminescence Imaging

Insufficient or excess drug doses, due to unknown actual drug concentrations at the focus, are one of the main causes of chemotherapy failure for cancers. In this regard, the real-time monitoring of the release of anticancer drugs from nanoparticle drug delivery systems is of crucial importance, but it remains a critical and unsolved challenge. Herein, we report the proposal and development of a novel concept of real-time monitoring of NIR-triggered drug release in vitro and in vivo by using simultaneous upconverted luminescence (UCL) and magnetic resonance (MR) imaging. Such a monitoring strategy features the high sensitivity of UCL and the high-resolution, noninvasiveness, and tissue-depth-independence of MR imaging. The dual-mode real-time and quantitative monitoring of drug release can be applied to determine online the drug concentrations in vivo in the tissue regions of interest and, therefore, to avoid insufficient or excess drug dosings.