Stimuli-responsive Drug Delivery Research Articles

Drug Loading in Poly(butyl cyanoacrylate)-Based Polymeric Microbubbles.

Microbubbles (MB) are routinely used ultrasound (US) contrast agents that have recently attracted increasing attention as stimuli-responsive drug delivery systems. To better understand MB-based drug delivery, we studied the role of drug hydrophobicity and molecular weight on MB loading, shelf-life stability, US properties, and drug release. Eight model drugs, varying in hydrophobicity and molecular weight, were loaded into the shell of poly(butyl cyanoacrylate) (PBCA) MB. In the case of drugs with progesterone as a common structural backbone (i.e., for corticosteroids), loading capacity and drug release correlated well with hydrophobicity and molecular weight. Conversely, when employing drugs with no structural similarity (i.e., four different fluorescent dyes), loading capacity and release did not correlate with hydrophobicity and molecular weight. All model drug-loaded MB formulations could be equally efficiently destroyed upon exposure to US. Together, these findings provide valuable insights on how the physicochemical properties of (model) drug molecules affect their loading and retention in and US-induced release from polymeric MB, thereby facilitating the development of drug-loaded MB formulations for US-triggered drug delivery.

A novel kinetic model to describe the ultra-fast triggered release of thermosensitive liposomal drug delivery systems

Thermosensitive liposomes, as one of the stimuli-responsive drug delivery systems, receive growing attention, due to their ability to generate rapid and massive drug release in the heated area, and marginal release of contents in non-heated parts of the body. This typical triggered release behavior cannot be fitted adequately by most of the current mathematical kinetic models. The aim of this study was to establish the proper kinetic equation to describe the rapid release of drugs from trigger-sensitive drug delivery systems. We summarized all commonly used kinetic models mentioned in the literature and fitted the release data with these models, finding that only the Korsmeyer-Peppas and the Weibull models show acceptable fitting results. To better describe the release from thermosensitive liposomes with a size below 100 nm, we took Laplace pressure as a release-driving force and proposed a new equation that demonstrates improved fitting in liposomes ranging down to a size of 70 nm. Our new kinetic model shows desirable fitting, not only at the optimal temperature but also of releases within the whole release-temperature range, providing a useful kinetic model to describe release profiles of smaller nano-sized stimuli-responsive drug delivery systems.

Stimuli-responsive Drug Delivery Nanocarriers in the Treatment of Breast Cancer.

Stimuli-responsive drug-delivery nanocarriers (DDNs) have been increasingly reported in the literature as an alternative for breast cancer therapy. Stimuli-responsive DDNs are developed with materials that present a drastic change in response to intrinsic/chemical stimuli (pH, redox and enzyme) and extrinsic/physical stimuli (ultrasound, Near-infrared (NIR) light, magnetic field and electric current). In addition, they can be developed using different strategies, such as functionalization with signaling molecules, leading to several advantages, such as (a) improved pharmaceutical properties of liposoluble drugs, (b) selectivity with the tumor tissue decreasing systemic toxic effects, (c) controlled release upon different stimuli, which are all fundamental to improving the therapeutic effectiveness of breast cancer treatment. Therefore, this review summarizes the use of stimuli-responsive DDNs in the treatment of breast cancer. We have divided the discussions into intrinsic and extrinsic stimuli and have separately detailed them regarding their definitions and applications. Finally, we aim to address the ability of these stimuli-responsive DDNs to control the drug release in vitro and the influence on breast cancer therapy, evaluated in vivo in breast cancer models.

Dendron-polymer hybrid mediated anticancer drug delivery for suppression of mammary cancer

Dendron-polymer-based nanoscale and stimuli-responsive drug delivery systems have shown great promise in tumor-targeting accumulation without significant toxicity. Here we report a dendronized polymer-doxorubicin (DOX) hybrid (DPDH) with an improved in vivo drug delivery efficiency for cancer therapy compared with a linear polymer-DOX conjugate (LPDC). The in vitro drug release profile of DOX indicates that DPDH displays pH-responsive drug release due to cleavage of hydrazone bonds since a greater amount of DOX is released at pH 5.2 at a faster rate than at pH 7.4. DPDH efficiently enters 4T1 cells and releases DOX to induce cytotoxicity and apoptosis. Owing to the dendronzied structure, DPDH has a significantly longer blood circulation time than LPDC. DPDH substantially enhances the therapeutic efficacy to suppress tumor growth in a 4T1 mammary cancer model than LPDC as well as free drug, evidenced from tumor growth inhibition, TUNEL assessment and histological analysis. Biosafety of DPDH is also confirmed from hemolysis, body weight shifts during treatment and pathological analysis. This study demonstrates the use of dendronized polymer-DOX hybrids for specific drug molecules is a promising approach for drug delivery.

Photo-Electro Active Nanocomposite Silk Hydrogel for Spatiotemporal Controlled Release of Chemotherapeutics: An In Vivo Approach toward Suppressing Solid Tumor Growth.

Conventional systemic chemotherapeutic regimens suffer from challenges such as nonspecificity, shorter half-life, clearance of drugs, and dose-limiting toxicity. Localized delivery of chemotherapeutic drugs through noninvasive spatiotemporally controllable stimuli-responsive drug delivery systems could overcome these drawbacks while utilizing drugs approved for cancer treatment. In this regard, we developed photoelectro active nanocomposite silk-based drug delivery systems (DDS) exhibiting on-demand drug release in vivo. A functionally modified single-walled carbon nanotube loaded with doxorubicin (DOX) was embedded within a cross-linker free silk hydrogel. The resultant nanocomposite silk hydrogel showed electrical field responsiveness and near-infrared (NIR) laser-induced hyperthermal effect. The remote application of these stimuli in tandem or independent manner led to the increased thermal and electrical conductivity of nanocomposite hydrogel, which effectively triggered the intermittent on-demand drug release. In a proof-of-concept in vivo tumor regression study, the nanocomposite hydrogel was administered in a minimally invasive way at the periphery of the tumor by covering most of it. During the 21-day study, drastic tumor regression was recorded upon regular stimulation of nanocomposite hydrogel with simultaneous or individual external application of an electric field and NIR laser. Tumor cell death marker expression analysis uncovered the induction of apoptosis in tumor cells leading to its shrinkage. Heart ultrasound and histology revealed no cardiotoxicity associated with localized DOX treatment. To our knowledge, this is also the first report to show the simultaneous application of electric field and NIR laser in vivo for localized tumor therapy, and our results suggested that such strategy might have high clinical translational potential.

Silanized Liquid-Metal Nanoparticles for Responsive Electronics

Room-temperature liquid-metal particles are a burgeoning material platform for stimuli-responsive electronics, self-healing circuitry, stretchable/flexible conductors, drug delivery, and wearable d...

Advanced Hydrogels Based Drug Delivery Systems for Ophthalmic Delivery.

Hydrogels are aqueous gels composed of cross-linked networks of hydrophilic polymers. Stimuli-responsive based hydrogels have gained focus over the past 20 years for treating ophthalmic diseases. Different stimuli-responsive mechanisms are involved in forming polymer hydrogel networks, including change in temperature, pH, ions, and others including light, thrombin, pressure, antigen, and glucose-responsive. Incorporation of nanocarriers with these smart stimuli-responsive drug delivery systems that can extend the duration of action by increasing ocular bioavailability and reducing the dosing frequency. This review will focus on the hydrogel drug delivery systems highlighting the gelling mechanisms and emerging stimuli-responsive hydrogels from preformed gels, nanogels, and the role of advanced 3D printed hydrogels in vision-threatening diseases like age-related macular degeneration and retinitis pigmentosa. It also provides insight into the limitations of hydrogels along with the safety and biocompatibility of the hydrogel drug delivery systems.

Biodegradable hollow mesoporous organosilica-based nanosystems with dual stimuli-responsive drug delivery for efficient tumor inhibition by synergistic chemo- and photothermal therapy

Engineering gated porous nanocarriers with multi-stimuli-response is rather fascinating for efficient tumor chemotherapy owing to the avoidance of premature drug leakage and the accurate control of site-specific drug delivery. Herein, a phase-change material (PCM) as a stimuli-responsive ‘‘gate-keeper’’ and copper sulfide (CuS) nanocrystal as a photothermal agent were introduced into biodegradable hollow mesoporous organosilica nanoparticles (HMONs) to construct a multifunctional nanosystem for dual stimuli-responsive drug delivery. The capping of PCM on HMONs enabled the prevention of drug leakage and the temperature-responsive drug release manner, and the reducing-responsive biodegradability of disulfide-hybridized HMONs allowed the tumor microenvironment (TME)-sensitive drug release. With the aid of the near-infrared (NIR)-thermal conversion of CuS nanocrystals, the prepared nanosystem could not only realize both endogenous and external stimuli-triggered drug release, but also achieve synergistic effects of chemo- and photothermal therapy for tumor inhibition. In result, such biocompatible and biodegradable PCM-gated HMONs@CuS nanosystem achieved effective delivery of doxorubicin (DOX) and precise drug release at tumor site, and exhibited remarkable in vitro and in vivo tumor inhibition efficacy by combination of chemotherapy and photothermal therapy, showing great prospect in tumor treatment.

Stepwise-activatable hypoxia triggered nanocarrier-based photodynamic therapy for effective synergistic bioreductive chemotherapy

Tumor cell populations are highly heterogeneous, which limit the homogeneous distribution and optimal delivery of nanomedicines, thereby inducing insufficient therapeutic benefits. We develop tumor microenvironment activatable and external stimuli-responsive drug delivery system (TAT+AzoNPs), which can improve photodynamic therapy (PDT) induced bioreductive chemotherapy in different tumor cells both proximal and distal to vessels. The TAT peptide on the surface of TAT+AzoNPs can both facilitate the cell uptake and the penetration of TAT+AzoNPs, owing to its responsiveness to tumor stimuli pH. TAT+AzoNPs can keep the cargoes (photosensitizer chlorine e6 (Ce6) and hypoxia activatable prodrug tirapazamine (TPZ)) and highly accumulate within tumor cells proximity and distal to vessels. The Azo-benzene bonds as the linkers between amphiphilic polymers remain stable under normoxia, but quite break at hypoxic conditions. Upon external laser irradiation, the intratumoral fate of TAT+AzoNPs involved two processes: 1) TAT+AzoNPs achieve efficient PDT on tumor cells proximal to vessel, since sufficient O2 supply; and 2) PDT-induced more hypoxia can trigger TPZ release by breakage of Azo-benzene bond as well as accelerate the activation of TPZ for improvingcombination therapy efficacy in tumor cells distal to vessel. This study gives a direction for the development of stepwise-activatable hypoxia triggered nanosystem for PDT-induced bioreductive chemotherapy for tumor cells in different distances to vessels.

Ultrasound-responsive polymersomes capable of endosomal escape for efficient cancer therapy

Stimuli-responsive anticancer drug delivery vehicles have attracted increasing attention in nanomedicine. However, controlled drug release in vivo is still an important challenge, as traditional stimuli lack maneuverability. To solve this problem, we designed an ultrasound and pH-responsive polymersome by self-assembly of poly(ethylene oxide)-block-poly(2-(diethylamino)ethyl methacrylate)-stat-poly(methoxyethyl methacrylate) [PEO-b-P(DEA-stat-MEMA)], where PEO acts as the corona-forming block, DEA acts as the endosomal escape segment, and MEMA acts as the ultrasound-responsive segment. This strategy combines the advantages of noninvasive ultrasonic stimulus which can be applied from outside to any organ regardless of depth, and the weakly acidic microenvironment of tumor tissue. In vitro experiments confirmed excellent endosomal escape ability, on-demand drug release behavior, low cytotoxicity, and high intracellular delivery efficiency of polymersomes. In vivo antitumor tests revealed that in the presence of sonication, the anticancer drug was released at an accelerated rate from these ultrasound-responsive polymersomes, and the DOX-loaded polymersomes + sonication group significantly inhibited tumor growth (95% reduction in tumor mass) without any side effects. Overall, this ultrasound-responsive polymersome provides us with a fresh insight into designing next-generation stimuli-responsive drug carriers with better maneuverability and higher chemotherapeutic efficiency.

Engineering Microneedles for Therapy and Diagnosis: A Survey.

Microneedle (MN) technology is a rising star in the point-of-care (POC) field, which has gained increasing attention from scientists and clinics. MN-based POC devices show great potential for detecting various analytes of clinical interests and transdermal drug delivery in a minimally invasive manner owing to MNs’ micro-size sharp tips and ease of use. This review aims to go through the recent achievements in MN-based devices by investigating the selection of materials, fabrication techniques, classification, and application, respectively. We further highlight critical aspects of MN platforms for transdermal biofluids extraction, diagnosis, and drug delivery assisted disease therapy. Moreover, multifunctional MNs for stimulus-responsive drug delivery systems were discussed, which show incredible potential for accurate and efficient disease treatment in dynamic environments for a long period of time. In addition, we also discuss the remaining challenges and emerging trend of MN-based POC devices from the bench to the bedside.

Soft and elastic hollow microcapsules embedded silicone elastomer films with enhanced water uptake and permeability for mechanical stimuli responsive drug delivery applications.

Polydimethylsiloxane (PDMS) film with significantly enhanced water permeability and uptake was prepared by incorporating spherical elastic hollow microcapsules (eHMCs) in it. eHMCs were prepared through O/W/O emulsification method. Water permeability and uptake of the film increased significantly in proportion to the amount of embedded eHMCs while minimizing the changes in elastic characteristics and transparency of PDMS. The release rate of loaded water soluble model drug from the eHMC-embedded PDMS film could be controlled by the magnitude of uniaxial mechanical stimulus applied over the film and initial drug loading amount, with negligible release of drug from the film in the absence of external stimulation. Thus, these biocompatible and elastic composite PDMS films are potentially useful, including as an easily accessible and instantly effective way of controlling hydrophilic drug release using the mechanical stimulus as well as a soft elastomer with enhanced water uptake and permeability.

Facile Construction of i-Motif DNA-Conjugated Gold Nanostars as Near-Infrared and pH Dual-Responsive Targeted Drug Delivery Systems for Combined Cancer Therapy.

Stimuli-responsive DNA-based nanostructures have emerged as promising vehicles for intelligent drug delivery. In this study, i-motif DNA-conjugated gold nanostars (GNSs) were fabricated in a facile manner as stimuli-responsive drug delivery systems (denoted as A-GNS/DNA/DOX) for the treatment of cancer via combined chemo-photothermal therapy. The i-motif DNA is sensitive to the environmental pH and can switch from a single-stranded structure to a C-tetrad (i-motif) structure as the environmental pH decreases from neutral (∼7.4) to acidic (<6.0). The loaded drug can then be released along with the conformational changes. To enhance cellular uptake and improve cancer cell selectivity, the aptamer AS1411, which recognizes nucleolins, was employed as a targeting moiety. The A-GNS/DNA/DOX nanocomposites were found to be highly capable of photothermal conversion and exhibited photostability under near-infrared (NIR) irradiation, and the pH and NIR irradiation effectively triggered the drug-release behaviors. In addition, the A-GNS/DNA/DOX nanocomposites exhibited good biocompatibility. The targeting recognition enabled the A-GNS/DNA/DOX to exhibit higher cellular uptake and therapeutic efficiency than the GNS/DNA/DOX. Notably, under NIR irradiation, a synergistic effect between chemotherapy and photothermal therapy can be achieved with the proposed delivery system, which exhibits much higher therapeutic efficiency both in monolayer cancer cells and tumor spheroids as compared with a single therapeutic method. This study highlights the potential of GNS/DNA nanoassemblies for intelligent anticancer drug delivery and combined cancer therapy.

The stimuli-responsive properties of doxorubicin adsorbed onto bimetallic Au@Pd nanodendrites and its potential application as drug delivery platform

Bimetallic nanoparticles have continued to attract interest as drug delivery systems in cancer therapy even though their nature of interaction with small molecules is limited. Currently, many delivery systems based on monometallic nanoparticles are being fabricated for loading of drugs, thus prompting the need to explore and get more understanding of dendritic bimetallic nanostructure-drug interaction. The bimetallic gold-core palladium-dendritic shell nanoparticles (Au@PdNDs) were synthesized by hot injection method and stabilized with methoxy polyethylene glycol thiol (mPEG-SH). An anti-cancer drug, doxorubicin (DOX) was conjugated to the bimetallic nanodendrites leading to the formation of DOX/Au@PdNDs.PEG complex. We used TEM, FTIR, and zeta-potential to study the drug-nanodendrites interaction. The effect of DOX binding and release capacity with regards to pH, adsorption kinetics, solvent polarity, isotherms and temperature on Au@PdNDs.PEG were investigated. The results showed a spontaneous heterogeneous binding of DOX on the Au@PdNDs.PEG surfaces and time-dependent loading capacity of ~90% maximum adsorption within 24h. Moreover, the experimental results showed that the adsorption isotherm data fitted well with the Freundlich model and a pseudo-second order adsorption kinetics. The desorption of DOX was triggered under simulated tumor microenvironmental conditions and should open new opportunities for potential multi stimuli-responsive drug delivery applications.

Stimuli-responsive/smart tablet formulations (under simulated physiological conditions) for oral drug delivery system based on glucuronoxylan polysaccharide

Objective: Development of stimuli-responsive intelligent drug delivery system (based on a polysaccharide, glucuronoxylan [GX]) with on-off switching properties under physiological conditions.Significance: As GX exhibits high swelling index and stimuli-responsive swelling/de-swelling properties, therefore, this material appeared highly useful to design pH, solvent and ionic stress-sensitive oral tablet formulations, which offered on-off switching properties. In this way, we could design intelligent/smart drug delivery systems for levosulpiride (LS) and theophylline (TF) with valuable pharmaceutical properties.Methods: GX-based tablet formulations were explored for stimuli-responsive, reversible swelling–deswelling behavior, dynamic swelling, and its kinetics. Tablet surface and channeling after swelling were observed using scanning electron microscopy (SEM). Drug release study was performed mimicking the physiological conditions like pH and transit time of gastrointestinal tract (GIT). Radiographic images of tablet path (in vivo) were recorded.Results: GX-based formulations exhibited high swelling in deionized water (DW), pH 6.8 and 7.4 while negligible swelling at pH 1.2. SEM images discovered the presence of microcracks and nanopores on the surface of tablets and showed channeling after swelling of tablets in DW. Sustained drug release was observed and found directly proportional to the concentration of GX in the formulations with negligible release at pH 1.2. In vivo radiographic evaluation indicated the retention of tablets in GIT for 7 h. Hemocompatibility studies showed the non-thrombogenic and non-hemolytic nature of GX.Conclusions: GX-based smart/stimuli-responsive formulations can control/sustain the release of drugs in GIT.

Engineered functionalized 2D nanoarchitectures for stimuli-responsive drug delivery

Functionalized 2D nanoarchitectures work as intelligent “host-conjugator” combined platforms for exogenous and endogenous stimuli-responsive drug delivery.

A stimuli-responsive anticancer drug delivery system with inherent antibacterial activities.

We describe a novel class of stimuli-sensitive sulfonium-based synthetic lipids, which exhibit several favorable biophysical properties of phospholipids. The potent sulfonium-based lipid was successfully disassembled by glutathione to release the encapsulated drug molecules in a controlled manner. The cationic lipid also showed lower cytotoxicity against mammalian cells and displayed moderate antibacterial activities.

Studies on interaction potency model based on drug synergy and therapeutic potential of triple stimuli-responsive delivery of doxorubicin and 5-fluoro-2-deoxyuridine against lymphoma using disulfide-bridged cysteine over mesoporous silica nanoparticles.

A triple stimuli-responsive drug delivery platform involving doxorubicin, 5-fluoro-2-deoxy uridine and folic acid was fabricated on mesoporous silica nanoparticles for targeting delivery against a highly aggressive murine lymphoma called Dalton's lymphoma. Fabrication of the unique construct by amalgamating active and passive targeting mechanisms offers a novel hyper-chimeric platform for a stimuli-responsive drug delivery system. The novel construct enables efficient and precise delivery of the precious cargo to the tumor sites. Active targeting by folic acid directs the doxorubicin and 5-fluoro-2-deoxy uridine in the close proximities of the tumor cells, causing efficient killing and significant growth inhibition. Isobologram models, zero interaction potency dose-response surface plots and matrices were generated to evaluate the combination synergism of the two drugs. Therapy with the dual drug-bearing construct in mice with established tumors significantly reduced the tumor load and enhanced the survival of the animals compared with the untreated control. Therapy with the dual delivery system also augmented the innate and adaptive immune defense mechanisms of the treated animals. CD8+ T cells, natural killer cells and the dendritic cells from the treated group following successful therapy with the novel construct showed enhanced cytotoxicity and growth inhibitory capacities against DL tumor cells.

Engineered bovine serum albumin-based nanoparticles with pH-sensitivity for doxorubicin delivery and controlled release

In this work, we prepared a stimuli-responsive system for drug delivery and controlled release by engineering the bovine serum albumin (BSA). The doxorubicin (DOX)-loaded BSA nanoparticles (NPs) were conveniently prepared using desolvation method, followed by crosslinking through Schiff base bonds, leading to pH-sensitive DOX-loaded system (DOXs@BSA NPs). The resulted DOXs@BSA NPs showed high drug loading capacity (21.4%), and the particle size was about 130 nm with narrow polydispersity and high negative surface charge (−20.5 mV). The pH-sensitivity of DOXs@BSA NPs was evidenced by the size changes and charge reversal after incubation at different pH values. The DOXs@BSA NPs showed high serum stability which indicated the prolonged circulation time. The in vitro drug release experiment showed that the release of DOX was obviously accelerated by acidity because of disassembly of NPs induced by cleavage of Schiff base bonds. The drug release mechanism was thoroughly studied using a semi-empirical model, further confirming the pH played an important role in drug controlled release process. The results of cytotoxicity assay revealed that DOXs@BSA NPs exhibited much higher toxic effects for tumor cells in comparison to the free DOX control. Collectively, these results demonstrated that DOXs@BSA NPs might be potential application for drug delivery and controlled release in cancer chemotherapy. Moreover, this work also showed that preparation of stimuli-responsive drug delivery system by engineering the commercial biomaterials could be a promising method to develop multi-functional nanomedicine.

Stimuli-responsive charge-reversal nano drug delivery system: The promising targeted carriers for tumor therapy.

The stimuli-responsive charge-reversal nano drug delivery system (CRNDDS) for the treatment of tumors has attracted much attention as an effective drug delivery system. The charge-reversal nanocarriers are either uncharged or negatively charged under normal physiological environment; however, they acquire positive charged in tumor tissue microenvironment. The process of charge reversal from negative-to-positive results in not only quick drug release in acidic environment but also enhance the cellular uptake of drug through electrostatic absorptive endocytosis resulting in improvement of cancer therapeutic outcome. In this review, we discuss the recent advances in the study of charge-reversal nanocarriers that could control the distribution of drugs in response to specific stimuli, such as pH, reduced glutathione (GSH) concentration, enzyme concentration, light and thermal stimulation. The applications of CRNDDS in the tumor treatment was also analyzed and summarized.