Intelligent Drug Delivery Systems Research Articles

Temperature and CO2 Dual-Responsive Pickering Emulsions Using Jeffamine M2005-Modified Cellulose Nanocrystals

Cellulose nanocrystals (CNCs) with excellent biodegradability are promising biomaterials for use as responsive Pickering emulsifiers. However, the high hydrophilicity of CNCs limits their emulsification ability. Some existing studies have utilized complicated covalent modification procedures to increase the hydrophobicity of CNCs. To simplify the modification process, we prepared hydrophobically modified CNCs (CNCs-M2005) via simple and controllable electrostatic interactions with thermosensitive M2005. The obtained CNCs-M2005 exhibited temperature and CO2 dual-responsive properties. Subsequently, stable oil/water Pickering emulsions were prepared using the partially hydrophobic CNCs-M2005 at 20 °C. However, demulsification occurred when the temperature increased to 60 °C. This temperature-induced demulsification resulted from the dehydration of polyethylene oxide and polypropylene oxide, causing the aggregation of the CNCs-M2005, as shown by dynamic light scattering and transmission electron microscopy experiments. In addition, demulsification was also achieved after bubbling CO2, which was attributed to the dissociation of the partially hydrophobic CNCs-M2005. The temperature and CO2 dual-responsive biosafe Pickering emulsions open up opportunity for the design of intelligent food, cosmetic, and drug delivery systems.

In Vitro and In Vivo Biocompatibility of Novel Zwitterionic Poly(Beta Amino)Ester Hydrogels Based on Diacrylate and Glycine for Site‐Specific Controlled Drug Release

AbstractNew (β‐aminoester) hydrogels (PBAE) based on di(ethylene glycol)diacrylate and glycine are successfully synthesized and characterized for the first time in this work. PBAE macromers are obtained using Michael addition. By changing the diacrylate/amine stoichiometric ratio, but maintaining it >1, samples with different chemical structure containing acrylate end‐groups are obtained. The hydrogels are synthesized from macromers utilizing free radical polymerization. Chemical structure of macromers and hydrogels is confirmed by proton nuclear magnetic resonance, and Fourier transform infra‐red spectroscopy. Swelling and degradation rates in physiological pH range change notably with pH and monomer molar ratio, validating pH sensitivity and zwitterionic behavior, which can be finely tuned by changing any of these parameters. In vitro cytotoxicity and in vivo acute embryotoxicity in zebrafish (Danio rerio) performed to assess the biocompatibility of the novel hydrogel materials and their degradation products reveal that materials are nontoxic and biocompatible. The Cephalexin in vitro drug release study, at pH values 2.20, 5.50, and 7.40, demonstrates pH‐sensitive delivery with the release profiles effectively controlled by pH and the hydrogel composition. PBAE hydrogels exhibit great potential for a variety of biomedical applications, including tissue regeneration and intelligent drug delivery systems.

Facile preparation of acid/CO2 stimuli-responsive sheddable nanoparticles based on carboxymethylated chitosan

The present study describes the facile preparation of acid/CO2 stimuli-responsive sheddable nanoparticles based on carboxymethylated chitosan (CMCS). Commercially available CMCS was grafted with monomethoxy polyethylene glycol (mPEG) chains via an acid/CO2 responsive linker, i.e., benzoic-imine, and then was used for the cross-linking with CaCl2. With a high CMCS concentration up to 7 mg/mL, stable nanoparticles were successfully prepared. The particle size grew slightly with increasing the molecular weight of mPEG. When the concentration of CaCl2 and the feed ratio of CMCS to mPEG increased, the particle size decreased at first and then increased after reaching a minimum size. When the particles were stimulated by CO2 or acid, benzoicimine cleaved quickly, and mPEG fell off the nanoparticles simultaneously, and then flocculation and precipitation occurred. These sheddable nanoparticles might have potential application in the biomedical field including the intelligent drug delivery system.

Tailored Design of an ROS-Responsive Drug Release Platform for Enhanced Tumor Therapy via "Sequential Induced Activation Processes".

The reactive oxygen species (ROS)-responsive intelligent drug delivery system has developed rapidly in recent years. However, because of the low concentration of ROS in most types of tumor cells, it is not possible to rapidly and effectively stimulate the drug delivery system to release the active drug. Here, we introduced "sequential induced activation processes" for efficient tumor therapy by designing a new ROS-responsive drug release platform. β-Lapachone, a positively charged nitrogen mustard (NM) prodrug, and two diblock molecules (mPEG-AcMH and PAsp-AcMH) are self-assembled to form prodrug primary micelles, which are further aggregated into nanoparticles that facilitate drug codelivery. When administered by intravenous injection, the nanoparticles reach the tumor site and enter the tumor cells by endocytosis. The β-lapachone released in the tumor cells induces a large amount of H2O2, and the ROS-responsive NM prodrug is activated to form activated NM, quinone methide, and boric acid under the induction of H2O2. The activated NM leads to tumor cell apoptosis.

Mussel-Derived, Cancer-Targeting Peptide as pH-Sensitive Prodrug Nanocarrier

In this work, we prepared a novel cancer chemotherapeutic nanocarrier through the self-assembly of a mussel-derived, cancer-targeting peptide with a pH-sensitive conjugation of antitumor drugs. The biomimetic peptide was designed with a fluorescent molecule fluorescein isothiocyanate for imaging, a RGD sequence for cancer-targeting and tetravalent catechol groups for dynamic conjugation of the antitumor drug bortezomib via pH-cleavable boronic acid-catechol esters. Our study demonstrated that the peptide-based prodrug nanocarrier dramatically the enhanced specific cellular uptake and cytotoxicity toward human breast cancer cells in vitro in comparison with free drug and nontargeting control nanoparticles. Likewise, the prodrug nanocarrier showed improved therapeutic efficacy and low systematic toxicity in vivo. Considering highly biomimetic nature of the peptide-based nanocarriers, rapid drug release from the dynamically conjugated prodrugs, and convenience of introducing cancer-targeting activity onto this nanosystem, we believe our work would provide new ideas for the development of intelligent and biocompatible drug delivery systems to improve the chemotherapy efficacy in clinic. Furthermore, the pH-sensitive drug conjugation mechanism on peptide-based nanocarriers would provide a hint for the exploitation of dynamic prodrug strategies and the development of highly biocompatible nanocarriers using biogenic materials, e.g., the proteinogenic nanomaterials decorated with drugs through dynamic covalent chemistry.

Development of multifunctional cobalt ferrite/hydroxyapatite nanocomposites by microwave assisted wet precipitation method: A promising platform for synergistic chemo-hyperthermia therapy

Abstract Functional nanocomposites capable of multimodal therapy hold great potential to improve the efficiency of cancer therapy. Herein, we report a magnetic nanocomposite of cobalt ferrite/hydroxyapatite followed by loading a chemotherapeutic drug (5-fluorouracil, FU) to construct the intelligent drug delivery system and/or hyperthermia carrier. To do that, cobalt ferrite/hydroxyapatite nanocomposite was successfully synthesized by microwave assisted wet precipitation method, subsequently, FU loaded onto the formed composites through adsorption method. This nanocomposite exhibits ferromagnetic behaviour with a magnetic saturation value of approximately 2.5–8.2 emu/g. Upon alternating magnetic field, it could generate hyperthermia temperature within a short time (43°C in 4.5 min) and facilitate the release of encapsulated FU from the composite with enhanced release rate. These multifunctional carriers also demonstrate a noticeable proliferative activity against healthy fibroblast cells (L929) and suppressed growth against osteosarcoma cells (MG63). Therefore, this studied nanoplatform might be a promising candidate for synergistic chemo-hyperthermia therapy.

Engineered pH‐responsive hydrazone‐carboxylate complexes‐encapsulated 2D matrices for cathepsin‐mediated apoptosis in cancer

Spurred by the current advancements in engineering various intelligent nanoparticle-based drug delivery systems, conjugation of drugs with the stimuli-responsive molecular switches has become one of the most efficient approaches to deliver a drug cargo in spatiotemporal controlled fashions. In this study, we fabricated an innovative pH-triggered hydrazone-carboxylate complex of doxorubicin (Dox), which was subsequently encapsulated in the layered double hydroxide (LDH) nanoparticles for effective cancer therapeutics. These two-dimensional (2D) biodegradable matrices efficiently delivered Dox by pH-triggered release in the acidic lysosomal environment and their subsequent escape to cytosol. Moreover, the delivered Dox molecules and high positively-charged surfaces of LDHs facilitated the cancer cell ablation via enhancing the cathepsins-mediated cell apoptosis assisted by free radical species generation. The critical advancements in the nanoparticle-based designs and substantial ablation of tumor cells through a free radical attack indicate that the designed pH-triggered drug composites can be used for efficient cancer therapeutics. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1184-1194, 2019.

Research progress in stimuli-responsive mesoporous silica nano drug delivery systems for tumor therapy

In recent years, mesoporous silica nanoparticles (MSNs) have been widely used in the construction of various intelligent drug delivery systems due to their unique and excellent properties. The stimuli-responsive drug delivery system based on mesoporous silica nanoparticles can effectively load anticancer drugs and target them to tumor cells, and then responsively release anticancer drugs under the action of specific stimulation signals. The method of specifically delivering anticancer drugs to target sites not only can greatly improvethe drug efficacy, but also effectively reduce the side effects of anticancer drugs on normal tissues and organs. Thereby the advantages of anticancer drugs in tumor therapy are improved. In this paper, the applications and developments of stimuli-responsive mesoporous silica nano drug delivery systems in tumor therapy were summarized. Key words: Mesoporous silica nanoparticles; Stimuli-responsive; Controlled release; Tumor therapy

Clay Minerals in Skin Drug Delivery

AbstractClays have played an important role in medicine since the dawn of mankind and are still applied widely as active ingredients and/or excipients in pharmaceutical formulations. Due to their outstanding properties of large retention capacity, swelling and rheological properties, and relative low cost, they have been used widely as advanced carriers for the efficient delivery of drugs by modifying their release (rate and/or time), increasing the stability of the drug, improving the dissolution profile of a drug, or enhancing their intestinal permeability. In addition, recent studies have shed new light on the potential of clay minerals in the nanomedicine field due to their biocompatibility, beneficial effects of clay nanoparticles on cellular adhesion, proliferation, and differentiation. Use as active ingredients and excipients are exerted via the oral and topical administration pathways. Skin drug delivery represents an attractive alternative to the oral route, providing local and/or systemic drug delivery. Due to their complex structures, however, most drugs penetrate the human skin only with difficulty. Enormous efforts have been invested, therefore, in developing advanced drug delivery systems able to overcome the skin barrier. Most strategies require the use of singular materials with new properties. In particular, and on the basis of their inherent properties, clay minerals are ideal candidates for the development of intelligent skin drug delivery systems. In this article, the properties of clay materials and their use in the skin-addressed pharmaceutical field are reviewed. A brief introduction of skin physiology and biopharmaceutical features of penetration by a drug through the skin layers is also included and is designed to shed light on the optimum properties of ideal nanosystems for advanced skin drug delivery. Special attention is devoted to the pharmacological functions of clays and their biomedical applications in pelotherapy, wound healing, regenerative medicine, antimicrobial, and dermocosmetics.

A Fatty Acid Induces the Functional Assembly of a Channel Protein into Phospholipid Vesicles

The release of encapsulated cargo is an important step towards the design of intelligent drug delivery systems or vesicle-based bioreactors. Controlling the integration of pore forming channels into phospholipid vesicle membranes provides a route to initiate content release that could be coupled to gene-expression systems. Here, we present the design of phospholipid vesicles that release cargo upon the temporally controlled assembly of pore-forming channels. Our approach was to design a synthetic vesicle in which membrane composition could be remotely changed to enable the assembly of a pore-forming channel protein, α-hemolysin (αHL), and trigger content release. We first observed that a membrane lacking a sufficient concentration of cholesterol is not compatible with channel assembly and we hypothesized that increasing membrane fluidity, through the addition of oleic acid (OA) micelles could promote channel assembly. Using a dye release assay, we first confirmed that increasing OA content in phospholipid membranes leads to pore assembly. Next, we demonstrated that remote addition of OA micelles to inactive membranes results in fatty acid membrane uptake and channel assembly. We then showed that our system provides a route to control the integration of αHL into vesicle membranes when the channel protein is produced through a cell-free expression system. We remotely added OA micelles to vesicles present in a cell-free expression system where the amount of protein expressed is difficult to control. OA addition led to functional pore assembly and dye release. We ultimately demonstrate a new way to utilize remote changes in membrane composition to control αHL assembly and content release. Our study contributes to the design of vesicle-based technologies and also reveals new insight into the relationship between membrane composition and cholesterol-dependent cytolysin channel assembly.

Redox/pH dual-stimuli responsive camptothecin prodrug nanogels for “on-demand” drug delivery

At present, chemotherapy remains to be one of the most important therapeutic approaches for malignant tumors. The tumor microenvironment(TME)-responsive intelligent drug delivery systems are still the hot research topics in delivering chemotherapeutic drugs. Camptothecin (CPT) possesses very strong antitumor activities, but its clinical application is hindered by its poor water-solubility and serious toxic side effects. Herein, a new intelligent and TME-responsive P(CPT-MAA) prodrug nanogel was developed for delivering CPT and reducing its side effects. P(CPT-MAA) prodrug nanogels were prepared with methacrylic acid (MAA), CPT monomer (CPTM) and N,N′-methylenebisacrylamide (Bis) via distillation-precipitation polymerization, in which CPT was covalently conjugated into the nanogels via redox-responsive disulfide linker. The as-prepared nanogels were spherical shapes with uniform size and narrow size distribution. With the help of redox-responsive property of disulfide linker and pH-responsive property of PMAA, the release of CPT from prodrug nanogels was redox/pH-dual dependent and could be accelerated by the increased concentration of GSH and the decreased pH value, which were favorable to realize the “on-demand” drug release in tumor cell and tumor tissue microenvironment. Furthermore, P(CPT-MAA) prodrug nanogels exhibited superior antitumor activity both in vitro and in vivo without observed side effects. Hence, the prepared P(CPT-MAA) prodrug nanogels may be a promise delivery system for chemotherapeutic agents.

A biomimetic cascade nanoreactor for tumor targeted starvation therapy-amplified chemotherapy

Targeted drug delivery with precisely controlled drug release and activation is highly demanding and challenging for tumor precision therapy. Herein, a biomimetic cascade nanoreactor (designated as Mem@GOx@ZIF-8@BDOX) is constructed for tumor targeted starvation therapy-amplified chemotherapy by assembling tumor cell membrane cloak and glucose oxidase (GOx) onto zeolitic imidazolate framework (ZIF-8) with the loading prodrug of hydrogen peroxide (H2O2)-sensitive BDOX. Biomimetic membrane camouflage affords superior immune evasion and homotypic binding capacities, which significantly enhance the tumor preferential accumulation and uptake for targeted drug delivery. Moreover, GOx-induced glycolysis would cut off glucose supply and metabolism pathways for tumor starvation therapy with the transformation of tumor microenvironments. Importantly, this artificial adjustment could trigger the site-specific BDOX release and activation for cascade amplified tumor chemotherapy regardless of the complexity and variability of tumor physiological environments. Both in vitro and in vivo investigations indicate that the biomimetic cascade nanoreactor could remarkably improve the therapeutic efficacy with minimized side effects through the synergistic starvation therapy and chemotherapy. This biomimetic cascade strategy would contribute to developing intelligent drug delivery systems for tumor precision therapy.

DISSECTING CYFIP1 AND CYFIP2 CONTRIBUTIONS TO COMPULSIVE-LIKE BEHAVIOR AND BINGE EATING IN MICE: IMPLICATIONS FOR EATING DISORDERS AND NEURODEVELOPMENTAL DISORDERS WITH HYPERPHAGIA

Combination therapies for cancer have attracted great attention recently due to their synergistic effects to improve the therapeutic efficacy. In order to concurrently deliver dual or multiple drugs within solid tumor and exert their therapeutic effect, developing an intelligent and safe drug delivery system is highly expected. In this work, we synthesized a series of dual thermo- and pH-responsive copolymers containing hydrophobic poly(ε-caprolactone) (PCL) and hydrophilic thermo-responsive poly(N-isopropylacrylamide) (PNIPAAm) that was copolymerized with a β-alanine-functionalized monomer (βA). Both thermo and pH-response in a suitable window for physiological environment can be achieved via adjusting the ratios of NIPAAm and acidic moieties. The chemotherapeutic drug doxorubicin (DOX) and photosensitizer (meso-tetraphenylchlorin, m-TPC) have been simultaneously encapsulated in PCL-b-P(NIPAAm-co-βA) polymeric micelles with hydrodynamic diameters around 231–269 nm. The in vitro release studies demonstrated the increased drug release at acidic pH 6. The cell viability treated with dual drug-loaded micelles showed improved therapeutic efficiency under light irradiation, indicating combined effect of DOX and m-TPC has potential as dual-modality for cancer treatment.

BSA modified, disulfide-bridged mesoporous silica with low biotoxicity for dual-responsive drug delivery

Abstract Siliceous materials based intelligent drug delivery systems (DDS) have attracted numerous attentions. Unfortunately, their intrinsic biologic inertia and non-degradability are critical issues need to be addressed because it hampers further clinical translation application. Herein, disulfide-bridged mesoporous silica nanoparticles (designed as mSiO2(s-s)) have been synthesized through nucleophilic substitution reaction, which have biodegradability in simulative tumor reducing conditions. Furthermore, folic acid (FA) decorated bull serum albumin (BSA) has been modified onto the surface of mSiO2(s-s) to improve tissue biocompatibility, prevent anticancer drugs leakage and endow effective targeting capacity. Therefore, the nanoparticles present good biodegradability, tissue biocompatibility, tumor cell targeting capacity and pH/glutathione (GSH) dual-responsive drug release capacity. This novel drug nanocarrier possesses biosafety and effective anti-cancer strategy, provides significant promising in future biomedical application.

Construction of a Glutathione-Responsive and Silica-Based Nanocomposite for Controlled Release of Chelator Dimercaptosuccinic Acid.

Dimercaptosuccinic acid (DMSA) is an oral heavy metal chelator. Although DMSA is the most acceptable chelator in the urinary excretion of toxic elements from children and adults, its defects in plasma binding and the membrane permeability limit its interaction with intracellular elements and affect its efficacy in chelation therapy. Herein, a novel nanocomposite composed of mesoporous silica nanoparticles (MSNs), disulfide bond, and DMSA was synthesized and characterized with a scanning/transmission electron microscope, IR and Raman spectra, and TGA analysis. The in vitro interactions with glutathione (GSH) and cellular uptake assays showed that it was able to be stable in extracellular environments such as in blood, be internalized by cells, and release DMSA inside via GSH-triggered disulfide cleavage reaction. The in vitro adsorption assays showed that MSNs-SH as its intracellular metabolite had strong adsorbability for models of Hg2+ or Pb2+. The hemolysis and cell viability assays showed that it was compatible with blood and cells even at a concentration of 1000 μg·mL−1. All above could not only enable it to be a GSH-responsive drug delivery system (DDS) for DMSA delivery but also to be a solution for its defects and efficacy. Thus, introduction of intelligent DDS might open a new avenue for DMSA-based chelation therapy.

Control releasing 5-aminosalicylic acid using pH-sensitive hydrogel with novel albumin cross-linker

Intelligent drug delivery systems are growing and changing too fast, these systems usually show a proper response at the proper time to one or several environmental factors. In the current research a biodegradable drug delivery system (pectin-g-PMA-co-PAAm) was designed and synthesized to release 5 aminosalicylic acid (5-ASA). The synthesized hydrogel is based on natural pectin and is in the form of simultaneous graft copolymerization of synthesized acryl-acid and acryl-amid. Using vinylized bovine serum albumin (VBSA) as cross linker agent is amongst important characteristics of this hydrogel. VBSA was synthesized through BSA modification with methylene-bis-acrylamide (MBA). In addition to having high water absorption, this hydrogel is pH-sensitive. In vitro tests under acid and base conditions of stomach show that this hydrogel is an appropriate option to release drugs through mouth. SEM analysis images show that synthesized hydrogel has a porous surface composed of nano and micro cavities.

Transporte autorregulador de fármacos: un sistema inteligente de administración de fármacos

Introducción: El objetivo principal de cualquier científico farmacéutico es desarrollar un sistema de administración de fármacos que sea seguro, efectivo, estable, que cumpla con los requisitos del paciente y cumpla con los requisitos de los clientes. Llevar a un gran interés de investigación para desarrollar el sistema de entrega de medicamentos que permitirá suministrar medicamentos «a demanda». Estos sistemas «sensibles a estímulos e inteligentes» han sido diseñados para administrar el farmaco en varios momentos o en varios sitios en el cuerpo, de acuerdo con un estímulo endógeno o aplicado externamente. Objetivos: Este artículo tiene como objetivo revisar diversas investigaciones en el campo de los sistemas autorreguladores de administración de fármacos en forma tabular para que uno pueda utilizar estos hallazgos para un mayor desarrollo de sistemas inteligentes de administración de fármacos. Método: Los investigadores han aplicado varios principios fisicoquímicos y esquemas químicos para obtener el patrón de liberación del fármaco según las necesidades del cuerpo. Dichos dispositivos se pueden usar para la administración inteligente de medicamentos necesarios para el tratamiento de muchas enfermedades, como la diabetes. Resultados y discusión: Este tipo de sistema inteligente primero detecta las señales causadas por la enfermedad, juzga la magnitud de las señales y luego libera la droga en respuesta directa. Conclusión: En este artículo, hemos discutido varias innovaciones en el campo de los sistemas autorreguladores de administración de fármacos y sugerimos que aquí hay mucho campo de investigación en este campo.

Development of photo and pH dual crosslinked coumarin-containing chitosan nanoparticles for controlled drug release

A new strategy has been developed to the fabrication of chitosan nanoparticles as anticancer drug nanocarriers with ultraviolet-responsive coumarin derivatives and pH-responsive imine groups. For this purpose 8-formyl-7-hydroxy-4-methylcoumarin (8-FHMC) was initially synthesized as novel and dual crosslinking agent in order to produce coumarin-containing chitosan nanoparticles via oil-in-water nanoemulsion system. The structure of the resultant compounds and nanoparticles were confirmed by means of 1H NMR, FT-IR, UV–vis spectroscopy and XRD. The morphology and size distribution of the coumarin-containing chitosan nanoparticles was also characterized using SEM, AFM and DLS. The drug-loaded coumarin-containing chitosan nanoparticles were stable at physiological conditions, and can also be disassociated by the cleavage of imine linkages in the crosslinking segments under acidic condition. Compared to non-photo-crosslinked chitosan nanoparticles, photo-crosslinked chitosan nanoparticles displayed controllable and slower release. Thus, we have showed that chitosan nanoparticles crosslinked by coumarin with photo- and pH-responsive properties is a promising and novel drug carrier for designing intelligent drug delivery systems.

Polymerization-Induced Self-Assembly of Functionalized Block Copolymer Nanoparticles and Their Application in Drug Delivery.

Drug delivery systems (DDS) based on functionalized polymeric nanoparticles have attracted considerable attention. Although great advances have been reported in the past decades, the fabrication efficiency and reproducibility of polymeric nanoparticles are barely satisfactory due to the intrinsic limitations of the traditional self-assembly method, which severely prevent further applications of the intelligent DDS. In the last decade, a new self-assembly method, which is usually called polymerization-induced self-assembly (PISA), has become a powerful strategy for the fabrication of the polymeric nanoparticles with bespoke morphology. The PISA strategy efficiently simplifies the fabrication of polymeric nanoparticles (combination of the polymerization and self-assembly in one pot) and allows the fabrication of polymeric nanoparticles at a relatively high concentration (up to 50 wt%), making it realistic for large-scale production of polymeric nanoparticles. In this review, the developments of PISA-based polymeric nanoparticles for drug delivery are discussed.

Implementation of Industrial Additive Manufacturing: Intelligent Implants and Drug Delivery Systems.

The purpose of this study is to demonstrate the ability of additive manufacturing, also known as 3D printing, to produce effective drug delivery devices and implants that are both identifiable, as well as traceable. Drug delivery devices can potentially be used for drug release in the direct vicinity of target tissues or the selected medication route in a patient-specific manner as required. The identification and traceability of additively manufactured implants can be administered through radiofrequency identification systems. The focus of this study is to explore how embedded medication and sensors can be added in different additive manufacturing processes. The concept is extended to biomaterials with the help of the literature. As a result of this study, a patient-specific drug delivery device can be custom-designed and additively manufactured in the form of an implant that can identify, trace, and dispense a drug to the vicinity of a selected target tissue as a patient-specific function of time for bodily treatment and restoration.