Stimuli-responsive Drug Delivery Research Articles

Tumor Microenvironment-Stimuli Responsive Nanoparticles for Anticancer Therapy.

Cancer is a disease that affects a large number of people all over the world. For treating cancer, nano-drug delivery system has been introduced recently with objective of increasing therapeutic efficiency of chemotherapeutic drug. The main characteristics of this system are the encapsulation of the insoluble chemotherapeutic cargo, increasing the period of circulation in the body, as well as the delivery of the drug at that specific site. Currently, the nano-drug delivery system based on the stimuli response is becoming more popular because of the extra features for controlling the drug release based on the internal atmosphere of cancer. This review provides a summary of different types of internal (pH, redox, enzyme, ROS, hypoxia) stimuli-responsive nanoparticle drug delivery systems as well as perspective for upcoming times.

Micro-/Nano-Structures on Biodegradable Magnesium@PLGA and Their Cytotoxicity, Photothermal, and Anti-Tumor Effects.

The size and structural control of particulate carriers for imaging agents and therapeutics are constant themes in designing smart delivery systems. This is motivated by the causal relationship between geometric parameters and functionalities of delivery vehicles. Here, both in vitro and in vivo, the controlling factors for cytotoxicity, photothermal, and anti-tumor effects of biodegradable magnesium@poly(lactic-co-glycolic acid (Mg@PLGA) particulate carriers with different sizes and shell thicknesses are investigated. Mg@PLGA microspheres fabricated by microfluidic emulsification are shown to have higher Mg encapsulation efficiency, 87%, than nanospheres by ultrasonic homogenization, 50%. The photothermal and anti-tumor effects of Mg@PLGA spheres are found to be dictated by their Mg content, irrelevant to size and structural features, as demonstrated in both in vitro cell assays and in vivo mice models. These results also provide important implications for designing and fabricating stimuli-responsive drug delivery vehicles.

Synthesis and Characterization of Dual-function H2O2-Responsive Nanoparticles for Drug Delivery to Treat Atherosclerosis

Oxidative stress is one of the major factors involved in pathogenesis of atherosclerosis. Here, a smart dual-function drug delivery system (DDS) that neutralized the plaques through its reaction with the oxidative microenvironment was fabricated. Micelles were obtained from the graft copolymer of serotonin hydrochloride, polyethylene glycol, p (itaconic acid) and aminophenylboronic-acid-linked rutin. Fluorescence carbon quantum dots (CDs) were attached to the surface of the micelles to provide dual functionality of precise treatment and diagnosis. DDS was simultaneously served as a stimuli-responsive drug delivery carrier and as a probe to detect plaques. In vitro experiments indicated that these “smart” nanoparticles could efficiently target macrophages and provide accurate imaging. At the same time, their “smart” responses to H 2 O 2 solved the problem of sudden drug release, which could significantly improve therapeutic effect of the delivered drug. A “smart” response nanoparticle was successfully developed by modifying the probe, carbon fluorescence quantum dots and H 2 O 2 -responsive structure, which could respectively detect plaques by probe, realize targeted delivery of AS therapeutic agents and achieve drug-release by controlling their responses to H 2 O 2 .

Targeted Stimuli-Responsive Mesoporous Silica Nanoparticles for Bacterial Infection Treatment.

The rise of antibiotic resistance and the growing number of biofilm-related infections make bacterial infections a serious threat for global human health. Nanomedicine has entered into this scenario by bringing new alternatives to design and develop effective antimicrobial nanoweapons to fight against bacterial infection. Among them, mesoporous silica nanoparticles (MSNs) exhibit unique characteristics that make them ideal nanocarriers to load, protect and transport antimicrobial cargoes to the target bacteria and/or biofilm, and release them in response to certain stimuli. The combination of infection-targeting and stimuli-responsive drug delivery capabilities aims to increase the specificity and efficacy of antimicrobial treatment and prevent undesirable side effects, becoming a ground-breaking alternative to conventional antibiotic treatments. This review focuses on the scientific advances developed to date in MSNs for infection-targeted stimuli-responsive antimicrobials delivery. The targeting strategies for specific recognition of bacteria are detailed. Moreover, the possibility of incorporating anti-biofilm agents with MSNs aimed at promoting biofilm penetrability is overviewed. Finally, a comprehensive description of the different scientific approaches for the design and development of smart MSNs able to release the antimicrobial payloads at the infection site in response to internal or external stimuli is provided.

Fabrication of a smart and biocompatible brush copolymer decorated on magnetic graphene oxide hybrid nanostructure for drug delivery application

This study aimed to improve the therapeutic efficacy of doxorubicin (DOX) as an anticancer drug via loading it in the nanostructure. Therefore, for the first time, a new stimuli-responsive brushes copolymer decorated on the magnetic graphene oxide surface (MG-PB) fabricated, as well as, its capability as a targeted and stimuli-responsive drug delivery nanostructure was evaluated as in vitro. In this regard, at first, the magnetic graphene oxide nanohybrid (MG) was synthesized. Modification of the MG with triethoxyvinylsilane (TEVS) introduced the vinylic groups on the MG surface (MG-TEVS) and offered the polymerization possibility of the acrylic monomers from the MG surface. The copolymer brushes of N-isopropylacrylamide (NIPAM) and acrylated β-cyclodextrin (Ac-β-CD) were grown from the MG-TEVS surface. The Fourier transform infrared (FT-IR), X-ray diffraction (XRD), scanning electron microscopy (SEM), and atomic force microscopy (AFM) analysis used to explore the successful growth of the PB brushes. The lower critical solution temperature (LCST) of the prepared nanosystem was determined at about 35 °C. DOX was loaded about 50.15% in MG-PB. The drug release results displayed the controlled release profile with ~ 65% of DOX release in pH 5.0, 40 °C. The obtained drug release kinetic results demonstrated that the first-order kinetic model is more fitted with experimental data and DOX release follows from the Fickian mechanism. Cell viability confirmed the biocompatibility of the MG-PB. Additionally, the quantitative and qualitative cellular uptake, 4′,6-diamidino-2-phenylindole (DAPI) staining, and cell cycle tests revealed the high anticancer performance of drug-loaded nanocarrier through the penetration within the cells and their killing as a result of DOX release. The targeted and stimuli-responsive drug release capability of the MG-BB could be the valuable advantages, hence, obtained results suggest the great potential of the ternary MG-PB hybrid nanostructure as a controlled anticancer drug delivery vehicle.

Reduction-responsive polymers for drug delivery in cancer therapy-Is there anything new to discover?

Among various types of stimuli-responsive drug delivery systems, reduction-responsive polymers have attracted great interest. In general, these systems have high stability in systemic circulation, however, they can respond quickly to differences in the concentrations of reducing species in specific physiological sites associated with a pathology. This is a particularly relevant strategy to target diseases in which hypoxic regions are present, as polymers which are sensitive to in-situ expressed antioxidant species can, through a local response, release a therapeutic at high concentration in the targeted site, and thus, improve the selectivity and efficacy of the treatment. At the same time, such reduction-responsive materials can also decrease the toxicity and side effects of certain drugs. To date, polymers containing disulfide linkages are the most investigated of the class of reduction-responsive nanocarriers, however, other groups such as selenide and diselenide have also been used for the same purpose. In this review article, we discussed the rationale behind the development of reduction-responsive polymers as drug delivery systems and highlight examples of recent progress. We include the most popular design methods to generate reduction-responsive polymeric carriers and their applications in cancer therapy, and question what areas may still need to be explored in a field with already a very large number of research articles. Finally, we consider the main challenges associated with the clinical translation of these nanocarriers and the future perspectives in this area. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Engineering of carbon nano-onion bioconjugates for biomedical applications

Engineered stimuli-responsive drug delivery strategies grasp enormous potential in biomedical applications for disease treatment due to their exploited therapeutic efficiency. In the current study, we developed poly 4-hydroxyphenyl methacrylate-carbon nano-onions (PHPMA-CNOs = f-CNOs) embedded bovine serum albumin (BSA) nanocomposite fibers by Forcespinning® (FS) technology for stimuli-responsive release of cargo, using doxorubicin (DOX) as a model drug. Nanocomposite fiber system showed thermosensitive drug release and exhibited around 72 and 95% of drug release at 37 and 43 °C, respectively. A slow and prolonged DOX release was observed over a 15-day study. The amount of drug released was determined by the concentration of the DOX payload, incubation temperature, and pH of the released medium. Owing to the f-CNOs incorporation, the mechanical strength (18.23 MPa) of hybrid BSA nanocomposite fibers was enhanced significantly. Besides, in vitro degradation, water contact angles, and thermal properties of nanocomposite fibers have augmented. During the in vitro cytotoxicity assessment, nanocomposite fibers exhibited improved cell viability against human fibroblast cells. Nonetheless, the external-stimuli-dependent and sustained DOX release perhaps reduces its circumventing side effects and show potential applications in biomedical research.

Polyelectrolyte complex templated synthesis of monodisperse, sub-100 nm porous silica nanoparticles for cancer targeted and stimuli-responsive drug delivery

Porous silica nanoparticles (PSiNPs) have long attracted interest in drug delivery research. However, conventional synthesis methods for sub-100 nm, functionalised PSiNPs typically give poor monodispersity, reproducibility, or involve complex synthetic protocols. We report a facile, reproducible, and cost-effective one-pot method for the synthesis of cancer targeting and pH responsive PSiNPs in this size range, without the need for post-synthetic modification. This was achieved by using monodisperse l-arginine (Arg)/ poly(acrylic acid) (PAA) polyelectrolyte complexes (PECs) as soft templates for silane hydrolysis and condensation. Highly uniform PSiNPs with tunable size control between 42 and 178 nm and disordered pore structure (1.1–2.7 nm) were obtained. Both PAA and Arg were retained within the PSiNPs, which enabled a high doxorubicin hydrochloride (Dox) loading capacity (22% w/w) and a 4-fold increase in drug release under weakly acidic pH compared to physiological pH. The surface presentation of Arg conferred significantly higher intracellular accumulation of Arg/PAA-PSiNPs in patient-derived glioblastoma cells compared to non-tumorigenic neural progenitor cells, which effectively translated to lower IC50 values for Dox-loaded Arg/PAA-PSiNPs than non-functionalised PSiNPs. This work brings forward new insights for the development of monodisperse PSiNPs with highly desirable built-in functionalities for biomedical applications.

Glutathione-Responsive Multifunctional "Trojan Horse" Nanogel as a Nanotheranostic for Combined Chemotherapy and Photodynamic Anticancer Therapy.

It remains a great challenge to design a multifunctional and robust nanoplatform for stimuli-responsive drug delivery toward a lesion, which tactfully integrates multiple molecules with therapeutic and diagnostic characteristics. Herein, we reported a facile and ingenious cross-linked nanogel (DSA) based on the chemical cross-link of drugs as a straightforward strategy to overcome the instability of the assembly. In DSA, doxorubicin (DOX) and 5-aminolevulinic acid (ALA) were cross-linked with a disulfide linker for realizing synergistic anticancer therapy. The stability of DSA was adjusted via balancing the hydrophobic/hydrophilic property with hydrophilic NH2-PEG1k. After regulating the coordination of the DOX part and ALA moiety, the drug-loaded nanogel exhibited superior chemotherapeutic efficacies. Additionally, the DSA could selectively biosynthesize fluorescent protoporphyrin IX (PpIX) in tumor cells, which could be applied for a real-time imaging probe of accurate cancer diagnosis. Besides, the in situ synthesized PpIX in mitochondria could serve as a photosensitizer to convert oxygen into toxic reactive oxygen species under a near infrared ray at 660 nm irradiation, leading to an excellent tumor-killing efficacy. This work proposed a unique strategy for designing a series of prodrug nanogels as a universal drug delivery platform for realizing precise disease therapy and diagnostics.

Encapsulated doxorubicin crystals influence lysolipid temperature-sensitive liposomes release and therapeutic efficacy in vitro and in vivo

Doxorubicin (DOX)-loaded lysolipid temperature-sensitive liposomes (LTSLs) are a promising stimuli-responsive drug delivery system that rapidly releases DOX in response to mild hyperthermia (HT). This study investigates the influence of loaded DOX crystals on the thermosensitivity of LTSLs and their therapeutic efficacy in vitro and in vivo. The properties of DOX crystals were manipulated using different remote loading methods (namely (NH4)2SO4, NH4-EDTA and MnSO4) and varying the lipid:DOX weight ratio during the loading step. Our results demonstrated that (NH4)2SO4 or NH4-EDTA remote loading methods had a comparable encapsulation efficiency (EE%) into LTSLs in contrast to the low DOX EE% obtained using the metal complexation method. Cryogenic transmission electron microscopy (cryo-TEM) revealed key differences in the nature of DOX crystals formed inside LTSLs based on the loading buffer or/and the lipid:DOX ratio used, resulting in different DOX release profiles in response to mild HT. The in vitro assessment of DOX release/uptake in CT26 and PC-3 cells revealed that the use of a high lipid:DOX ratio exhibited a fast and controlled release profile in combination with mild HT, which correlated well with their cytotoxicity studies. Similarly, in vivo DOX release, tumour growth inhibition and mice survival rates were influenced by the physicochemical properties of LTSLs payload. This study demonstrates, for the first time, that the characteristics of DOX crystals loaded into LTSLs, and their conformational rearrangement during HT, are important factors that impact the TSLs performance in vivo.

Progress of Stimuli-Responsive Nanoscale Metal Organic Frameworks as Controlled Drug Delivery Systems.

Development of controlled drug delivery systems can improve the pharmacokinetic characteristics of drug molecules in the human body, thereby significantly improving the utilization rate of drugs and reducing toxicity and side effects caused by their high concentrations, which can occur when delivery is not controlled. Metal organic frameworks are a new class of very promising crystalline microporous materials, especially when the size is reduced to the nanometer range. Metal-organic frameworks exhibit large specific surface areas, tunable compositions, and easy functionalization. In recent years, an increasing number of studies have reported the remarkable advances in multifunctional nanoscale metal-organic frameworks in drug delivery. To review the latest research involving advances in stimuli-responsive nanoscale metal organic frameworks as drug delivery systems in controlled-release drugs. We first introduce the two main strategies associated with nanoscale metal organic frameworks used in drug loading: direct assembly and post-encapsulation. We next focus on the latest discoveries of nanoscale metal-organic framework-based stimulus response systems for drug delivery, including pH, magnetics, light, ion, temperature, and other stimuli, as well as multiple stimulus- responsive drug delivery systems. Finally, we discuss the challenges and future developmental directions of nanoscale metal-organic framework-based controlled drug release.

Stimulus-Responsive Nanomedicines for Disease Diagnosis and Treatment.

Stimulus-responsive drug delivery systems generally aim to release the active pharmaceutical ingredient (API) in response to specific conditions and have recently been explored for disease treatments. These approaches can also be extended to molecular imaging to report on disease diagnosis and management. The stimuli used for activation are based on differences between the environment of the diseased or targeted sites, and normal tissues. Endogenous stimuli include pH, redox reactions, enzymatic activity, temperature and others. Exogenous site-specific stimuli include the use of magnetic fields, light, ultrasound and others. These endogenous or exogenous stimuli lead to structural changes or cleavage of the cargo carrier, leading to release of the API. A wide variety of stimulus-responsive systems have been developed—responsive to both a single stimulus or multiple stimuli—and represent a theranostic tool for disease treatment. In this review, stimuli commonly used in the development of theranostic nanoplatforms are enumerated. An emphasis on chemical structure and property relationships is provided, aiming to focus on insights for the design of stimulus-responsive delivery systems. Several examples of theranostic applications of these stimulus-responsive nanomedicines are discussed.

Membrane-cross-linked polymersomes with tumor pH-tunable selective permeability as intelligent nanoreactors and drug delivery vehicles

Stimuli-responsive polymersomes have attracted great attention not only as smart drug delivery vehicles but also as intelligent artificial nanoreactors. Herein, we develop a series of membrane-cross-linked (MCL) polymersomes with cross-linking density-mediated and tumor pH-tunable selective membrane permeability for stimuli-responsive drug delivery and controllable enzymatic reaction. The diblock copolymers consisting of poly(ethylene glycol) (PEG) and copolymerized with methacrylate monomers containing piperidine or coumarin moieties were synthesized and self-assembled into polymersomes that can encapsulate both small molecule doxorubicin hydrochloride (DOX) and large molecule glucose oxidase (GOD). After photo-cross-linking, the optimized cross-linking density and pH-responsive segments endow the polymersomes with superior stability and ultra pH-sensitive selective membranes permeability upon changing pH from 7.4 to 6.5. Drug release and enzymatic reaction are triggered by pH change via the enhanced membrane permeability of the polymersomes loading DOX and GOD. With diffusion of small molecules into or out of the polymersomes including DOX, glucose, and O2, the massively generated hydrogen peroxide (H2O2) under the catalysis of GOD and the released DOX can synergistically kill cancer cells. Thus, the polymersomes with the tumor pH-responsive and cross-linking density-mediated membrane permeability show promising applications as a unique platform for cancer therapy.

MMP-13 enzyme and pH responsive theranostic nanoplatform for osteoarthritis

Stimulus-responsive therapy permits precise control of therapeutic effect only at lesion of interest, which determines it a promising method for diagnosis and imaging-guided precision therapy. The acid environment and overexpressed matrix metalloproteinases-13 (MMP-13) are typical markers in osteoarthritis (OA), which enables the development of stimulus-responsive drug delivery system with high specificity for OA. We herein demonstrate a nano-micelle based stimuli-responsive theranostic strategy with reporting and drug release controlled by acidic pH and MMP-13 for OA therapy. Such nanoplatform is incorporated with a motif specifically targeting on cartilage, a motif responsive to matrix metalloproteinases-13 to specifically report OA condition and biodynamics of nano-micelles, an anti-inflammatory drug (e.g., psoralidin (PSO)) from traditional Chinese medicine, and a biocompatible polymeric skeleton for sustainable drug release in response to the acidic OA condition. The high effectiveness of this targeted precision therapy is demonstrated comprehensively by both in vitro and vivo evidences.

Fabrication of claviform fluorescent polymeric nanomaterials containing disulfide bond through an efficient and facile four-component Ugi reaction.

Multicomponent reactions (MCRs) have attracted broad interest for preparation of functional nanomaterials especially for the synthesis of functional polymers. Herein, we utilized an "old" MCR, the four-component Ugi reaction, to synthesize disulfide bond containing poly(PEG-TPE-DTDPA) amphiphilic copolymers with aggregation-induced emission (AIE) feature. This four-component Ugi reaction was carried out under rather mild reaction conditions, such as room temperature, no gas protection and absent of catalysts. The amphiphilic poly(PEG-TPE-DTDPA) copolymers with high number-average molecular weight (up to 86,440Da) can self-assemble into claviform fluorescent polymeric nanoparticles (FPNs) in aqueous solution, and these water-dispersed nanoparticles exhibited strong emission, large Stokes shift (142nm), low toxicity and remarkable ability in cellular imaging. Moreover, owing to the introduction of 3,3'-dithiodipropionic acid with disulfide bond, the resultant AIE-active poly(PEG-TPE-DTDPA) could display reduction-responsiveness and be utilized for synthesis of photothermal agents in-situ. Therefore, the AIE-active poly(PEG-TPE-DTDPA) could be promising for controlled intracellular delivery of biological activity molecules and fabrication of multifunctional AIE-active materials. Therefore, these novel AIE-active polymeric nanoparticles could be of great potential for various biomedical applications, such as biological imaging, stimuli-responsive drug delivery and theranostic applications.

Aptamer-functionalized Fe3O4@MOF nanocarrier for targeted drug delivery and fluorescence imaging of the triple-negative MDA-MB-231 breast cancer cells

The development of efficient drug delivery and imaging approaches is of great importance for both diagnostic and therapeutic purposes. This is especially important for the triple-negative breast cancers for which chemotherapy is often the mainstay of treatment. Metal-organic frameworks (MOFs) have recently attracted tremendous attention as nanocarriers that can be loaded with a wide variety of therapeutic as well as bioimaging agents. Herein, the Fe3O4 core UiO-66-NH2 MOF shell nanostructures, Fe3O4@MOF, were loaded with the anticancer drug doxorubicin (DOX), and the loaded nanostructures were conjugated to highly fluorescent carbon dots (CDs) and then capped with the nucleolin-binding aptamer, AS1411. The Fe3O4@MOF-DOX-CDs-Apt nanocarriers were specifically unlocked in the presence of the nucleolin-overexpressing cancer cells, resulted in the release of the loads. The drug delivery process rendered more efficient by pH-dependent controlled release kinetics that provides an enhanced therapeutic outcome. The stimuli-responsive drug delivery system reveals a rather selective permeation of the Fe3O4@MOF-DOX-CDs-Apt nanocarriers into the triple-negative MDA-MB-231 human breast cancer cells, compared to the normal HUVEC cells. Cytotoxicity experiments revealed that the nanocarriers inhibit cell proliferation and induce selective apoptosis towards the MDA-MB-231 cancer cells (>77% at 24 ​h); whereas, less than 10% apoptosis was induced in the normal HUVEC cells. In addition, we encapsulated CDs into the nanocarriers, thereby, the nanocarriers exhibit fluorescence imaging functionality, thus can effectively contribute to monitoring biodistribution of the nanocarriers in vitro. Based on these findings, the Fe3O4@MOF-DOX-CDs-Apt nanocarriers can serve as a promising multifunctional material for cancer therapy and cellular bioimaging.

Azo-inserted responsive hybrid liposomes for hypoxia-specific drug delivery

Stimuli-responsive drug delivery systems using endogenous stimuli from tumor microenvironments such as acidic pH, over-expressed enzyme, and high redox potential as triggers have shown tremendous promise in cancer therapy. However, their clinical application is severely limited because of tumor heterogeneity. Hypoxia, a physiological feature observed in almost all solid tumors and even in nodules with very small size, has currently emerged as a more general but efficient stimulus to trigger release. Herein, we developed hypoxia-responsive hybrid liposomes (HR-HLPs), composed of azo-inserted organokoxysilane-based lipid analogue as a responsive component and commercial phospholipid for reducing the rigidity of liposomal membrane caused by azo, for drug delivery targeting tumor hypoxia. HR-HLPs had the advantages of high structural stability to avoid premature drug leakage when circulating in the blood and high sensitivity in responding to hypoxia once reaching tumor sites. HR-HLPs exhibit deep tumor penetration capability, enabling effective delivery to hypoxic regions distant from tumor vessels. Moreover, HR-HLPs could selectively release their payload, co-localizing with over-expressed hypoxia inducible factor 1α (HIF-1α) in vitro and in vivo. As a result, HR-HLPs showed improved therapeutic outcome accompanied by reduced adverse effects. The results highlighted the potential application of azo-inserted responsive hybrid liposomes for hypoxia-targeted drug delivery. Statement of Significance1.A hypoxia-responsive hybrid liposomal drug delivery system is developed for specific drug delivery targeting tumor hypoxia.2.The hybrid liposomes have high structural stability to avoid premature drug leakage under normal physiological condition and high sensitivity in responding to hypoxia once reaching tumor sites.3.The hybrid liposomes exhibit deep tumor penetration capability, enabling effective delivery to hypoxic regions distant from tumor vessels and co-localization with over-expressed HIF-1α in vitro and in vivo.

Biodegradable thermoresponsive oligochitosan nanoparticles: Mechanisms of phase transition and drug binding-release

Oligochitosan, a low molecular weight derivative of the cationic biopolymer, chitosan, currently shows a great potential of application as a biodegradable non-toxic stimuli-sensitive drug carrier. This paper aimed to elucidate the thermoresponsive potential of oligochitosan and the temperature-controlled drug binding and release to shed light on oligochitosan potential in stimuli-responsive drug delivery. Mechanisms of thermoresponsive behavior of oligochitosan induced by β-glycerophosphate (GP) were investigated using ITC, DSC, and DLS. Upon heating, the aqueous oligochitosan solution underwent a cooperative transition of the microphase separation type resulting in the formation of stable nano-sized particles. Energetics of the GP-oligochitosan interaction (evaluated by ITC) revealed a positive enthalpy of the GP binding to oligochitosan, which pointed to a notable contribution of dehydration and the related rearrangement of the polysaccharide hydration shell. Energetics of the thermal phase transition of oligochitosan was investigated by DSC upon variation of the solvent dielectric constant and GP concentration. The dependences of the transition parameters on these variables were determined and used for the analysis of the oligochitosan thermoresponsivity mechanism. The binding of ibuprofen to the thermotropic oligochitosan nanogel particles and its release from them were evaluated under near-physiological conditions. Relevantly, the oligochitosan nanoparticles surpassed some reference macromolecular adsorbers by the affinity for the drug and by the delayed release kinetics.

Tumor Microenvironment-Responsive Peptide-Based Supramolecular Drug Delivery System.

Physical and biochemical differences between tumor tissues and normal tissues provide promising triggering factors that can be utilized to engineer stimuli-responsive drug delivery platforms for cancer treatment. Rationally designed peptide-based supramolecular architectures can perform structural conversion by responding to the tumor microenvironment and achieve the controlled release of antitumor drugs. This mini review summarizes recent approaches for designing internal trigger-responsive drug delivery platforms using peptide-based materials. Peptide assemblies that exhibit a stimuli-responsive structural conversion upon acidic pH, high temperature, high oxidative potential, and the overexpressed proteins in tumor tissues are emphatically introduced. We also discuss the challenges of current peptide-based supramolecular delivery platforms against cancer.

Redox responsive paclitaxel dimer for programmed drug release and selectively killing cancer cells

Redox stimulus responsive drug delivery systems have been widely investigated and proved to be promising prospects for efficient cancer therapy due to the abnormal high level of reactive oxygen species and glutathione in tumor microenvironment. Herein, three paclitaxel dimers (named as PTX2-R, R = S, Se and Te) bridged with alkyl sulfide, selenide or telluride are synthesized. These dimers can self-assemble into stable uniform nanoparticles (named as PTX2-R NPs, R = S, Se and Te) with impressively high drug loading. As expected, sulfur/selenium/tellurium bonds exhibit different redox responsiveness, thereby affecting the drug release and cytotoxicity. Of note, tellurium bridged paclitaxel dimer shows ultra-sensitivity to hydrogen peroxide, which rapidly cleaves into two paclitaxel under the subsequent dithiothreitol stimulation. Our findings provide deep insight into the redox sensitivity of chalcogenide elements and offer the rational design strategies to biologically redox condition for programmed drug release.