Stimuli-responsive Nanomedicines Research Articles

Reactive oxygen species-responsive nanotherapy for the prevention and treatment of cerebral ischemia–reperfusion injury

Vascular recanalization intervention is the primary recommended approach for the treatment of ischemic stroke. However, the damage caused by cerebral ischemia-reperfusion (I/R) poses a significant challenge for effective treatment. The aim of this study was to address this challenge by developing multifunctional nanoparticles (NPs). Cu4.6O NP was encapsulated by zein-Se-Se-DHA (Dz), the diselenide bond-conjugated zein and docosahexaenoic acid (DHA), and then coated by platelet membrane (PLTM) to form Cu4.6O@Dz@PLTM (MDzCu) NP. MDzCu with the PLTM coating showed strong targeting ability to the cerebral ischemic lesions in the rat model of cerebral I/R injury. Furthermore, in the reactive oxygen species (ROS)-rich brain microenvironment, both Cu4.6O and DHA are released from MDzCu, exerting ROS scavenging, promoting microglia polarization, and providing neuroprotective effects, ultimately alleviating cerebral I/R injury. This study presents several novel findings, such as the use of Cu0/Cu+ NPs for brain-related diseases, ROS scavenger-assisted DHA therapy for the central nervous system (CNS), and the application of stimuli-responsive NPs with diselenides to treat I/R injuries. This study provides insights into the development of stimuli-responsive nanomedicines with cell membrane coatings for the targeted treatment of brain diseases.

Application of stimuli-responsive nanomedicines for the treatment of ischemic stroke.

Ischemic stroke (IS) refers to local brain tissue necrosis which is caused by impaired blood supply to the carotid artery or vertebrobasilar artery system. As the second leading cause of death in the world, IS has a high incidence and brings a heavy economic burden to all countries and regions because of its high disability rate. In order to effectively treat IS, a large number of drugs have been designed and developed. However, most drugs with good therapeutic effects confirmed in preclinical experiments have not been successfully applied to clinical treatment due to the low accumulation efficiency of drugs in IS areas after systematic administration. As an emerging strategy for the treatment of IS, stimuli-responsive nanomedicines have made great progress by precisely delivering drugs to the local site of IS. By response to the specific signals, stimuli-responsive nanomedicines change their particle size, shape, surface charge or structural integrity, which enables the enhanced drug delivery and controlled drug release within the IS tissue. This breakthrough approach not only enhances therapeutic efficiency but also mitigates the side effects commonly associated with thrombolytic and neuroprotective drugs. This review aims to comprehensively summarize the recent progress of stimuli-responsive nanomedicines for the treatment of IS. Furthermore, prospect is provided to look forward for the better development of this field.

Homology-Activated Ultrasensitive Nanomedicines for Precise NIR-II FL/MRI Imaging-Guided "Knock-On" Dynamic Therapy in Rheumatoid Arthritis.

Stimuli-responsive nanomedicines represent a pivotal technology for in situ on-demand drug release and offer multiple advantages over conventional drug delivery systems to combat rheumatoid arthritis(RA). However, the lack of sensitivity to a single-stimuli source or the inability to synchronize multi-stimuli responses can easily lead to challenges in achieving precise-theranostics of RA. Herein, a homology-activated ultrasensitive nanomedicines MnO2-CQ4T-GOx(MCG NMs) is designed for NIR-II fluorescence(NIR-II FL)/magnetic resonance imaging(MRI)-guided effective "knock-on" dynamic anti-RA therapy. Building upon the characteristics of the RA-microenvironment, the MCG innovatively construct a MnO2-Mn2+ system, which can normalized activation sites. The ultrasensitive-responsive degradation is achieved using the multi-stimuli processes in the RA-microenvironment, triggering release of functional small molecules. The produced Mn2+ can exert Fenton-like activity to generate •OH from H2O2, thus providing the effective chemodynamic therapy(CDT). Moreover, the up-regulation of H2O2 by GOx-catalysis not only sensitizes the MnO2-Mn2+ system but also achieves self-enhancing CDT efficacy. The NIR-II FL quenching of CQ4T-BSA in the aggregated state occurs in MCG NMs, which can be rapidly and precisely "turn-on" via the MnO2-Mn2+ system. Meanwhile, the integration of activated Mn2+-based MRI imaging has successfully developed an activatable dual-modal imaging. Feedback imaging-guided precise photodynamic therapy of CQ4T-BSA can achieve efficient "knock-on" dynamic therapy for RA.

Tumor Abnormality-Oriented Nanomedicine Design.

Anticancer nanomedicines have been proven effective in mitigating the side effects of chemotherapeutic drugs. However, challenges remain in augmenting their therapeutic efficacy. Nanomedicines responsive to the pathological abnormalities in the tumor microenvironment (TME) are expected to overcome the biological limitations of conventional nanomedicines, enhance the therapeutic efficacies, and further reduce the side effects. This Review aims to quantitate the various pathological abnormalities in the TME, which may serve as unique endogenous stimuli for the design of stimuli-responsive nanomedicines, and to provide a broad and objective perspective on the current understanding of stimuli-responsive nanomedicines for cancer treatment. We dissect the typical transport process and barriers of cancer drug delivery, highlight the key design principles of stimuli-responsive nanomedicines designed to tackle the series of barriers in the typical drug delivery process, and discuss the "all-into-one" and "one-for-all" strategies for integrating the needed properties for nanomedicines. Ultimately, we provide insight into the challenges and future perspectives toward the clinical translation of stimuli-responsive nanomedicines.

Microfluidic synthesis of intelligent nanoclusters of ultrasmall iron oxide nanoparticles with improved tumor microenvironment regulation for dynamic MR imaging-guided tumor photothermo-chemo-chemodynamic therapy

The development of intelligent stimuli-responsive nanomedicines by integrating tumor microenvironment (TME)-responsive imaging and drug delivery characteristics remains to be essential for precision medicine. Here, we report a microfluidic synthesis approach to process preformed nanoclusters (NCs) assembled from cystamine-crosslinked ultrasmall iron oxide (Fe3O4) nanoparticles to be coated with polydopamine (PDA), loaded with the cisplatin and further camouflaged with cancer cell membranes (CCMs). The created multifunctional NCs (for short, FDPC NCs) with a size of 35.4 nm display good colloidal stability, and possess excellent abilities in tumor microenvironment modulation for intracellular reactive oxygen species production and glutathione (GSH) depletion, in photothermal conversion efficiency, and in anticancer activity, all surpassing the counterpart materials synthesized through traditional wet-chemical method. Due to the CCM camouflage to render the FDPC NCs with homologous tumor targeting, GSH-triggered dissociation of the NCs to form single Fe3O4 nanoparticles, and the GSH- and pH-responsive release of cisplatin and Fe, the developed FDPC NCs can achieve dynamic T2/T1-switchable magnetic resonance imaging and tri-mode photothermo-chemo-chemodynamic therapy of tumors under near infrared laser irradiation. Such developed high-quality FDPC NCs through the microfluidic synthesis may be used for multi-mode precision theranostics of other tumor types and have a great clinical translation potential.

Paclitaxel-loaded and folic acid-modified PLGA nanomedicine with glutathione response for the treatment of lung cancer.

Targeted delivery and smart response of nanomedicine hold great promise for improving the therapeutic efficacy and alleviating the side effects of chemotherapy agents in cancer treatment. However, availability of only a few studies that discuss organic nanomedicines with these properties limits the development prospects of nanomedicines. In the present study, folic acid (FA)-targeted delivery and glutathione (GSH) smart responsive nanomedicine were rationally designed for paclitaxel (PTX) delivery for the treatment of lung cancer. Compared with other stimuli-responsive nanomedicines, this nanocarrier was not only sensitive to biologically relevant GSH for on-demand drug release but also biodegradable into biocompatible products after fulfilling its delivery task. The nanomedicine first entered tumor cells via FA and its receptor-mediated endocytosis. After the lysosomal escape, poly(lactic-co-glycolic acid) (PLGA) nanomedicine was triggered by a higher level of GSH and released its cargo into the tumor microenvironment. In vitro and in vivo results revealed that the PLGA nanomedicine not only inhibited the proliferation and promoted the apoptosis of lung cancer cells significantly but also possessed less toxic side effects when compared with free PTX. Therefore, the proposed drug delivery system demonstrates the potential of a multifunctional nano-platform to enhance bioavailability and reduce the side effects of chemotherapy agents.

The Integration of Reactive Oxygen Species Generation and Prodrug Activation for Cancer Therapy

Abstract The combination of chemotherapeutic drugs and reactive oxygen species (ROS) can improve cancer treatment outcome. Many ROS-generation strategies can specifically consume tumor-inherent oxygen and generate ROS, resulting in amplified ROS level and aggravated hypoxia. Therefore, the ROS generation strategy can integrate with prodrug activation strategy to realize synergetic therapy. In recent years, stimuli-responsive nanomedicines have been developed to realize the integration of ROS generation and prodrug activation. Triggered by a stimulus, nanomedicines can generate ROS at the tumor site, which can further activate the release of active drugs. In this review, we will summarize the latest progress of these nanomedicines and discuss the perspectives and challenges.

Smart stimuli-responsive biopolymeric nanomedicines for targeted therapy of solid tumors.

Solid tumors form a permissive microenvironment with irregular features, including high pressured tumor interstitial fluid with acidic pH, co-adaptation of cancer cells with other cells likethe immune system cells, abnormal metabolism and anomalous overexpression of various pieces of molecular machinery. The functional expressions of several oncomarkers in different solid tumors have led to the development of targeted drug-delivery systems (DDSs). As a new class of DDSs, stimuli-responsive nanomedicines (SRNMs) have been developed using advanced nanobiomaterials such as biopolymers that show excellent biocompatibility with low inherent immunogenicity. In this review, we aim to overview different types of SRNMs, present deep insights into the stimuli-responsive biopolymers and discuss the most up-to-date progress in the design and development of SRNMs used as advanced DDSsfor targeted therapy of cancer.

Microfluidic Shear Processing Control of Biological Reduction Stimuli-Responsive Polymer Nanoparticles for Drug Delivery

We demonstrate microfluidic manufacturing of glutathione (GSH)-responsive polymer nanoparticles (PNPs) with controlled in vitro pharmacological properties for selective drug delivery. This work leverages previous fundamental work on microfluidic control of the physicochemical properties of GSH-responsive PNPs containing cleavable disulfide groups in two different locations (core and interface, DualM PNPs). In this paper, we employ a two-phase gas-liquid microfluidic reactor for the flow-directed manufacturing of paclitaxel-loaded or DiI-loaded DualM PNPs (PAX-PNPs or DiI-PNPs, where DiI is a fluorescent drug surrogate dye). We find that both PAX-PNPs and DiI-PNPs exhibit similar flow-tunable sizes, morphologies, and internal structures to those previously described for empty DualM PNPs. Fluorescent imaging of DiI-PNP formulations shows that microfluidic manufacturing greatly improves the homogeneity of drug dispersion within the PNP population compared to standard bulk microprecipitation. Encapsulation of PAX in DualM PNPs significantly increases its selectivity to cancerous cells, with various PAX-PNP formulations showing higher cytotoxicity against cancerous MCF-7 cells than against non-cancerous HaCaT cells, in contrast to free PAX, which showed similar cytotoxicity in the two cell lines. In addition, the characterization of DualM PNP formulations formed at various microfluidic flow rates reveals that critical figures of merit for drug delivery function-including encapsulation efficiencies, GSH-triggered release rates, rates of cell uptake, cytotoxicities, and selectivity to cancerous cells-exhibit microfluidic flow tunability that mirrors trends in PNP size. These results highlight the potential of two-phase microfluidic manufacturing for controlling both structure and drug delivery function of biological stimuli-responsive nanomedicines toward improved therapeutic outcomes.

A tumor targeted near-infrared light-controlled nanocomposite to combat with multidrug resistance of cancer

Stimuli-responsive nanomaterials have emerged as promising drug delivery systems for tumor therapy, as they can specifically respond to tumor-associated stimuli and release the loaded drugs in a controllable manner. However, most currently available stimuli-responsive nanomedicines rely on surrounding extreme stimulus to trigger the activity, which can be inefficient under dynamic and complex living conditions. Herein, we report a near-infrared (NIR) light-responsive nanocomposite, which can generate reactive oxygen species to efficiently trigger the decomposition upon NIR laser irradiation. This nanocomposite is fabricated by conjugating polyamidoamine-pluronic F68 and graphene oxide via diselenide bond, and encapsulating the NIR photosensitizer indocyanine green and chemotherapeutic drug doxorubicin (DOX) as payloads. Under NIR light, the nanocomposite shows lysosomal escape, controlled drug release, and nuclear trafficking of DOX inside multidrug resistant (MDR) MCF-7/ADR cells. Interestingly, this nanocomposite effectively down-regulates ABCB1 gene and P-glycoprotein of MCF-7/ADR cells, exhibiting significant cytotoxicity. In vivo anti-tumor study demonstrates an effective accumulation and superior therapeutic efficacy of this multifunctional nanocomposite in MCF-7/ADR tumors, representing a great potential for clinical treatment of MDR cancer.

Stimuli-Responsive Nanomedicines for Overcoming Cancer Multidrug Resistance.

Chemotherapy is still a main option for cancer therapy, but its efficacy is often unsatisfying due to multidrug resistance (MDR). The tumor microenvironment is considered a dominant factor causing MDR. Stimuli-responsive nanomedicines exhibit many superiorities for reversal of MDR. As smart systems, stimuli-responsive nanomedicines are desirable for achieving site-specific accumulation and triggered drug release in response to slight changes in physicochemical properties in pathological conditions or to exogenous stimuli. In this review, we highlight the current progress of various nanomedicines with different stimuli-responsive capabilities for overcoming MDR. The materials, design, construction as well as efficacy in overcoming MDR of these nanomedicines are discussed. Eventually, we look forward to forthcoming intelligent nanoparticle systems with new mechanisms to deliver drugs for practical applications in conquering cancer MDR.

Nanomedicine technology: current achievements and new trends

Nanomedicines consist of biodegradable or biocompatible submicron-sized colloidal particles encapsulating a drug. Nanomedicine technology has emerged following pioneering work in the 1970s and has given rise to an enormous number of novel delivery systems and applications. Advances in chemistry and engineering have yielded a large panel of biocompatible and biodegradable materials from which nanomedicines can be made. We briefly review the main different types of existing nanomedicines, focusing particularly on those used in the clinic. We then examine the biological barriers nanomedicines must cross to reach their target after intravenous injection, and how these barriers can be overcome. Although mostly conceived for intravenous administration, nanomedicines hold potential for delivery by other routes, such as the oral, ocular and pulmonary routes, which we examine. Finally, we focus on new trends in nanomedicine technology such as stimuli-responsive nanomedicines and the combination of nanomedicines with imaging agents to yield the so-called nanotheranostics.