Premature Drug Leakage Research Articles

Hollow Magnetic Nanocarrier-Based Microrobot Swarms for NIR-Responsive Targeted Drug Delivery and Synergistic Therapy.

Nanocarriers are frequently used for drug delivery due to their large surface area, biocompatibility, and photothermal effects. However, they face the problem of premature drug leakage during drug transport. To address this challenge, we developed near-infrared light (NIR)-responsive hollow magnetic nanocarriers (HMC) by incorporating a chitosan-based molecular valve onto hollow magnetic nanocarriers (CHMC) to enable NIR-triggered drug release. Despite this advancement, this material still encounters the challenge of inadequate targeting. Recognizing the efficacy of magnetically driven micro/nanorobot swarms in remote wireless control, targeted motion, and efficient transport, we merged CHMC with magnetically controlled micro/nanorobot swarms. We evaluated their performance under programmable magnetic fields, which can be precisely controlled in biological fluid and directed toward targeting cells. Additionally, they demonstrated the ability to execute a responsive drug release under NIR irradiation. Ultimately, we confirmed their capacity for targeted delivery, responsive drug release, and photothermal therapy for liver cancer treatment in vivo. This approach heralds new possibilities for responsive drug therapy facilitated by micro/nanorobot swarms, offering promising advancements in medical treatment.

Transforming cancer detection and treatment with nanoflowers.

Nanoflowers, an innovative class of nanoparticles with a distinctive flower-like structure, have garnered significant interest for their straightforward synthesis, remarkable stability, and heightened efficiency. Nanoflowers demonstrate versatile applications, serving as highly sensitive biosensors for rapidly and accurately detecting conditions such as diabetes, Parkinson's, Alzheimer's, and foodborne infections. Nanoflowers, with their intricate structure, show significant potential for targeted drug delivery and site-specific action, while also exhibiting versatility in applications such as enzyme purification, water purification from dyes and heavy metals, and gas sensing through materials like nickel oxide. This review also addresses the structural characteristics, surface modification, and operational mechanisms of nanoflowers. The nanoflowers play a crucial role in preventing premature drug leakage from nanocarriers. Additionally, the nanoflowers contribute to averting systemic toxicity and suboptimal therapy efficiency caused by hypoxia in the tumor microenvironment during chemotherapy and photodynamic therapy. This review entails the role of nanoflowers in cancer diagnosis and treatment. In the imminent future, the nanoflowers system is poised to revolutionize as a smart material, leveraging its exceptional surface-to-volume ratio to significantly augment adsorption efficiency across its intricate petals. This review delves into the merits and drawbacks of nanoflowers, exploring synthesis techniques, types, and their evolving applications in cancer.

Design of pH/Redox Co-Triggered Degradable Diselenide-Containing Polyprodrug via a Facile One-Pot Two-Step Approach for Tumor-Specific Chemotherapy.

The diselenide bond has attracted intense interest for drug delivery systems (DDSs) for tumor chemotherapy, owing to it possessing higher redox sensitivity than the disulfide one. Various redox-responsive diselenide-containing carriers have been developed for chemotherapeutics delivery. However, the premature drug leakage from these DDSs was significant enough to cause toxic side effects on normal cells. Here, a pH/redox co-triggered degradable polyprodrug was designed as a drug self-delivery system (DSDS) by incorporating drug molecules as structural units in the polymer main chains, using a facile one-pot two-step approach. The proposed PDOX could only degrade and release drugs by breaking both the neighboring acid-labile acylhydrazone and the redox-cleavable diselenide conjugations in the drug's structural units, triggered by the higher acidity and glutathione (GSH) or reactive oxygen species (ROS) levels in the tumor cells. Therefore, a slow solubility-controlled drug release was achieved for tumor-specific chemotherapy, indicating promising potential as a safe and efficient long-acting DSDS for future tumor treatment.

Regulating Drug Release Performance of Acid-Triggered Dimeric Prodrug-Based Drug Self-Delivery System by Altering Its Aggregation Structure.

Dimeric prodrugs have been investigated intensely as carrier-free drug self-delivery systems (DSDSs) in recent decades, and their stimuli-responsive drug release has usually been controlled by the conjugations between the drug molecules, including the stimuli (pH or redox) and responsive sensitivity. Here, an acid-triggered dimeric prodrug of doxorubicin (DOX) was synthesized by conjugating two DOX molecules with an acid-labile ketal linker. It possessed high drug content near the pure drug, while the premature drug leakage in blood circulation was efficiently suppressed. Furthermore, its aggregation structures were controlled by fabricating nanomedicines via different approaches, such as fast precipitation and slow self-assembly, to regulate the drug release performance. Such findings are expected to enable better anti-tumor efficacy with the desired drug release rate, beyond the molecular structure of the dimeric prodrug.

Core-crosslinked polyprodrug nanoparticles via facile crosslinking-induced self-assembly for tumor intracellular acid-triggered doxorubicin delivery

Premature drug leakage from the drug delivery systems (DDSs) causes severe toxic side effects on the normal cells, restricting their practical application in tumor chemotherapy. Here, core-crosslinked polyprodrug nanoparticles were designed by facile crosslinking-induced self-assembly of polyethylene glycol-b-poly(p-formylphenyl methacrylate) (PEG-PFPMA) di-block copolymer via acid-labile Schiff base bonds, with a pH-responsive doxorubicin-doxorubicin dimer (Di-DOX-ADH) as crosslinker. Owing to the unique structure, the chemotherapeutic drug, doxorubicin (DOX), could be released only when the Schiff base bond and hydrazone bond on both sides of the DOX unit were cleaved. Thus, a leakage-free tumor intracellular acid-triggered on-demand drug release was achieved with cumulative DOX release of 80 % in the simulated tumor intracellular microenvironment in 80 h. The proposed core-crosslinked polyprodrug nanoparticles could be internalized by the HepG2 cells and released DOX therein, exhibiting an enhanced tumor growth inhibition than free DOX.

Chitosan oligosaccharide-functionalized nano-prodrug for cascade chemotherapy through oxidative stress amplification

Redox nanoparticles have been extensively developed for chemotherapy. However, the intracellular oxidative stress induced by constant aberrant glutathione (GSH), reactive oxygen species (ROS) and gamma-glutamyl transpeptidase (GGT) homeostasis remains the primary cause of evading tumor apoptosis. Herein, an oxidative stress-amplification strategy was designed using a pH-GSH-H2O2-GGT sensitive nano-prodrug for precise synergistic chemotherapy. The disulfide bond- conjugated doxorubicin prodrug (DOX-ss) was constructed as a GSH-scavenger. Then, phenylboronic acid (PBA), DOX-ss and poly (γ-glutamic acid) (γ-PGA) were successively conjugated using chitosan oligosaccharide (COS) to obtain the nano-prodrug PBA-COS-ss-DOX/γ-PGA. The PBA-COS-ss-DOX/γ-PGA prodrug could tightly attach to the polymer chain segment by atom transfer radical polymerization. Simultaneously, the drug interacted relatively weakly with the polymer by encapsulating ionic crosslinkers in DOX@PBA-COS/γ-PGA. The disulfide bond of the DOX-ss prodrug as a GSH-scavenger could be activated using overexpressed GSH to release DOX. Particularly, PBA-COS-ss-DOX/γ-PGA could prevent premature drug leakage and facilitate DOX delivery by GGT-targeting and intracellular H2O2-cleavable linker in human hepatocellular carcinoma (HepG2) cells. Concurrently, the nano-prodrug induced strong oxidative stress and tumor cell apoptosis. Collectively, the pH-GSH-H2O2-GGT responsive nano-prodrug shows potential for synergistic tumor therapy.

GSH-activable heterotrimeric nano-prodrug for precise synergistic therapy of TNBC

Combination chemotherapy is an effective approach for triple-negative breast cancer (TNBC) therapy, especially when drugs are administered at specific optimal ratios. However, at present, strategies involving precise and controllable ratios based on effective loading and release of drugs are unavailable. Herein, we designed and synthesized a glutathione (GSH)--responsive heterotrimeric prodrug and formulated it with an amphiphilic polymer to obtain nanoparticles (DSSC2 NPs) for precise synergistic chemotherapy of TNBC. The heterotrimeric prodrug was prepared using docetaxel (DTX) and curcumin (CUR) at the optimal synergistic ratio of 1: 2. DTX and CUR were covalently conjugated by disulfide linkers. Compared with control NPs, DSSC2 NPs had quantitative/ratiometric drug loading, high drug co-loading capacity, better colloidal stability, and less premature drug leakage. After systemic administration, DSSC2 NPs selectively accumulated in tumor tissues and released the encapsulated drugs triggered by high levels of GSH in cancer cells. In vitro and in vivo experiments validated that DSSC2 NPs released DTX and CUR at the predefined ratio and had a highly synergistic therapeutic effect on tumor suppression in TNBC, which can be attributed to ratiometric drug delivery and synchronous drug activation. Altogether, the heterotrimeric prodrug delivery system developed in this study represents an effective and novel approach for combination chemotherapy.

Engineered exosomes with enhanced stability and delivery efficiency for glioblastoma therapy

Due to the blood-brain barrier (BBB), the application of chemical drugs for glioblastoma treatment is severely limited. Recently, exosomes have been widely applied for drug delivery to the brain. However, the differences in brain targeting efficiency among exosomes derived from different cell sources, as well as the premature drug leakage during circulation, still limit the therapeutic efficacy. Here, we designed a functional oligopeptide-modified exosome loaded with doxorubicin (Pep2-Exos-DOX) for glioblastoma treatment. BV2 mouse microglial cell line was selected as the exosome source due to the favorable BBB penetration. To avoid drug release in the circulation, a redox-response oligopeptide was designed for incorporation into the membranes of exosomes to lock the drug during circulation. The enrichment of the drug in glioblastoma was confirmed. Pharmacodynamic evaluation showed Pep2-Exos-DOX possessed significant anti-cancer activity against glioblastoma as well as relative biosafety. This exosome-based drug delivery system modified with redox-response oligopeptides provides us a novel strategy for brain diseases treatment.

An ATP-responsive ZIF-based NIR fluorescence nanosystem for enhanced chemo-photodynamic therapy of tumors.

The combination of chemotherapy and photodynamic therapy holds immense potential for achieving synergistic anti-tumor efficacy. However, challenges such as poor stability and premature drug release prior to reaching tumor sites impede the widespread application of this synergistic therapeutic approach. In this study, a novel ATP-responsive NIR fluorescence nanosystem (CDZ) for imaging-guided chemotherapy and PDT has been developed. This nanosystem, based on ZIF-90, encapsulates the chemotherapy drug doxorubicin (DOX) and the photosensitizer asymmetrical cyanine dye Cy through self-assembly. The obtained nanosystem CDZ could efficiently avoid premature drug leakage in the blood circulation due to its high stability in the physiological environment and accumulates at the tumor sites via the enhanced permeability and retention (EPR) effect. Upon uptake by tumor cells, the skeleton structure of CDZ is disrupted by overexpressed ATP levels, leading to the release of DOX, which inhibits cancer cell proliferation and induces cell death. Additionally, the released photosensitizer Cy emits strong NIR fluorescence signals, enabling real-time imaging of ATP levels in tumors. Moreover, under NIR light irradiation, this nanosystem generates high levels of ROS, achieving effective phototherapy even in deeper tumor regions. In tumor model mice, CDZ demonstrated a high rate of tumor inhibition without causing damage to major organs. This ZIF-based NIR fluorescence nanosystem, combining chemotherapy and photodynamic therapy, holds promise as a solution for treating and monitoring cancer without the associated risks of resistance and systemic toxicity.

Utilizing Macrophages Missile for Sulfate-Based Nanomedicine Delivery in Lung Cancer Therapy.

Nanomaterial-based drug delivery systems are susceptible to premature drug leakage and systemic toxicity due to lack of specific targeting, and live-cell drug delivery is also prone to be restricted by drug carrier-cell interactions. Here, a method is established to adsorb drug-loaded nanomaterials externally to the live cells, which reduces cytotoxicity caused by drug uptake and improves the bioactivity of the carrier cells and drug release at the lesion site. It was found that polyphenols act like "double-sided tape" to bridge metal-organic framework (MOF) nanoparticles with live macrophages (Mφ), attaching MOFs to the Mφ surface and minimizing intracellular uptake, with no negative effect on cell proliferation. On this basis, a "macrophage missile" with peroxymonosulfate (PMS)-loaded MOF nanoparticles on the cell surface was constructed. As a "propellant", the Mφ, in which bioactivity is preserved, can selectively identify and target tumor cells, precisely bringing nanomedicines to the lesion. MOF nanoparticles are used to load and catalyze PMS, which acts as an exogenous source of reactive oxygen species, showing higher efficacy and lower toxicity in an oxygen-independent manner. The primary study results demonstrate that this innovative combination of biology and nanomaterials remarkably enhances tumor targeting and therapeutic efficacy while reducing systemic side effects. This approach is expected to provide a more effective and safer treatment for lung cancer and holds promise for broader applications in other cancer therapies.

Contact Lens with pH Sensitivity for On-Demand Drug Release in Wearing Situation.

Drug-releasing contact lenses are emerging therapeutic systems for treating ocular diseases. However, their applicability is limited by the burst release of drugs during lens wear and premature drug leakage during packaging, rendering the precise control of release duration or dose difficult. Here, we introduce a pH-sensitive contact lens exhibiting on-demand drug release only during lens wear and negligible premature drug leakage during packaging and transportation, which is accomplished by incorporating drug-loaded mesoporous silica nanoparticles (MSNs) coated with a pH-sensitive polymer into the contact lens. The compositionally optimized pH-sensitive polymer has a lower critical solution temperature (LCST) at >45 °C at pH 7.4, whereas its LCST decreases to <35 °C under acidic conditions (pH ∼ 6.5). Consequently, the MSN-incorporated contact lens sustainably releases the loaded drugs only in the acidic state at 35 °C, which corresponds to lens-wear conditions, through the MSN pores that open because of the shrinkage of polymer chains. Conversely, negligible drug leakage is observed from the contact lens under low-temperature or neutral-pH conditions corresponding to packaging and transportation. Furthermore, compared with the plain contact lens, the pH-sensitive contact lens exhibits good biocompatibility and unchanged bulk characteristics, such as optical (transmittance in the visible-light region), mechanical (elastic modulus and tensile strength), and physical (surface roughness, oxygen permeability, and water content) properties. These findings suggest that the pH-sensitive contact lens can be potentially applied in ocular disease treatment.

Targeting and repolarizing M2-like tumor-associated macrophage-mediated MR imaging and tumor immunotherapy by biomimetic nanoparticles

Anti-tumor M1-like and pro-tumor M2-like tumor-associated macrophages (TAMs) coexist in tumor microenvironments (TME). The adverse effects of these M1/M2 subsets on tumors directly affect the current strategies to improve anti-tumor immune response. Therefore, it has attracted great attention to change the tumor immunosuppressive microenvironment by reprogramming TAMs. In this paper, we constructed biomimetic nanoparticles (HMMDN-Met@PM) targeting M2-like TAMs for macrophage re-polarization. In detail, the core of the biomimetic nanoparticles is metformin-loaded hollow mesoporous manganese dioxide nanoparticles (HMMDN-Met). Benefited from the hollow and porous structure of HMMDN, metformin, the regulator of M1/M2 adopted in this work, can be easily and widely loaded into HMMDN. Moreover, macrophage membranes were utilized for HMMDN-Met coating (HMMDN-Met@MM) to prevent the premature drug leakage and provide specific molecular recognition/TME targeting. In addition, M2 macrophage targeting peptide (M2pep) was modified on the surface of macrophage membrane to specifically deliver the drug to M2-like TAMs to promote the polarization of M2 to M1 macrophages. Through in vitro and in vivo studies, we found that the expression of surface markers and inflammatory factors CD206, Arg-1 and IL-10 of type M2 macrophages decreased, while the surface markers of type M1 macrophages and the expression of inflammatory factors CD80, TNF-α and iNOS increased, indicating the successful re-polarization of M2 macrophages and finally realizing the inhibition of tumor growth. At the same time, under the acidic and GSH conditions of tumor, HMMDN was decomposed into Mn2+, which is a contrast agent for magnetic resonance imaging, thus realizing the tracking of tumor. This work practices biomimetic nanosystem in targeted imaging and immunotherapy, paving the way for strategy designing for tumor inhibition.

Design of GSH-triggered disintegrable dendritic polyurethane as bioreducible unimolecular micelles for tumor-specific chemotherapeutic drug delivery

Unimolecular micelles have attracted intensely attention as drug delivery systems (DDSs) in tumor chemotherapy owing to their superior stability. However, their drug release performance is mainly determined by the hydrophilic-hydrophobic property of their cores, in which the chemotherapeutic drugs were loaded. Here, GSH-triggered disintegrable dendritic polyurethane was designed via a facile one-pot approach, with disulfide-containing diisocyanate. After PEGylation, it self-assembled into bioreducible unimolecular micelles with highly hydrophobic cores for chemotherapeutics-loading, showing a minimized premature drug leakage during blood circulation. After tumor cellular internalization, the GSH-triggered disintegration of the dendritic polyurethane-based cores in the unimolecular micelles occurred to release the loaded model drug (DOX), possessing tumor-specific chemotherapy with an enhanced tumor growth inhibition than free DOX.

Dynamically assembled nanomedicine based on host-guest molecular recognition for NIR laser-excited chemotherapy and phototheranostics.

Nanomedicines combining multimodal therapeutic modalities supply opportunities to eliminate tumors in a safe and efficient manner. However, the rigid encapsulation and covalent conjugation of different therapeutic reagents suffer from the complicated preparation process, premature drug leakage and severe adverse events. Herein, we report a self-enhanced supramolecular nanomedicine (SND) based on the host-guest molecular recognition between β-cyclodextrin (β-CD) and camptothecin (CPT) for trimodal synergistic chemotherapy, photodynamic therapy (PDT) and photothermal therapy (PTT) using a single 670 nm near-infrared (NIR) laser. Thioketal bond and polyethylene glycol (PEG) segment are introduced into the structure of CPT-tk-PEG prodrug, thus the premature release of CPT is efficiently inhibited and the specific drug release is realized at tumor site where singlet oxygen (1O2)-generated PDT is performed. A boron dipyrromethene (BODIPY) theranostic agent is anchored onto β-CD, endowing SND with capabilities of fluorescence imaging, PDT and PTT. Benefiting from the supramolecular assembly, not only the solubility of CPT is improved by 40 times, but also the blood circulation time and tumor accumulation of SND are greatly promoted. In vivo, SND can effectively induce the immunogenic cell death (ICD) of tumor cells, thus performing prominent inhibition against both primary and distal tumors, and even anti-metastasis effect against liver without causing obvious systemic toxicity. STATEMENT OF SIGNIFICANCE: Although nanomedicines supply opportunities to eliminate tumors in an efficient manner, they usually suffer from premature drug leakage, complicated preparation process and severe side effects owing to the rigid encapsulation or covalent conjugation. Based on the host-guest molecular recognition, we developed a self-enhanced SND for synergistic chemotherapy, photodynamic therapy and photothermal therapy. Introduction of thioketal bond in CPT prodrug avoided the premature drug release, and the specific drug release was realized in the tumor cells. Profiting from the facile supramolecular assembly strategy, SND not only displayed a primary anticancer efficacy with a low systemic toxicity, but also efficiently inhibited the growth of distal tumors, contributing a vaccine-like function to eradicate the recurrent and metastatic tumors.

Integrin-targeting disulfide-crosslinked micellar docetaxel eradicates lung and prostate cancer patient-derived xenografts

Actively targeted nanomedicines though conceptually attractive for tumor therapy are extremely hard to realize due to problems of premature drug leakage, excessive liver accretion, inadequate tumor uptake, and/or retarded drug release inside tumor cells. Here, we systemically studied the influence of disulfide crosslinking on the in vitro and in vivo performance of integrin-targeting micellar docetaxel (t-MDTX). Of note, t-M5DTX with a high disulfide content was clearly advantageous in terms of stability, intracellular drug release, anti-tumor activity toward αVβ3-overexpressing A549 cells, blood circulation and therapeutic efficacy in orthotopic A549-luc lung tumor-bearing mice. t-MDTX induced extraordinary tumor targetability with tumor-to-normal tissue ratios of 1.7–8.3. Further studies indicated that t-M5DTX could effectively eradicate αVβ3-overexpressing lung and prostate cancer patient-derived xenografts (PDX), in which ca. 80% mice became tumor-free. This integrin-targeting disulfide-crosslinked micellar docetaxel emerges as a promising actively targeted nanoformulation for tumor therapy. Statement of significanceNanomedicines have a great potential in treating advanced tumor patients; however, their tumor-targeting ability and therapeutic efficacy remain unsatisfactory. In addition to PEGylation and ligand selection, particle size, stability and drug release behavior are also critical to their performance in vivo. In this paper, we find that small and cRGD-guided disulfide-crosslinked micellar docetaxel (t-MDTX) induces superior tumor uptake and retention but without increasing liver burden, leading to extraordinary selectivity and inhibition of αvβ3 overexpressing lung tumors. t-MDTX is further shown to effectively treat αvβ3-positive patient-derived tumor models, lending it a high potential for clinical translation.

Exosome membrane-sheathed and multi-stimuli-responsive MnO2 nanoparticles with self-oxygenation and energy depletion abilities potentiate the sonodynamic therapy of hypoxic tumors

Sonodynamic therapy (SDT), which employs ultrasound (US) to activate sonosensitizers to generate reactive oxygen species (ROS), has emerged as an effective approach for treating deep-seated tumors. However, poor biocompatibility of sonosensitizers and hypoxic tumor microenvironments are significant challenges for in vivo SDT. Herein, hollow manganese dioxide nanoparticles (MnO2 NPs) encapsulating the sonosensitizer, indocyanine green (ICG), were developed for enhanced sonodynamic cancer therapy by high ICG loading and tumor hypoxia relief. A glycolysis inhibitor, FX11, was co-loaded into MnO2 NPs to boost SDT efficacy via FX11-induced energy depletion. Because of the high biocompatibility, low immunogenicity, and efficient intracellular delivery of exosomes, ICG- and FX11-loaded MnO2 NP [M(ICG/FX11)] was coated with exosome membranes for safe and efficient in vivo SDT. The exosome membrane-coated M(ICG/FX11) [Exo-M(ICG/FX11)] exhibited triple pH/H2O2/US-responsive drug release while avoiding premature drug leakage. Exo-M(ICG/FX11) was efficiently internalized by MCF-7 human breast cancer cells and catalyzed the endogenous H2O2 to generate O2 to relieve tumor hypoxia. Consequently, Exo-M(ICG/FX11) markedly boosted intracellular ROS levels upon US irradiation. Moreover, Exo-M(ICG/FX11) effectively inhibited glycolytic pathways, thereby potentiating the anticancer efficacy of SDT. An in vivo study using tumor-xenografted mice demonstrated that Exo-M(ICG/FX11) effectively accumulated in tumors and alleviated tumor hypoxia. Notably, Exo-M(ICG/FX11) combined with US substantially suppressed tumors in mice without causing systemic toxicity, owing to the synergistic effect of O2 supplied-SDT and energy-depleting chemotherapy. This study demonstrates that biomimetic Exo-M(ICG/FX11) is a safe and efficient nanoplatform for the treatment of hypoxic tumors.

H2O2-responsive polymer prodrug nanoparticles with glutathione scavenger for enhanced chemo-photodynamic synergistic cancer therapy

The combination of chemotherapy and photodynamic therapy (PDT) based on nanoparticles (NPs) has been extensively developed to improve the therapeutic effect and decrease the systemic toxicity of current treatments. However, overexpressed glutathione (GSH) in tumor cells efficiently scavenges singlet oxygens (1O2) generated from photosensitizers and results in the unsatisfactory efficacy of PDT. To address this obstacle, here we design H2O2-responsive polymer prodrug NPs with GSH-scavenger (Ce6@P(EG-a-CPBE) NPs) for chemo-photodynamic synergistic cancer therapy. They are constructed by the co-self-assembly of photosensitizer chlorin e6 (Ce6) and amphiphilic polymer prodrug P(EG-a-CPBE), which is synthesized from a hydrophilic alternating copolymer P(EG-a-PD) by conjugating hydrophobic anticancer drug chlorambucil (CB) via an H2O2-cleavable linker 4-(hydroxymethyl)phenylboronic acid (PBA). Ce6@P(EG-a-CPBE) NPs can efficiently prevent premature drug leakage in blood circulation because of the high stability of the PBA linker under the physiological environment and facilitate the delivery of Ce6 and CB to the tumor site after intravenous injection. Upon internalization of Ce6@P(EG-a-CPBE) NPs by tumor cells, PBA is cleaved rapidly triggered by endogenous H2O2 to release CB and Ce6. Ce6 can effectively generate abundant 1O2 under 660nm light irradiation to synergistically kill cancer cells with CB. Concurrently, PBA can be transformed into a GSH-scavenger (quinine methide, QM) under intracellular H2O2 and prevent the depletion of 1O2, which induces the cooperatively strong oxidative stress and enhanced cancer cell apoptosis. Collectively, such H2O2-responsive polymer prodrug NPs loaded with photosensitizer provide a feasible approach to enhance chemo-photodynamic synergistic cancer treatment.

Yeast cell membrane-camouflaged PLGA nanoparticle platform for enhanced cancer therapy.

Temozolomide (TMZ) is an oral DNA-alkylating drug used in colorectal cancer (CRC) chemotherapy. In this work, we proposed a safe and biomimetic platform for macrophages-targeted delivery of TMZ and O6-benzylguanine (O6-BG). TMZ was loaded in poly (D, l-lactide-coglycolide) (PLGA) nanoparticles, followed by sequential coating with O6-BG-grafted chitosan (BG-CS) layers and yeast shell walls (YSW) via layer-by-layer assembly (LBL) process, forming TMZ@P-BG/YSW biohybrids. Due to the yeast cell membrane-camouflage, TMZ@P-BG/YSW particles exhibited significantly enhanced colloidal stability as well as low premature drug leakage in simulated gastrointestinal conditions. In vitro drug release profiles of TMZ@P-BG/YSW particles revealed noticeable higher TMZ release in simulated tumor acidic environment within 72 h. Meanwhile, O6-BG could down-regulate MGMT expression in CT26 colon carcinoma cells, ultimately facilitating TMZ-induced tumor cell death. After oral delivery of yeast cell membrane-camouflaged particles containing fluorescent tracer (Cy5), TMZ@P-BG/YSW and bare YSW displayed high retention time of 12 h in the colon and small intestine (ileum). Correspondingly, oral gavage administration of TMZ@P-BG/YSW particles afforded favorable tumor-specific retention and superior tumor growth inhibition. Overall, TMZ@P-BG/YSW is validated to be a safe, targetable and effective formulation, paving a new avenue towards highly effective and precise treatment of malignancies.

Hypoxia‐Responsive Nanoscale Coordination Polymer Enhances the Crosstalk Between Ferroptosis and Immunotherapy

AbstractThe immunosuppressive tumor microenvironment (TME) severely limits the clinical applications of cancer immunotherapy. Herein, a hypoxia‐responsive delivery system is constructed simply by coordinating ferric (Fe3+) with mitoxantrone (MTO), sulfasalazine (SAS), and hypoxia‐sensitive dopamine derivative of polyethylene glycol (PEG) using “one‐pot” reaction for the “closed‐loop” synergistic enhancement of ferroptosis and immunotherapy. Hypoxia‐sensitive PEG ensures the integrity of delivery system in circulation to prevent the premature leakage of drugs, and the detachment of PEG in the interior hypoxic TME can facilitate the deep penetration and the subsequent tumor uptake. The released iron and MTO induce the generation of reactive oxygen species (ROS), while SAS inhibits the elimination of lipid peroxides by inhibiting SLC7A11 subunit of glutamate‐cystine antiporter, which synergistically induces immunogenic ferroptosis to promote dendritic cells maturation and T cells activation. The activated CD8+ T cells then release interferon γ (IFN‐γ) and in turn enhance ferroptosis by downregulating the expression of SLC7A11. As a result, the “closed‐loop” synergistic enhancement between ferroptosis and immunotherapy significantly prevents tumor growth and prolonged survival time of tumor‐bearing mice with no obvious systemic toxicity. The excellent therapeutic effect together with the scalable synthesis and controllable quality will promise its translation to clinic as a novel immunotherapy.

Transforming a Toxic Non-Ionizable Drug into an Efficacious Liposome via Ionizable Prodrug and Remote Loading Strategies against Malignant Breast Tumors.

Liposomes (lipos), one of the most successful nanotherapeutics in the clinic, have made a rapid advance over the past few years. However, still, several challenges exist for lipos for clinical practice, such as low drug loading and premature drug leakage during in vivo circulation. Paclitaxel (PTX), a commonly used first-line drug for cancer chemotherapy, was chosen as the model drug. Due to its non-ionizable and water-insoluble characteristics, the drug-loading efficiency of the marketable PTX lipos, Lipusu, is only 6.76%. Herein, we designed an ionizable PTX prodrug (PTXP) by modifying phenylboronic acid on the C2' hydroxyl group of PTX for the remote loading of liposomal formulations through the pH gradient method. Compared with Lipusu, PTXP lipos displayed a 34% higher loading efficiency and an encapsulation efficiency of approximately 95%. A series of in vitro/vivo experiments indicated that PTXP lipos possess colloidal stability, prolonged blood circulation, high tumor site accumulation, potent anti-tumor effects, and safety. A combination of ionizable prodrugs and remote loading has proved to be an effective and simple strategy to achieve high liposomal encapsulation efficiency of poorly soluble non-ionizable drugs for clinical application.