Glutathione-Responsive and Hydrogen Sulfide Self-Generating Nanocages Based on Self-Weaving Technology To Optimize Cancer Immunotherapy.

As an ideal drug carrier, it should possess high drug loading and encapsulation efficiency and precise drug targeting release. Herein, we utilized a template-guided self-weaving technology of phase-separated silk fibroin (SF) in reverse microemulsion (RME) to fabricate a kind of hyaluronic acid (HA) coated SF nanocage (HA-gNCs) for drug delivery of cancer immunotherapy. Due to the hollow structure, HA-gNCs were capable of simultaneous encapsulation of the anti-inflammatory drug betamethasone phosphate (BetP) and the immune checkpoint blockade (ICB) agent PD-L1 antibody (αPD-L1) efficiently. Another point worth noting was that the thiocarbonate cross-linkers used to strengthen the SF shell of HA-gNCs could be quickly broken by overexpressed glutathione (GSH) to reach responsive drug release inside tumor tissues accompanied by hydrogen sulfide (H2S) production in one step. The synergistic effect of released BetP and generated H2S guaranteed chronological modulation of the immunosuppressive tumor microenvironment (ITME) to amplify the therapeutic effect of αPD-L1 for the growth, metastasis, and recurrence of tumors. This study highlighted the exceptional prospect of HA-gNCs as a self-assistance platform for cancer drug delivery.

Glutathione degradable manganese-doped polydopamine nanoparticles for photothermal therapy and cGAS-STING activated immunotherapy of lung tumor.

Photothermal therapy (PTT), which utilizes nanomaterials to harvest laser energy and convert it into heat to ablate tumor cells, has been rapidly developed for lung tumor treatment, but most of the PTT-related nanomaterials are not degradable, and the immune response associated with PTT is unclear, which leads to unsatisfactory results of the actual PTT. Herein, we rationally designed and prepared a manganese ion-doped polydopamine nanomaterial (MnPDA) for immune-activated PTT with high efficiency. Firstly, MnPDA exhibited 57.2% photothermal conversion efficiency to accomplish high-efficiency PTT, and secondly, MnPDA can be stimulated by glutathione (GSH) to the release of Mn2+, and it can produce ·OH in a Fenton-like reaction with the overexpressed H2O2 and stimulate the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. These two synergistically can effectively remove lung tumor cells that have not been ablated by PTT, resulting in an 86.7% tumor suppression rate under laser irradiation of MnPDA in vivo, and further significantly activated the downstream immune response, as evidenced by an increased ratio of cytotoxic T cells to immunosuppressive Treg cells. Conclusively, the GSH degradable MnPDA nanoparticles can be used for photothermal therapy and cGAS-STING-activated immunotherapy of lung tumors, which provides a new idea and strategy for the future treatment of lung tumors.

Bi-functional astaxanthin macromolecular nanocarriers to alleviate dextran sodium sulfate-induced inflammatory bowel disease.

Dextran sulfate sodium is one of the important members in the field of polysaccharide biotechnology, which can induce inflammatory bowel disease (IBD) in the gastrointestinal tract. Nevertheless, the application of astaxanthin (AST) and epigallocatechin-3-gallate (EGCG), known for their pronounced antioxidant and anti-inflammatory properties, is encumbered by limited stability and bioavailability. To surmount this challenge, dual nutritional macromolecular nanoparticles were provided for alleviating IBD. The forementioned strategy entailed the utilization of EGCG as a wall material via the Mannich reaction, resulting in the creation of specialized nanocarriers capable of mitochondrial targeting and glutathione-responsive AST delivery. In vitro investigations, these nanocarriers demonstrated an enhanced propensity for mitochondrial accumulation, leading to proficient elimination of reactive oxygen species and preservation of optimal mitochondrial membrane potential about 1.5 times stronger than free AST and EGCG. Crucially, in vivo experiments showed that the colon length of IBD mice treated with these nanocarriers increased by 51.29 % and facilitated the polarization of M2 macrophages. Moreover, the assimilation of these nanocarriers exerted a favorable impact on the composition of gut microbiota. These findings underscore the immense potential of dual nutrition nanocarriers in contemporaneously delivering hydrophobic biological activators through oral absorption, thereby presenting a highly promising avenue for combating IBD.

One-Pot Synthesis of Affordable Redox-Responsive Drug Delivery System Based on Trithiocyanuric Acid Nanoparticles.

Redox-responsive drug delivery systems present a promising avenue for drug delivery due to their ability to leverage the unique redox environment within tumor cells. In this work, we describe a facile and cost-effective one-pot synthesis method for a redox-responsive delivery system based on novel trithiocyanuric acid (TTCA) nanoparticles (NPs). We conduct a thorough investigation of the impact of various synthesis parameters on the morphology, stability, and loading capacity of these NPs. The great drug delivery potential of the system is further demonstrated in vitro and in vivo by using doxorubicin as a model drug. The developed TTCA-PEG NPs show great drug delivery efficiency with minimal toxicity on their own both in vivo and in vitro. The simplicity of this synthesis, along with the promising characteristics of TTCA-PEG NPs, paves the way for new opportunities in the further development of redox-responsive drug delivery systems based on TTCA.

Glutathione-Responsive Tannic Acid-Assisted FRET Nanomedicine for Cancer Therapy.

In cancer combination therapy, a multimodal delivery vector is used to improve the bioavailability of multiple anti-cancer hydrophobic drugs. Further, targeted delivery of therapeutics along with simultaneous monitoring of the drug release at the tumor site without normal organ toxicity is an emerging and effective strategy for cancer treatment. However, the lack of a smart nano-delivery system limits the application of this therapeutic strategy. To overcome this issue, a PEGylated dual drug, conjugated amphiphilic polymer (CPT-S-S-PEG-CUR), has been successfully synthesized by conjugating two hydrophobic fluorescent anti-cancer drugs, curcumin (CUR) and camptothecin (CPT), through an ester and a redox-sensitive disulfide (-S-S-) linkage, respectively, with a PEG chain via in situ two-step reactions. CPT-S-S-PEG-CUR is spontaneously self-assembled in the presence of tannic acid (TA, a physical crosslinker) into anionic, comparatively smaller-sized (~100 nm), stable nano-assemblies in water in comparison to only polymer due to stronger H-bond formation between polymer and TA. Further, due to the spectral overlap between CPT and CUR and a stable, smaller nano-assembly formation by the pro-drug polymer in water in presence of TA, a successful Fluorescence Resonance Energy Transfer (FRET) signal was generated between the conjugated CPT (FRET donor) and conjugated CUR (FRET acceptor). Interestingly, these stable nano-assemblies showed a preferential breakdown and release of CPT in a tumor-relevant redox environment (in the presence of 50 mM glutathione), leading to the disappearance of the FRET signal. These nano-assemblies exhibited a successful cellular uptake by the cancer cells and an enhanced antiproliferative effect in comparison to the individual drugs in cancer cells (AsPC1 and SW480). Such promising in vitro results with a novel redox-responsive, dual-drug conjugated, FRET pair-based nanosized multimodal delivery vector can be highly useful as an advanced theranostic system towards effective cancer treatment.

Disulfide Bond-Based SN38 Prodrug Nanoassemblies with High Drug Loading and Reduction-Triggered Drug Release for Pancreatic Cancer Therapy.

Purpose: Chemotherapy is a significant and effective therapeutic strategy that is frequently utilized in the treatment of cancer. Small molecular prodrug-based nanoassemblies (SMPDNAs) combine the benefits of both prodrugs and nanomedicine into a single nanoassembly with high drug loading, increased stability, and improved biocompatibility. Methods: In this study, a disulfide bond inserted 7-ethyl-10-hydroxycamptothecin (SN38) prodrug was rationally designed and then used to prepare nanoassemblies (SNSS NAs) that were selectively activated by rich glutathione (GSH) in the tumor site. The characterization of SNSS NAs and the in vitro and in vivo evaluation of their antitumor effect on a pancreatic cancer model were performed. Results: In vitro findings demonstrated that SNSS NAs exhibited GSH-induced SN38 release and cytotoxicity. SNSS NAs have demonstrated a passive targeting effect on tumor tissues, a superior antitumor effect compared to irinotecan (CPT-11), and satisfactory biocompatibility with double dosage treatment. Conclusion: The SNSS NAs developed in this study provide a new method for the preparation of SN38-based nano-delivery systems with improved antitumor effect and biosafety.

Glutathione-Responsive Nanoparticles of Camptothecin Prodrug for Cancer Therapy.

Camptothecin (CPT) is a potent chemotherapeutic agent for various cancers, but the broader application of CPT is still hindered by its poor bioavailability and systemic toxicity. Here, a prodrug that releases CPT in response to glutathione (GSH), which is commonly overexpressed by cancer cells is reported. Through assembling with PEGylated lipids, the prodrug is incorporated within as-assembled nanoparticles, affording CPT with a prolonged half-life in blood circulation, enhanced tumor targetingability, and improved therapeutic efficacy. Furthermore, such prodrug nanoparticles can also promote dendritic cell maturation and tumor infiltration of CD8+ T cells, providing a novel strategy to improve the therapeutic efficacy of CPT.

RGD peptide modified platinum nanozyme Co-loaded glutathione-responsive prodrug nanoparticles for enhanced chemo-photodynamic bladder cancer therapy.

Bladder cancer is one of the most common malignant tumors in the urinary system worldwide. The poor permeability and uncontrollable release of drug and hypoxia of tumor tissues were the main reasons leading to poor therapeutic effect of chemo-photodynamic therapy for bladder cancer. To solve the above problems, a tumor-targeting peptide Arg-Gly-Asp (RGD) modified platinum nanozyme (PtNP) co-loaded glutathione (GSH)-responsive prodrug nanoparticles (PTX-SS-HPPH/Pt@RGD-NP) was constructed. Firstly, a GSH-responsive prodrug (PTX-SS-HPPH) was prepared by introducing a disulfide bond between paclitaxel (PTX) and photosensitizer 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH), which could realize the GSH-responsive release of the drug at the tumor sites. Also, the distearoylphosphoethanolamine-poly (ethylene glycol)-RGD peptide (DSPE-PEG-RGD) modified the prodrug to enhance the targeting and permeability ability to bladder cancer cells. Besides, to alleviate the hypoxia of tumor tissues, PtNP was introduced to produce oxygen (O2) and improve photodynamic therapy efficiency. The results showed that the PTX-SS-HPPH/Pt@RGD-NP could achieve GSH-responsive drug release in tumor microenvironment, enhance the drug accumulation time and permeability at tumor sites in T24 subcutaneous tumor model and T24 orthotopic bladder tumor model, and alleviate hypoxia in tumor tissues, thus realizing enhanced chemo-photodynamic therapy for bladder cancer, and providing new strategies and methods for clinical treatment of bladder cancer.

Programmed initiation and enhancement of cGAS/STING pathway for tumour immunotherapy via tailor-designed ZnFe2O4-based nanosystem.

The cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)/stimulator of interferon genes (STING) signalling pathway has been a promising target for anticancer immunity, but rationally activating and enhancing this pathway in tumour cells is critical. Herein, a glutathione sensitive ZnFe2O4-based nanosystem is developed to programmatically initiate and enhance the STING signalling pathway in tumour cells. The prepared ZnFe2O4 nanoparticles were coated with cancer cell membrane (CCM), which enabled the nanosystem target tumour cells. In tumour cells, ZnFe2O4 nanoparticles could be disintegrated by responding to high level glutathione, and the released Fe3+ generated reactive oxygen species to induce the DNA leakage into the cytoplasm to stimulate cGAS. Then Zn2+ promoted cGAS-DNA phase separation to intensify the cGAS enzymatic activity. In addition, the low dose encapsulation of paclitaxel (PTX) acting as an antimitotic agent (ZnFe2O4-PTX@CCM) ensured the sustained activation of cGAS/STING pathway. The in vitro and in vivo results confirmed that ZnFe2O4-PTX@CCM elevated the cGAS/STING activity, promoted dendritic cell maturation, increased cytotoxic T lymphocyte and natural killer cells infiltration, eventually inhibiting the tumour progress and postoperative recurrence. This study provided feasible references on constructing STING activation nanosystem for tumour immunotherapy.

Bioresponsive Polymers for Nanomedicine-Expectations and Reality!

Bioresponsive polymers in nanomedicine have been widely perceived to selectively activate the therapeutic function of nanomedicine at diseased or pathological sites, while sparing their healthy counterparts. This idea can be described as an advanced version of Paul Ehrlich's magic bullet concept. From that perspective, the inherent anomalies or malfunction of the pathological sites are generally targeted to allow the selective activation or sensory function of nanomedicine. Nonetheless, while the primary goals and expectations in developing bioresponsive polymers are to elicit exclusive selectivity of therapeutic action at diseased sites, this remains difficult to achieve in practice. Numerous research efforts have been undertaken, and are ongoing, to tackle this fine-tuning. This review provides a brief introduction to key stimuli with biological relevance commonly featured in the design of bioresponsive polymers, which serves as a platform for critical discussion, and identifies the gap between expectations and current reality.

Prostate-specific membrane antigen targeted, glutathione-sensitive nanoparticles loaded with docetaxel and enzalutamide for the delivery to prostate cancer.

Prostate cancer (PCa) is the most common malignant tumor in men. Chemotherapy with docetaxel (DTX) and novel hormonal agents such as enzalutamide (EZL) and abiraterone are the preferred first-line therapeutic regimens. Prostate-specific membrane antigen (PSMA) is overexpressed on the surface of PCa cells. This study aimed to prepare a PSMA targeted (Glutamate-Urea-Lysine, GUL ligand modified), glutathione (GSH)-sensitive (Cystamine, SS), DTX and EZL co-loaded nanoparticles (GUL-SS DTX/EZL-NPs) to treat PCa. Polyethylene glycol (PEG) was conjugated with oleic acid (OA) using a GSH-sensitive ligand: cystamine (PEG-SS-OA). GUL was covalently coupled to PEG-SS-OA to achieve GUL-PEG-SS-OA. GUL-PEG-SS-OA was used to prepare GUL-SS DTX/EZL-NPs. To evaluate the in vitro and in vivo efficiency of the system, human prostate cancer cell lines and PCa cells bearing mice were applied. Single drug-loaded nanoparticle and free drugs systems were utilized for the comparison of the anticancer ability. GUL-SS DTX/EZL-NPs showed a size of 143.7 ± 4.1 nm, with a PDI of 0.162 ± 0.037 and a zeta potential of +29.1 ± 2.4 mV. GUL-SS DTX/EZL-NPs showed high cancer cell uptake of about 70%, as well as higher cell growth inhibition efficiency (a maximum 79% of cells were inhibited after treatment) than single drug-loaded NPs and free drugs. GUL-SS DTX/EZL-NPs showed the most prominent tumor inhibition ability and less systemic toxicity. The novel GUL-SS DTX/EZL-NPs could be used as a promising system for PCa therapy.

Glutathione-Responsive Pyraclostrobin-Loaded Polyurea Microcapsules for Their Intelligent Controlled Release.

The utilization of intelligent controlled release technology to create stimuli-responsive pesticide formulations has been shown to effectively improve pesticide efficacy and reduce environmental pollution. Herein, a glutathione-responsive release polyurea (PU) microcapsules (MCs) loaded with pyraclostrobin were developed via the interface polymerization method. The pyraclostrobin-loaded PU-MCs showed a regular spherical shape with an average diameter of 480 nm. It also showed good thermal stability and rheological properties. Furthermore, the pyraclostrobin-loaded PU-MCs exhibited favorable wettability on wheat leaves, which was beneficial for enhancing the retention capacity of pesticide droplets and improving pesticide utilization. The pyraclostrobin can be released from MCs and directly proportional to glutathione (GSH) concentrations with Fickian diffusion. Importantly, the control efficacy of pyraclostrobin-loaded PU-MCs against Fusarium graminearum was positively correlated with GSH, indicating a promising candidate for a controlled release of pesticides in agriculture and laying the foundation for further field experiments.

Glutathione-responsive molecular nanoparticles from a dianionic bolaamphiphile and their use as carriers for targeted delivery.

The formation in aqueous media of molecular nanoparticles from a bolaamphiphile (SucIleCsa) incorporating a disulfide moiety is described. The particles can be loaded efficiently with the lipophilic mitochondrial marker DiOC6(3), quenching its fluorescence, which is recovered upon reductive particle disassembly. DiOC6(3) transport into human colorectal adenocarcinoma cells (HT-29) is demonstrated using flow cytometry and confocal scanning fluorescence microscopy. A significant increase in intracellular fluorescence is observed when the cells are stimulated to produce glutathione (GSH). These new molecular nanoparticles can be considered a theranostic tool that simultaneously achieves targeted delivery of lipophilic substances and signals high levels of GSH.

Superstable and Large-Scalable Organosilica-Micellar Hybrid Nanosystem via a Confined Gelation Strategy for Ultrahigh-Dosage Chemotherapy.

Although various drug nanocarriers have been developed for treating solid tumors, their clinical transformation is greatly limited by the difficulties in quantity production and unpredictable in vivo toxic effects. Herein, a facile "confined-gelation" strategy is developed to quantity-produce intelligent pluronic organosilica micelles (designated as IPOMs) with an undetectable critical micelle concentration (CMC), which features the self-assembly induced core confinement by block copolymers, the inner hydrolysis-condensation of silane to the oligomer skeleton, and oxidative cross-linking of disulfide skeleton to core gelation. The docetaxel-loaded IPOMs (DTX@IPOMs) with precise glutathione (GSH) responsiveness not only display an ultrahigh tolerated dose (360 mg/kg) in healthy Kunming mice model but also exhibit a remarkable tumor inhibition efficacy in both subcutaneous and orthotopic mice tumor models upon an extraordinarily large dosage (50 mg/kg). The present confined-gelation strategy provides a novel pathway to design and quantity-produce low-toxic and high-efficacy organic-inorganic hybrid nanodrugs in future clinical transformations.

Interface-Engineered Paclitaxel-Based Hollow Mesoporous Organosilica Nanoplatforms for Photothermal-Enhanced Chemotherapy of Tumor.

Having benefited from the combination of different therapeutic modalities, functionalized nanoplatforms with synergistic strategies have aroused great interest in anticancer treatment. Herein, an engineered, a biodegradable hollow mesoporous organosilica nanoparticle (HMON)-based nanoplatform was fabricated for photothermal-enhanced chemotherapy of tumor. For the first time, we demonstrated that HMONs could serve as nanocarriers for co-delivering of both the paclitaxel and photothermal agent new indocyanine green (IR820), denoted as Paclitaxel/IR820@ HMONs-PEG. The as-prepared nanosystem exhibited a high paclitaxel-loading capacity of 28.4%, much higher than most paclitaxel-loaded nanoformulations. Furthermore, incorporating thioether bonds (S-S) into the HMONs' framework endowed them with GSH-responsive biodegradation behavior, leading to the controllable release of drugs under a tumor reducing microenvironment, and hindered the premature release of paclitaxel. Upon being irradiated with an NIR laser, the obtained co-delivery nanosystem exhibited great photothermal properties generated from IR820. The fabricated nanocomposites could significantly suppress tumor growth under NIR laser irradiation, as validated by in vitro and in vivo assessments. Combined with outstanding biocompatibility, the constructed nanosystem holds great potential in combinational antitumor therapy.

Engineering glutathione-responsive near-infrared polymeric prodrug system for fluorescence imaging in tumor therapy.

The release and biodistribution of drugs in the body have an important impact on tumor diagnosis and treatment. Near-infrared (NIR) fluorescent active fluorophores with good photostability are used to detect drug release and perform in vivo imaging. Here, we developed a glutathione-responsive NIR prodrug POEGMA-b-P(CPT-CyOH) (PCC) for effective cancer diagnosis and treatment, whereby the camptothecin (CPT) and NIR fluorophore CyOH in PCC are connected by disulfide bonds. In vitro experiments confirmed that PCC was quickly taken up by cells. The high concentration of tumor intracellular glutathione caused the cleavage of the PCC disulfide bonds, leading to the release of the chemotherapeutic drug CPT, indicating that PCC can promote apoptosis. Moreover, owing to the fluorescent properties of CyOH, PCC was successfully used for in vivo imaging to observe the drug penetration and enrichment capabilities in tumors. Finally, PCC successfully inhibited tumor growth, indicating that the prodrug has a good anti-tumor effect. This work provides new strategies for chemical drug delivery and precise cancer treatment.

Chemoattractants driven and microglia based biomimetic nanoparticle treating TMZ-resistant glioblastoma multiforme.

Currently, clinical treatment for temozolomide (TMZ)-resistant glioblastoma multiforme (GBM) is still a difficult problem. The aim of this paper is to set up a new GBM-targeted drug delivery system to treat TMZ-resistant GBM. Zoledronate (ZOL) not only induces apoptosis of TMZ-resistant GBM cells by down-regulation of farnesyl pyrophosphate synthetase (FPPS) but also increases the proportion of M1-type GBM associated macrophages (GAM). Based on chemoattractants secreted by GBM cells, a ZOL loaded nanoparticle coated with microglia cell membrane (ZOL@CNPs) was prepared to deliver ZOL to central nervous system to treat TMZ-resistant GBM. ZOL@CNPs was actively recruited to TMZ-resistant GBM region by CX3CL1/CX3CR1 and CSF-1/CSF-1R signal axis, and the release of ZOL from ZOL@CNPs was triggered by glutathione in GBM cells. ZOL@CNPs inhibited the growth of TMZ-resistant GBM through inducing apoptosis and inhibiting the migration and invasion of TMZ-resistant GBM cells. Besides, the immunosuppressive and hypoxic microenvironment, playing an important role in the growth of TMZ-resistant GBM, was significantly improved by ZOL@CNPs through increasing the proportion of M1-type GAM and blocking the expression of HIF-1α. ZOL@CNPs has a great potential application in the treatment for TMZ-resistant GBM.

Glutathione-Responsive Magnetic Nanoparticles for Highly Sensitive Diagnosis of Liver Metastases.

Liver metastasis (LM) occurs in various cancers, and its early and accurate diagnosis is of great importance. However, the detection of small LMs is still a great challenge because of the subtle differences between normal liver tissue and small metastases. Herein, we prepare glutathione (GSH)-responsive hyaluronic acid-coated iron oxide nanoparticles (HIONPs) for highly sensitive diagnosis of LMs through a facile one-pot method. HIONPs greatly enhance the signal of MRI in tumor metastases as T1 contrast agent (CA), whereas they substantially decrease the signal of liver as T2 CA as they aggregate into clusters upon the high GSH in liver. Consequently, MRI contrasted by HIONPs clearly distinguishes metastatic tumors (bright) from surrounding liver tissues (dark). HIONPs with superior LM contrasting capability and facile synthesis are very promising for clinical translation and indicate a new strategy to develop an ultrasensitive MRI CA for LM diagnosis that exploits high GSH level in the liver.

A sulfur dioxide polymer prodrug showing combined effect with doxorubicin in combating subcutaneous and metastatic melanoma.

Melanoma, as the most aggressive and treatment-resistant skin malignancy, is responsible for about 80% of all skin cancer mortalities. Prone to invade into the dermis and form distant metastases significantly reduce the patient survival rate. Therefore, early treatment of the melanoma in situ or timely blocking the deterioration of metastases is critical. In this study, a sulfur dioxide (SO2) polymer prodrug was designed as both an intracellular glutathione (GSH)-responsive SO2 generator and a carrier of doxorubicin (DOX), and used for the treatment of subcutaneous and metastatic melanoma. Firstly, chemical conjugation of 4-N-(2,4-dinitrobenzenesulfonyl)-imino-1-butyric acid (DIBA) onto the side chains of methoxy poly (ethylene glycol) grafted dextran (mPEG-g-Dex) resulted in the synthesis of the amphiphilic polymer prodrug of SO2, mPEG-g-Dex (DIBA). The obtained mPEG-g-Dex (DIBA) could self-assemble into stable micellar nanoparticles and exhibited a glutathione-responsive SO2 release behavior. Subsequently, DOX was encapsulated into the core of mPEG-g-Dex (DIBA) micelles to form DOX-loaded nanoparticles (PDDN-DOX). The formed PDDN-DOX could be internalized by B16F10 cells and synchronously release DOX and SO2 into the tumor cells. As a result, PDDN-DOX exerted synergistic anti-tumor effects in B16F10 melanoma cells because of the oxidative damage properties of SO2 and toxic effects of DOX. Furthermore, in vivo experiments verified that PDDN-DOX had great potential for the treatment of subcutaneous and metastasis melanoma. Collectively, our present work demonstrates that the combination of SO2-based gas therapy and chemotherapeutics offers a new avenue for inhibiting melanoma progression and metastases.

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.