A dual-responsive doxorubicin-indoximod conjugate for programmed chemoimmunotherapy.
Ontology highlight
ABSTRACT:
SUBMITTER: Yang Z
PROVIDER: S-EPMC9257650 | biostudies-literature | 2022 Jul
REPOSITORIES: biostudies-literature
Publications
A dual-responsive doxorubicin-indoximod conjugate for programmed chemoimmunotherapy.
Yang Zhaoxuan Z Huang Jiaqi J Lin Yaying Y Luo Xiangjie X Lin Haojin H Lin Hongyu H Gao Jinhao J
RSC chemical biology 20220530 7
Herein we report a dual-responsive doxorubicin-indoximod conjugate (DOXIND) for programmed chemoimmunotherapy. This conjugate is able to release doxorubicin and indoximod upon exposure to appropriate stimuli for synergistic chemotherapy and immunotherapy, respectively. We demonstrate its promoting effects on immune response and inhibiting effects on tumor growth through a series of <i>in vitro</i> and <i>in vivo</i> experiments. ...[more]
Similar Datasets
Project description:BackgroundThe enhancement of tumor retention and cellular uptake of drugs are important factors in maximizing anticancer therapy and minimizing side effects of encapsulated drugs. Herein, a delivery nanoplatform, armed with a pH-triggered charge-reversal capability and self-amplifiable reactive oxygen species (ROS)-induced drug release, is constructed by encapsulating doxorubicin (DOX) in pH/ROS-responsive polymeric micelle.ResultsThe surface charge of this system was converted from negative to positive from pH 7.4 to pH 6.8, which facilitated the cellular uptake. In addition, methionine-based system was dissociated in a ROS-rich and acidic intracellular environment, resulting in the release of DOX and α-tocopheryl succinate (TOS). Then, the exposed TOS segments further induced the generation of ROS, leading to self-amplifiable disassembly of the micelles and drug release.ConclusionsWe confirms efficient DOX delivery into cancer cells, upregulation of tumoral ROS level and induction of the apoptotic capability in vitro. The system exhibits outstanding tumor inhibition capability in vivo, indicating that dual stimuli nano-system has great potential to function as an anticancer drug delivery platform.
| S-EPMC7517807 | biostudies-literature
Project description:The antitumor immune response induced by chemotherapy has attracted considerable attention. However, the immunosuppressive tumor microenvironment hinders the immune activation effect of cancer chemotherapy. TGF-β plays a key role in driving tumor immunosuppression and can prevent effective antitumor immune response through multiple roles. In this study, a dual-responsive prodrug micelle (PAOL) is designed to co-deliver LY2109761 (a TGF-β receptor I/II inhibitor) and oxaliplatin (OXA, a conventional chemotherapy) to remodel tumor microenvironment and trigger immunogenic cell death (ICD) to induce antitumor immunity response. Under hypoxia tumor environment, the polyethylene glycol shell of the micelle cleavages, along with the release of LY2109761 and OXA prodrug. Cytotoxic effect of OXA is then activated by glutathione-mediated reduction in tumor cells and the activated OXA significantly enhances tumor immunogenicity and promotes intratumoral accumulation of cytotoxic T lymphocytes. Meanwhile, TGF-β blockade through LY2109761 reprograms tumor microenvironment by correcting the immunosuppressive state and regulating tumor extracellular matrix, which further maintaining OXA induced immune response. Therefore, due to the capability of boosting tumor-specific antitumor immunity, the bifunctional micelle presents markedly synergistic antitumor efficacies and provides a potent therapeutic strategy for chemoimmunotherapy of solid tumors.
| S-EPMC9090387 | biostudies-literature
Project description:After molecule targeted drug, monoclonal antibody and antibody-drug conjugates (ADCs), peptide-drug conjugates (PDCs) have become the next generation targeted anti-tumor drugs due to its properties of low molecule weight, efficient cell penetration, low immunogenicity, good pharmacokinetic and large-scale synthesis by solid phase synthesis. Herein, we present a lytic peptide PTP7-drug paclitaxel conjugate assembling nanoparticles (named PPP) that can sequentially respond to dual stimuli in the tumor microenvironment, which was designed for passive tumor-targeted delivery and on-demand release of a tumor lytic peptide (PTP-7) as well as a chemotherapeutic agent of paclitaxel (PTX). To achieve this, tumor lytic peptide PTP-7 was connected with polyethylene glycol by a peptide substrate of legumain to serve as hydrophobic segments of nanoparticles to protect the peptide from enzymatic degradation. After that, PTX was connected to the amino group of the polypeptide side chain through an acid-responsive chemical bond (2-propionic-3-methylmaleic anhydride, CDM). Therefore, the nanoparticle (PPP) collapsed when it encountered the weakly acidic tumor microenvironment where PTX molecules fell off, and further triggered the cleavage of the peptide substrate by legumain that is highly expressed in tumor stroma and tumor cell surface. Moreover, PPP presents improved stability, improved drug solubility, prolonged blood circulation and significant inhibition ability on tumor growth, which gives a reasonable strategy to accurately deliver small molecule drugs and active peptides simultaneously to tumor sites.
| S-EPMC9176665 | biostudies-literature
Project description:The use of smart nanocarriers that can modulate therapeutic release aided by biological cues can prevent undesirable cytotoxicity caused by the premature release of cytotoxic drugs during nanocarrier circulation. In this report, degradable nanocarriers based on pH/reduction dual-responsive nanogels were synthesized to encapsulate doxorubicin hydrochloride (DOX) and specifically boost the release of DOX in conditions characteristic of the cancer microenvironment. Nanogels containing anionic monomer 2-carboxyethyl acrylate (CEA) and N,N'-bis(acryloyl)cystamine (CBA) as a degradable crosslinker have been successfully synthesized via photoinitiated free radical polymerization. The loading process was conducted after polymerization by taking advantage of the electrostatic interaction between the negatively charged nanogels and the positively charged DOX. In this case, a high drug loading capacity (DLC) of up to 27.89% was achieved. The entrapment of DOX into a nanogel network could prevent DOX from aggregating in biological media at DOX concentrations up to ~160 µg/mL. Anionic nanogels had an average hydrodynamic diameter (dH) of around 90 nm with a negative zeta (ζ) potential of around -25 mV, making them suitable for targeting cancer tissue via the enhanced permeation effect. DOX-loaded nanogels formed a stable dispersion in different biological media, including serum-enriched cell media. In the presence of glutathione (GSH) and reduced pH, drug release was enhanced, which proves dual responsivity. An in vitro study using the HCT 116 colon cancer cell line demonstrated the enhanced cytotoxic effect of the NG-CBA/DOX-1 nanogel compared to free DOX. Taken together, pH/reduction dual-responsive nanogels show promise as drug delivery systems for anticancer therapy.
| S-EPMC9505369 | biostudies-literature
Project description:The self-assembly behaviour of dual-responsive block copolymers and their ability to solubilize the anticancer drug doxorubicin (DOX) has been investigated using all-atom molecular dynamics (MD) simulations, MARTINI coarse-grained (CG) force field simulation and Scheutjens-Fleer self-consistent field (SCF) computations. These diblock copolymers, composed of poly{γ-2-[2-(2-methoxyethoxy)ethoxy]ethoxy-ε-caprolactone} (PMEEECL) and poly(β-amino ester) (PAE) are dual-responsive: the PMEEECL block is thermoresponsive (becomes insoluble above a certain temperature), while the PAE block is pH-responsive (becomes soluble below a certain pH). Three MEEECL20-AE M compositions with M = 5, 10, and 15, have been studied. All-atom MD simulations have been performed to calculate the coil-to-globule transition temperature (T cg) of these copolymers and finding appropriate CG mapping for both PMEEECL-PAE and DOX. The output of the MARTINI CG simulations is in agreement with SCF predictions. The results show that DOX is solubilized with high efficiency (75-80%) at different concentrations inside the PMEEECL-PAE micelles, although, interestingly, the loading efficiency is reduced by increasing the drug concentration. The non-bonded interaction energy and the RDF between DOX and water beads confirm this result. Finally, MD simulations and SCF computations reveal that the responsive behaviour of PMEEECL-PAE self-assembled structures take place at temperature and pH ranges appropriate for drug delivery.
| S-EPMC9048636 | biostudies-literature
Project description:Immunotherapy based on checkpoint blockade has been regarded as one of the most promising approaches towards many types of cancers. However, low response rate hinders its application due to insufficient tumor immunogenicity and immunosuppressive tumor microenvironment. To achieve an overall enhanced therapeutic outcome, we developed a dual-functional immuno-stimulatory polymeric prodrug carrier modified with pendent indoximod, an indoleamine 2,3-dioxygenase (IDO) inhibitor that can be used to reverse immune suppression, for co-delivery of Doxorubicin (Dox), a hydrophobic anticancer agent that can promote immunogenic cell death (ICD) and elicit antitumor immunity. The resulted carrier denoted as POEG-b-PVBIND, consisting of poly (oligo (ethylene glycol) methacrylate) (POEG) hydrophilic blocks and indoximod conjugated hydrophobic blocks, is rationally designed to improve immunotherapy by synergistically modulating the tumor microenvironment (TME). Our data showed that Dox-triggered ICD promoted intra-tumoral infiltration of CD8+ T cells and IFN-γ-production by CD8+ T cells. Meanwhile, cleaved indoximod significantly increased CD8+ T cell infiltration while reducing the immunosuppressive T regulatory cells (Tregs). More importantly, Dox/POEG-b-PVBIND micelles led to significantly improved tumor regression in an orthotopic murine breast cancer model compared to both Dox-loaded POEG-b-PVB micelles (a control inert carrier) and POEG-b-PVBIND micelles alone, confirming combination effect of indoximod and Dox in improving the overall antitumor activity. STATEMENT OF SIGNIFICANCE: Indoleamine 2,3-dioxygenase (IDO) is an enzyme that can induce immune suppressive microenvironment in tumors. As a well-studied IDO inhibitor, indoximod (IND) represents a promising agent for cancer immunotherapy and could be particularly useful in combination with other chemotherapeutic agents. However, three major problems hinder its application: (1) IND is barely soluble in water; (2) IND delivery efficiency is limited (3) simultaneous delivery of two agents into tumor site is still challenging. Currently, most reports largely focus on improving the pharmacokinetic profile of IND alone via different formulations such as IND prodrug and IND nanocrystal. However, there is limited information about IND based co-delivery systems, especially for delivering hydrophobic chemotherapeutic agents. Here, we developed a new dual-functional polymeric prodrug carrier modified with a number of pendent IND units (denoted as POEG-b-PVBIND). POEG-b-PVBIND shows immunostimulatory and antitumor activities by itself. More importantly, POEG-b-PVBIND polymer is able to self-assemble into nano-sized micelles that are highly effective in formulating and codelivering other hydrophobic agents including doxorubicin (Dox), sunitinib (Sun), and daunorubicin (Dau), which can elicit antitumor immunity via promoting immunogenic cell death (ICD). We have shown that our new combination therapy led to a significantly improved antitumor activity in an aggressive murine breast cancer model (4T1.2).
| S-EPMC6513707 | biostudies-literature
Project description:Nanoparticle-based drug delivery system offers a promising platform for combination cancer therapy. However, the inefficient drug release in cells reduces the therapeutic efficacy of cancer nanomedicines. Herein, a PEGylated poly(α-lipoic acid) copolymer (mPEG-PαLA) was prepared and used as a reduction/pH dual responsive nanocarrier to simultaneously deliver paclitaxel (PTX) and doxorubicin (DOX) for osteosarcoma therapy. The amphiphilic mPEG-PαLA could efficiently encapsulate both PTX and DOX during its self-assembly into micelles in aqueous solution to generate PTX and DOX co-loaded nanoparticles (NP-PTX-DOX). The as-prepared NP-PTX-DOX showed enhanced PTX and DOX release in response to reductive and acidic stimuli. Moreover, the dual-drug loaded nanoparticles were efficiently internalized by K7 osteosarcoma cells and released drugs intracellularly, as confirmed by flow cytometry analysis and confocal laser scanning microscopy. Consequently, NP-PTX-DOX exhibited synergistic therapeutic effects and induced enhanced cell apoptosis in K7 cells. Furthermore, NP-PTX-DOX presented improved biodistribution and higher tumor growth inhibition efficacy compared to the control groups in a murine osteosarcoma model. Altogether, the results of this work indicate that the proposed strategy is promising for osteosarcoma therapy using mPEG-PαLA copolymer as a dual-responsive nanocarrier to co-deliver anticancer drugs.
| S-EPMC7470123 | biostudies-literature
Project description:This work reports a multifunctional nanocarrier based on hollow mesoporous silica nanoparticles (HMSNs) for targeting tumor therapy. Doxorubicin (DOX) was loaded into HMSNs and blocked with cytochrome C conjugated lactobionic acid (CytC-LA) via redox-cleavable disulfide bonds and pH-disassociation boronate ester bonds as intermediate linkers. The CytC-LA was used both as sealing agent and targeting motif. A series of characterizations demonstrated the successful construction of the drug delivery system. The system demonstrated pH and redox dual-responsive drug release behavior in vitro. The DOX loading HMSNs system displayed a good biocompatibility, which could be specifically endocytosed by HepG2 cells and led to high cytotoxicity against tumor cells by inducing cell apoptosis. In vivo data (tumor volume, tumor weight, terminal deoxynucleotidyl transferase dUTP nick end labeling and hematoxylin and eosin staining) proved that the system could deliver DOX to tumor site with high efficiency and inhibit tumor growth with minimal toxic side effect.
| S-EPMC6371689 | biostudies-literature
Project description:BackgroundAcute myeloid leukemia (AML) showed limited clinical therapeutic efficiency with chemotherapy for its multi-distributed lesions and hard-to-kill leukemia cells deep in the bone marrow.ResultsHere, a biomimetic nanosystem (DR@PLip) based on platelet membrane (PM) coating and doxorubicin (DOX)/ginsenoside (Rg3) co-loading was developed to potentiate the local-to-systemic chemoimmunotherapy for AML. The PM was designed for long-term circulation and better leukemia cells targeting. The participation of Rg3 was proved to enhance the tumor sensitivity to DOX, thus initiating the anti-tumor immune activation and effectively combating the leukemia cells hiding in the bone marrow.ConclusionsIn conclusion, the strategy that combining immediate chemotherapy with long-term immunotherapy achieved improved therapeutic efficiency and prolonged survival, which provided a new perspective for the clinical treatment of AML.
| S-EPMC9195256 | biostudies-literature
Project description:Chemoimmunotherapy is an emerging combinatorial modality for the treatment of cancers resistant to common first-line therapies, such as chemotherapy and checkpoint blockade immunotherapy. We used biodegradable nanoparticles as delivery vehicles for local, slow and sustained release of doxorubicin, two immune adjuvants and one chemokine for the treatment of resistant solid tumors. Methods: Bio-compatible poly(lactic-co-glycolic acid)-PEG nanoparticles were synthesized in an oil/water emulsion, using a solvent evaporation-extraction method. The nanoparticles were loaded with a NIR-dye for theranostic purposes, doxorubicin cytostatic agent, poly (I:C) and R848 immune adjuvants and CCL20 chemokine. After physicochemical and in vitro characterization the nanoparticles therapeutic efficacy were carried-out on established, highly aggressive and treatment resistant TC-1 lung carcinoma and MC-38 colon adenocarcinoma models in vivo. Results: The yielded nanoparticles average size was 180 nm and -14 mV surface charge. The combined treatment with all compounds was significantly superior than separate compounds and the compounds nanoparticle encapsulation was required for effective tumor control in vivo. The mechanistic studies confirmed strong induction of circulating cancer specific T cells upon combined treatment in blood. Analysis of the tumor microenvironment revealed a significant increase of infiltrating leukocytes upon treatment. Conclusion: The multi-drug loaded nanoparticles mediated delivery of chemoimmunotherapy exhibited excellent therapeutic efficacy gain on two treatment resistant cancer models and is a potent candidate strategy to improve cancer therapy of solid tumors resistant to first-line therapies.
| S-EPMC6771237 | biostudies-literature