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Carbon monoxide (CO) has emerged as a potential antitumor agent by inducing the dysfunction of mitochondria and the apoptosis of cancer cells. However, it remains challenging to deliver appropriate amount of CO into tumor to ensure efficient tumor growth suppression with minimum side effects. Herein we developed a CO prodrug-loaded nanomedicine based on the self-assembly of camptothecin (CPT) polyprodrug amphiphiles. The polyprodrug nanoparticles readily dissociate upon exposure to endogenous H 2 O 2 in the tumor, resulting in rapid release of CPT and generation of high-energy intermediate dioxetanedione. The latter can transfer the energy to neighboring CO prodrugs to activate CO production by chemiexcitation, while CPT promotes the generation of H 2 O 2 in tumors, which in turn facilitates cascade CPT and CO release. As a result, the polyprodrug nanoparticles display remarkable tumor suppression in both subcutaneous and orthotopic breast tumor-bearing mice owing to the self-augmented CPT release and CO generation. In addition, no obvious systemic toxicity was observed in mice treated with the metal-free CO prodrug-loaded nanomedicine, suggesting the good biocompatibility of the polyprodrug nanoparticles. Our work provides new insights into the design and construction of polyprodrug nanomedicines for synergistic chemo/gas therapy. We reported a CO prodrug-loaded polyprodrug nanoparticle for self-augmented synergistic chemo/gas cancer therapy. The polyprodrug nanoparticle can release CPT in the presence of H 2 O 2 and the energy produced during this process can activate the CO prodrug to generate CO. The released CPT induces H 2 O 2 generation in tumor cells to initiate consistent CPT and CO release, thus realizing effective tumor suppression via orchestrated chemo/gas therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

In terms of treatment strategies, IO therapy has surpassed targeted therapy as the most popular strategy in anticancer drug R&D [[1]]. Types of cell therapy expanded from one single class (CAR-T) to six classes including CAR-T, autologous circulating T cells, NK cell-derived therapies, TCR-T, engineered T cells, and tumor-infiltrating T cells (Fig. More diverse cancer types studied in phase 1 trials 67.9% (247 trials) of phase 1 oncology trials enrolled patients with specific types of cancer. [Extracted from the article]

Abstract: We report a type of photosensitizer (PS)-loaded micelles integrating cyanine dye as potential theranostic micelles for precise anatomical tumor localization via dual photoacoustic (PA)/near-infrared fluorescent (NIRF) imaging modalities, and simultaneously superior cancer therapy via sequential synergistic photothermal therapy (PTT)/photodynamic therapy (PDT). The micelles exhibit enhanced photostability, cell internalization and tumor accumulation. The dual NIRF/PA imaging modalities of the micelles cause the high imaging contrast and spatial resolution of tumors, which provide precise anatomical localization of the tumor and its inner vasculature for guiding PTT/PDT treatments. Moreover, the micelles can generate severe photothermal damage on cancer cells and destabilization of the lysosomes upon PTT photoirradiation, which subsequently facilitate synergistic photodynamic injury via PS under PDT treatment. The sequential treatments of PTT/PDT trigger the enhanced cytoplasmic delivery of PS, which contributes to the synergistic anticancer efficacy of PS. Our strategy provides a dual-modal cancer imaging with high imaging contrast and spatial resolution, and subsequent therapeutic synergy of PTT/PDT for potential multimodal theranostic application. [Copyright &y& Elsevier]

MicroRNAs (miRNAs) have been implicated to play a central role in the development of drug resistance in a variety of malignancies. However, many studies were conducted at the in vitro level and could not provide the in vivo information on the functions of miRNAs in the anticancer drug resistance. Here, we introduced a dual reporter gene imaging system for noninvasively monitoring the kinetic expression of miRNA-16 during chemoresistance in gastric cancer both in vitro and in vivo. Human sodium iodide symporter (hNIS) and firefly luciferase (Fluc) genes were linked to form hNIS/Fluc double fusion reporter gene and then generate human gastric cancer cell line NF-3xmir16 and its multidrug resistance cell line NF-3xmir16/VCR. Radioiodide uptake and Fluc luminescence signals in vitro correlated well with viable cell numbers. The luciferase activities and radioiodide uptake in NF-3xmir16 cells were remarkably repressed by exogenous or endogenous miRNA-16. The NF-3xmir16/VCR cells showed a significant increase of 131I uptake and luminescence intensity compared to NF-3xmir16 cells. The radioactivity from in vivo99mTc-pertechnetate imaging and the intensity from bioluminescence imaging were also increased in NF-3xmir16/VCR compared with that in NF-3xmir16 tumor xenografts. Furthermore, using this reporter gene system, we found that etoposide (VP-16) and 5-fluorouracil (5-FU) activated miRNA-16 expression in vitro and in vivo, and the upregulation of miRNA-16 is p38MAPK dependent but NF-κB independent. This dual imaging reporter gene may be served as a novel tool for in vivo imaging of microRNAs in the chemoresistance of cancers, as well as for early detection and diagnosis in clinic. [ABSTRACT FROM AUTHOR]

Abstract: Noninvasive imaging techniques have been considered important strategies in the clinic to monitor tumor early response to therapy. In the present study, we applied RGD peptides conjugated to iron oxide nanoparticles (IONP-RGD) as contrast agents in magnetic resonance imaging (MRI) to noninvasively monitor the response of a vascular disrupting agent VEGF121/rGel in an orthotopic glioblastoma model. RGD peptides were firstly coupled to IONPs coated with a crosslinked PEGylated amphiphilic triblock copolymer. In vitro binding assays confirmed that cellular uptake of particles was mainly dependent on the interaction between RGD and integrin αvβ3 of human umbilical vein endothelial cells (HUVEC). The tumor targeting of IONP-RGD was observed in an orthotopic U87 glioblastoma model. Finally, noninvasive monitoring of the tumor response to VEGF121/rGel therapy at early stages of treatment was successfully accomplished using IONP-RGD as a contrast agent for MRI, a superior method over common anatomical approaches which are based on tumor size measurements. This preclinical study can accelerate anticancer drug development and promote clinical translation of nanoprobes. [Copyright &y& Elsevier]

Abstract: TRAIL has received considerable attention as a potential anti-cancer agent due to its specific ability to target tumors. However, recombinant TRAIL has several limitations, such as, its short biological half-life, its inherent instability, and its potential hepatotoxicity. In this study, we developed a sustained release nanoparticle formulation of TRAIL and investigated its therapeutic effects in tumor-bearing mice. TRAIL-loaded nanoparticles (NPs) were prepared by mixing PEGylated heparin (PEG-HE), poly-l-lysine (PLL), and TRAIL. NPs prepared by the ionic interaction between polymer and TRAIL showed uniform spherical structures of diameter 213.3 ± 9.7 nm and a surface charge of 5.33 ± 1.2 mV. An in vitro study of the bioactivity of TRAIL in NPs showed that TRAIL-loaded PEG-HE/PLL NPs (TRAIL-PEG-NPs) were slightly less cytotoxic than TRAIL in vitro. To investigate pharmacokinetic parameters, TRAIL and TRAIL-PEG-NPs were intravenously injected into SD rats. The PEG-NP-based formulation demonstrated a 28.3 fold greater half-life than TRAIL alone. To evaluate the anti-tumor effect, TRAIL, TRAIL-loaded HE/PLL NPs (TRAIL-NPs), and TRAIL-PEG-NPs were intravenously injected into HCT-116 tumor-bearing BALB/c athymic mice. The TRAIL-PEG-NP formulation efficiently suppressed tumor growth (>70%), and histological findings confirmed that NPs induced significant tumor cell apoptosis without inducing liver toxicity. The PEG-exposed NP fabrication method applied in this study could be widely applied to protein and peptide delivery systems. [Copyright &y& Elsevier]

The combination of chemotherapeutic drugs and reactive oxygen species (ROS) is a promising strategy to achieve improved anticancer effect. Herein, a nanomedicine (LaCIONPs) that can achieve tumor‐specific chemotherapeutic drug release and ROS generation is developed for cancer chemo/chemodynamic combination therapy. The LaCIONPs are constructed by encapsulation of iron oxide nanoparticles (IONPs) and β‐lapachone (La) in nanostructure assembled by hydrogen peroxide (H2O2)‐responsive polyprodrug and pH‐responsive polymer. Through the enhanced permeability and retention effect, the nanosized LaCIONPs can accumulate in tumor tissue. After the LaCIONPs are internalized by tumor cells, the structure of LaCIONPs is disintegrated in acidic intracellular environment, leading to rapid release of La and iron ions. Then the released La generates massive H2O2 through tumor specific catalysis. On the one hand, H2O2 further reacts with iron ions to produce highly toxic hydroxyl radicals for chemodynamic therapy. On the other hand, H2O2 also activates the release of camptothecin from the polyprodrug for chemotherapy. The potent antitumor effect of the LaCIONPs is demonstrated by both in vitro and in vivo results. Therefore, the LaCIONP is a promising nanomedicine for tumor‐specific chemo/chemodynamic combination therapy. A pH and hydrogen peroxide (H2O2) dual‐responsive nanomedicine is developed for tumor‐specific chemo/chemodynamic combination therapy. Once the nanomedicines enter cancer cells through endocytosis, their structure is disintegrated, resulting in rapid release of β‐lapachone and iron ions. The β‐lapachone generates H2O2 inside cells, which further produces highly toxic hydroxyl radicals through the Fenton reaction and activates chemotherapeutic drug release. [ABSTRACT FROM AUTHOR]