Polymeric nanoreactors (NRs) have distinct advantages to improve chemical reaction efficiency, but the in vivo applications are limited by lack of tissue-specificity. Herein, novel glucose oxidase (GOD)-loaded therapeutic vesicular NRs (theraNR) are constructed based on a diblock copolymer containing poly(ethylene glycol) (PEG) and copolymerized phenylboronic ester or piperidine-functionalized methacrylate (P(PBEM-co-PEM)). Upon systemic injection, theraNR are inactive in normal tissues. At a tumor site, theraNR are specifically activated by the tumor acidity via improved permeability of the membranes. Hydrogen peroxide (H O ) production by the catalysis of GOD in theraNR increases tumor oxidative stress significantly. Meanwhile, high levels of H O induce self-destruction of theraNR releasing quinone methide (QM) to deplete glutathione and suppress the antioxidant ability of cancer cells. Finally, theraNR efficiently kill cancer cells and ablate tumors via the synergistic effect.

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Abstract:To quantitatively access the effects of drought stress during different growth stages of soybean on development process and yield, a pot-culture experiment was conducted in China's Huaibei Plain with different irrigation treatments over two seasons (2015 and 2016). Two drought stress levels (mild and severe) were applied at four growth stages for the experiment (S: seedling stage; B: branching stage; FPS: flowering and pod-setting stage; and PF: pod-filling stage). The effects of drought stress at different stages on growth and yield were evaluated and compared. Results of this two-year study showed that all growth and yield parameters were significantly affected by the water deficit during the sensitive FPS. Compared to the full irrigation treatment, severe drought stress during FPS caused a 22% loss of final plant height, 61% loss of the leaf area per plant (LAP), and 67% loss of final aboveground dry matter (ADM). Yield components also declined dramatically with water deficits during FPS and PF. Significant seed yield losses of 73-82% per plant were observed in the plants exposed to drought stress during FPS, and were also associated with the highest nonviable pod percentage of 13%. The greatest losses in 100-seed weight (42-48%) were observed under drought stress during PF. A rising trend in response to increasing soil water deficit (SWD) was observed for LAP, yield, and ADM losses. The slope (k) values of these fitting curves varied at different treatments, the highest value of k (7.37 and 8.47 in two years, respectively) was also observed in the sensitive FPS.

Relative to normal cells, tumor cells lack adequate capability of reactive oxygen scavenging. Thus, tumor cells can be selectively killed by increasing the concentration of reactive oxygen species in tumor tissue. In this report, we construct an integrated multifunctional polymeric nanoparticle which can selectively improve hydrogen peroxide (HO) levels in tumor tissue and convert them into more active hydroxyl radicals by Fenton reaction. First, the diblock copolymers containing polyethylene glycol (PEG) and poly(glutamic acid) modified by β-cyclodextrin (β-CD) were synthesized. The block copolymer, ferrocenecarboxylic acid hexadecyl ester (DFc), and ascorbyl palmitate (PA) were coassembled in aqueous solution to obtain stable core-shell micelles through the inclusion complexation between β-CD moieties in the block copolymer and ferrocene (Fc) groups from DFc. After intravenous injection, the particles achieved significant accumulation in tumor tissue where ascorbic acid at the pharmacological concentration promotes the production of HO, and subsequently Fenton reaction was catalyzed by Fc groups to produce hydroxyl radicals to efficiently kill cancer cells and suppress tumor growth. The micellar systems possess great potentials toward cancer therapy through synergistic HO production and conversion into hydroxyl radicals specifically in tumor tissue.

The improved antioxidant system of cancer cells renders them well-adaptive to the intrinsic oxidative stress in tumor tissues. On the other hand, cancer cells are more sensitive to elevated tumor oxidative stress as compared with normal cells due to their deficient reactive oxygen species-eliminating systems. Oxidation therapy of cancers refers to the strategy of killing cancer cells through selectively increasing the oxidative stress in tumor tissues. In this article, to amplify the oxidation therapy, we develop integrated nanoparticles with the properties to elevate tumor oxidative stress and concurrently suppress the antioxidative capability of cancer cells. The amphiphilic block copolymer micelles of poly(ethylene glycol)-b-poly[2-((((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)carbonyl)oxy)ethyl methacrylate] (PEG-b-PBEMA) are integrated with palmitoyl ascorbate (PA) to form hybrid micelles (PA-Micelle). PA molecules at pharmacologic concentrations serve as a prooxidant to upregulate the hydrogen peroxide (HO) level in tumor sites and the PBEMA segment exhibits HO-triggered release of quinone methide for glutathione depletion to suppress the antioxidative capability of cancer cells, which synergistically and selectively kill cancer cells for tumor growth suppression. Given the significantly low side toxicity against normal tissues, this novel integrated nanoparticle design represents a novel class of nanomedicine systems for high-efficiency oxidation therapy with the potentials to be translated to clinical applications.

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