No abstract

Direct intracellular delivery of antibodies has gained much attention, although only a few agents have been developed, and none of them has reached clinical stages. The main obstacles here are the insufficient characteristics of delivery systems including stability and appropriate ability for intracellular antibody release. We tailored the structure of polyion complex (PIC) micelles by loading transiently charge-converted antibody derivatives for achieving enhanced stability, delivery to cytosol, and precise antigen recognition inside cells. Citraconic anhydride was used for the charge conversion of the antibody; the optimized degree of modification was identified to balance the stability of PIC micelles in the extracellular compartment and prompt pH-triggered disintegration after their translocation into the acidic endosomal compartment of target cells. The use of a mixture of homo- and block-catiomers in an appropriate ratio to construct PIC micelles substantially enhanced the endosomal escaping efficacy of the loaded antibody, leading to improved recognition of intracellular antigens.

Nanomedicines capable of smart operation at the targeted site have the potential to achieve the utmost therapeutic benefits. Providing nanomedicines that respond to endogenous stimuli with an additional external trigger may improve the spatiotemporal control of their functions, while avoiding drawbacks from their inherent tissue distribution. Herein, by exploiting the permeabilization of endosomes induced by photosensitizer agents upon light irradiation, we complemented the intracellular action of polymeric micelles incorporating camptothecin (CPT), which can sharply release the loaded drug in response to the reductive conditions of the cytosol, as an effective strategy for precisely controlling the function of these nanomedicines in vivo, while advancing toward a light-activated chemotherapy. These camptothecin-loaded micelles (CPT/m) were stable in the bloodstream, with minimal drug release in extracellular conditions, leading to prolonged blood circulation and high accumulation in xenografts of rat urothelial carcinoma. With the induction of endosomal permeabilization with the clinically approved photosensitizer, Photofrin, the CPT/m escaped from the endocytic vesicles of cancer cells into the cytosol, as confirmed both in vitro and in vivo by real-time confocal laser microscopies, accelerating the drug release from the micelles only in the irradiated tissues. This spatiotemporal switch significantly enhanced the in vivo antitumor efficacy of CPT/m without eliciting any toxicity, even at a dose 10-fold higher than the maximum tolerated dose of free CPT. Our results indicate the potential of reduction-sensitive drug-loaded polymeric micelles for developing safe chemotherapies after activation by remote triggers, such as light, which are capable of permeabilizing endosomal compartments.

Boron neutron capture therapy (BNCT) is a promising radiotherapy for treating glioblastoma multiforme (GBM). However, the penetration of drugs (e.g., sodium borocaptate and BSH) for BNCT into brain tumors is limited by cerebral vesicular protective structures, the blood–brain barrier, and the blood–brain tumor barrier (BTB). Although BSH has been reported to be selectively taken up by tumors, it is rapidly excreted from the body and cannot achieve a high tumor-to-normal brain ratio (T/N ratio) and tumor-to-blood ratio (T/B ratio). Despite the development of large-molecular weight boron compounds, such as polymers and nanoparticles, to enhance the permeation and retention effect, their effects remain insufficient for clinical use. To improve the efficiency of boron delivery to the tumor site, we propose combinations of self-assembled boron-containing polyanion [polyethylene glycol-b-poly­((closo-dodecaboranyl)­thiomethylstyrene) (PEG-b-PMBSH)] nanoparticles (295 ± 2.3 nm in aqueous media) coupled with cationic microbubble (B-MB)-assisted focused ultrasound (FUS) treatment. Upon FUS sonication (frequency = 1 MHz, pressure = 0.3–0.7 MPa, duty cycle = 0.5%, sonication = 1 min), B-MBs can simultaneously achieve safe BTB opening and boron drug delivery into tumor tissue. Compared with the MBs of the PEG-b-PMBSH mixture group (B + MBs), B-MBs showed 3- and 2.3-fold improvements in the T/N (4.4 ± 1.4 vs 1.3 ± 0.1) and T/B ratios (1.4 ± 0.6 vs 0.1 ± 0.1), respectively, after 4 min of FUS sonication. The spatial distribution of PEG-b-PMBSH was also improved by the complex of PEG-b-PMBSH with MBs. The findings presented herein, in combination with the expanding clinical application of FUS, may improve BNCT and treatment of GBM.

No abstract

Although the adverse effects of excessively generated reactive oxygen species (ROS) on the body during aerobic exercise have been debated, there are few reports on the remarkable effects of the application of conventional antioxidants on exercise performance. The conventional antioxidants could not enhance exercise performance due to their rapid excretion from the body and serious adverse effects on the cellular respiratory system. In this study, impact of the original antioxidant self-assembling nanoparticle, redox-active nanoparticle (RNP), is investigated on the exercise performance of rats during running experiments. With an increase in the dose of the administered RNP, the all-out time of the rat running extends in a dose-dependent manner. In contrast, with an increase in the dose of the low-molecular-weight (LMW) antioxidant, the all-out running time of the rats decreases. The control group and LMW antioxidant treated group decrease in the number of red blood cells (RBCs) and increase oxidative stress after running. However, the RNP group maintains a similar RBC level and oxidative stress as that of the sedentary group. The results suggest that RNP, which shows long-blood circulation without disturbance of mitohormesis, effectively removes ROS from the bloodstream to suppresses RBC oxidative stress and damage, thus improving exercise performance.

Oxidative stress‐induced off‐target effects limit the therapeutic window of radiation therapy. Although many antioxidants have been evaluated as radioprotective agents, none of them are in widespread clinical use, owing to the side effects of the antioxidants themselves and the lack of apparent benefit. Aiming for a truly effective radioprotective agent in radiation cancer therapy, the performance of a self‐assembling antioxidant nanoparticle (herein denoted as redox nanoparticle; RNP) is evaluated in the local irradiation of a subcutaneous tumor‐bearing mouse model. Since RNP is covered with a biocompatible shell layer and possesses a core–shell type structure of several tens of nanometers in size, its lifetime in the systemic circulation is prolonged. Moreover, since 2,2,6,6‐tetramethylpiperidine‐1‐oxyl (TEMPO), one of the most potent antioxidants, is covalently encapsulated in the core of RNP, it exerts intense antioxidant activity and induces fewer adverse effects by avoiding leakage of the TEMPO molecules. Preadministration of RNP to the mouse model effectively mitigates side effects in normal tissues and significantly extends the survival benefit of radiation cancer therapy. Moreover, RNP pretreatment noticeably increases the apoptosis/necrosis ratio of radiation‐induced cell death, a highly desirable property to reduce the chronic side effects of ionizing irradiation.

No abstract