No abstract

Nanodiamond as a drug carrier is of great significance in improving cancer therapy by overcoming chemoresistance. However, its clinical application is severely limited because of insufficient tumor vascular penetration. To address this limitation, pullulan-all-trans-retinal (pullulan-ATR) self-assembled nanoparticles were prepared as nanocarriers, which encapsulated doxorubicin-loaded nanodiamonds, to construct a core−shell structured coloading nanosystem. The obtained composite nanoparticles show a homogeneous size distribution with good dispersity and pH sensitivity. Furthermore, ultrasound was utilized to promote the intratumoral penetration of these nanoparticles. As a result, the intracellular retention of DOX was efficiently enhanced, and DOX in the tumor tissue reached 17.3% of the injected dosage. The antitumor effect of this combined strategy was remarkably improved in both the DOX-sensitive HepG2 and DOX-resistant HepG2/ADR tumor models in vivo. This new strategy might serve as a powerful method to address the limitation of nanodiamonds and provide innovative ideas for the application of nanoparticles in clinical cancer therapy.

The combination of high-intensity focused ultrasound (HIFU) and chemotherapy has promising potential in the synergistic treatment of various types of solid tumors. However, the clinical efficacy of HIFU in combination chemotherapy is often impeded by the preexisting hypoxia tumor microenvironment-induced multidrug resistance (MDR). Therefore, it is imperative for HIFU combined with chemotherapy to overcome MDR by improving the tumor hypoxic microenvironment. Hence, we developed highly stable nanoparticles (P@BDOX/β-lapachone-NO-NPs) with intracellular nitric oxide (NO)and reactive oxygen species (ROS)-generating capabilities at the tumor site to relieve the hypoxic tumor microenvironment in solid tumors. Doxorubicin prodrug (boronate-DOX, BDOX) and β-lapachone were concurrently loaded onto actively targeted pH (low) insertion peptides (pHLIPs)-poly(ethylene glycol) and nitrated gluconic acid copolymers. Our results showed that the ability of P@BDOX/βlapachone-NO-NPs to generate NO and ROS simultaneously is vital for the sensitization of hypoxic solid tumors for chemotherapy, as evidenced by the suppression of tumor cells and tissues (in vitro and in the nude mice model). Thus, this combined therapy holds considerable potential in the management of hypoxic solid tumors.

No abstract

Stimulus-responsive drug delivery nanosystems (DDSs) are of great significance in improving cancer therapy for intelligent control over drug release. However, among them, many DDSs are unable to realize rapid and sufficient drug release because most internal stimulants might be consumed during the release process. To address the plight, an abundant supply of stimulants is highly desirable. Herein, a core crosslinked pullulan-di-(4,1-hydroxybenzylene)­diselenide nanosystem, which could generate abundant exogenous-stimulant reactive oxygen species (ROS) via tumor-specific NAD­(P)­H:quinone oxidoreductase-1 (NQO1) catalysis, was constructed by the encapsulation of β-lapachone. The enzyme-catalytic-generated ROS induced self-triggered cascade amplification release of loaded doxorubicin (DOX) in the tumor cells, thus achieving efficient delivery of DOX to the nuclei of tumor cells by breaking the diselenide bond of the nanosystem. As a result, the antitumor effect of this nanosystem was significantly improved in the HepG2 xenograft model. In general, this study offers a new paradigm for utilizing the interaction between the loaded agent and carrier in the tumor cells to obtain self-triggered drug release in the design of DDSs for enhanced cancer therapy.