The precise and selective delivery of chemodrugs into tumors represents a critical requirement for anti-cancer therapy. Intelligent delivery systems that are responsive to a single internal or external stimulus often lack sufficient cancer selectivity, which compromises the drug efficacy and induces undesired side effects. To overcome this dilemma, we herein report a cancer-targeting vehicle which allows highly cancer-selective drug release in response to cascaded external (light) and internal (hypoxia) dual triggers. In particular, doxorubicin (DOX)-loaded, hypoxia-dissociable nanoparticles (NPs) were prepared from self-assembled polyethylenimine-nitroimidazole (PEI-NI) micelles that were further co-assembled with hyaluronic acid-Ce6 (HC). Upon accumulation in tumor cells, tumor site-specific light irradiation (660 nm, 10 mW cm⁻²) generated high levels of reactive oxygen species (ROS) and greatly enhanced the hypoxic levels to induce NP dissociation and accordingly DOX release. A synergistic anti-cancer efficacy between DOX-mediated chemotherapy and Ce6-mediated photodynamic therapy (PDT) was thus achieved, resulting in reduced side effects to normal tissues/cells. This study therefore provides an effective method to control the cancer-specific drug delivery by responding to cascaded multiple triggers, and it renders promising applications for the programmed combination of chemotherapy and PDT toward cancer treatment.

Preoperative nomogram for identifying invasive pulmonary adenocarcinoma in patients with pure ground-glass nodule: A multi-institutional study

The benefit of adjuvant chemotherapy (ACT) remains unknown for patients with stage I lung adenocarcinoma (ADC) with spread through air spaces (STAS). This study investigated the effect of adjuvant chemotherapy in stage I ADC/STAS-positive patients. A total of 3346 patients with stage I ADC from five institutions in China were identified from 2009 to 2013, of whom 1082 were diagnosed with STAS (32.3%). By using the Kaplan–Meier method and Cox proportional hazard regression model, we explored the impact of STAS on prognosis, and determined if the use of adjuvant chemotherapy was associated with improved outcomes in patients with stage I ADC/STAS-positive. A validation cohort was also included in this study. Patients with stage I ADC/STAS-positive in the primary cohort had unfavorable overall survival (OS) and disease-free survival (DFS). A multivariate Cox regression model confirmed the survival disadvantages of STAS in patients with stage I ADC [OS: hazards ratio (HR) = 1.877, 95% confidence interval (CI): 1.579–2.231; p < 0.001; DFS: HR = 1.895, 95% CI: 1.614–2.225; p < 0.001]. Lobectomy was associated with better OS and DFS than sublobar resection (SR) in both stage IA and IB ADC/STAS-positive. Similar results were observed in the validation cohort. For patients with stage IB ADC/STAS-positive, ACT was revealed as an independent factor for favorable survival (OS: HR = 0.604, 95% CI: 0.397–0.919; p = 0.018; DFS: HR = 0.565, 95% CI: 0.372–0.858; p = 0.007). However, among patients with stage IA ADC/STAS-positive, ACT was associated with improved outcomes only for those undergoing SR (OS: HR = 0.787, 95% CI: 0.359–0.949; p = 0.034; DFS: HR = 0.703, 95% CI: 0.330–0.904; p = 0.029). The presence of STAS was correlated with poor prognosis in patients with stage I ADC. Our study suggested that ACT might be considered for patients with stage IB ADC/STAS-positive and those with stage IA ADC/STAS-positive who underwent SR.

Adipose-derived stem cells (ASCs) are promising therapeutic cells for ischemic heart diseases, due to the ease and efficiency of acquisition, the potential of myocardial lineage differentiation, and the paracrine effects. Recently, many researchers have claimed that the ASC-based myocardial repair is mainly attributed to its paracrine effects, including the anti-apoptosis, pro-angiogenesis, anti-inflammation effects, and the inhibition of fibrosis, rather than the direct differentiation into cardiovascular lineage cells. However, the usage of ASCs comes with the problems of low cardiac retention and survival after transplantation, like other stem cells, which compromises the effectiveness of the therapy. To overcome these drawbacks, researchers have proposed various strategies for improving survival rate and ensuring sustained paracrine secretion. They also investigated the safety and efficacy of phase I and II clinical trials of ASC-based therapy for cardiovascular diseases. In this review, we will discuss the characterization and paracrine effects of ASCs on myocardial repair, followed by the strategies for stimulating the paracrine secretion of ASCs, and finally their clinical usage.

As one of the intractable challenges in the clinic, the treatment of acute liver failure (ALF) is limited due to high mortality and resource cost. RNA interference (RNAi) provides a new modality for the anti-inflammatory therapy of ALF, while its therapeutic efficacy is greatly hampered by the lack of effective carriers to cooperatively overcome the various systemic barriers. Herein, we developed macrophage-targeting and reactive oxygen species (ROS)-responsive polyplexes to enable efficient systemic delivery of TNF-α siRNA (siTNF-α) to attenuate hepatic inflammation in mice bearing ALF. Se-PEI, obtained from the cross-linking of 600 Da polyethylenimine (PEI) via the ROS-responsive diselenide bond, was developed to condense siTNF-α, and the obtained polyplexes were further coated with carboxylated mannan (Man-COOH). Man-COOH coating allowed active targeting of polyplexes to macrophages with over-expressed mannose receptors (MRs), and it shielded the surface positive charges to enhance the serum stability of polyplexes. Se-PEI could be degraded by ROS in inflammatory macrophages to promote intracellular siRNA release to potentiate the gene knockdown efficiency, and in the meantime reduce the material cytotoxicity associated with high molecular weight. As such, i.v. injected Man-COOH/Se-PEI/siTNF-α polyplexes afforded notable TNF-α silencing by ∼80% in inflamed liver tissues at 500 μg siRNA per kg, and notably reduced serum TNF-α levels to achieve potent anti-inflammatory performance against ALF.