Rationale: Treatment for Parkinson's disease (PD) is challenged by the presence of the blood-brain barrier (BBB) that significantly limits the effective drug concentration in a patient's brain for therapeutic response throughout various stages of PD. Curcumin holds the potential for α-synuclein clearance to treat PD; however, its applications are still limited due to its low bioavailability and poor permeability through the BBB in a free form.Methods: Herein, this paper fabricated curcumin-loaded polysorbate 80-modified cerasome (CPC) nanoparticles (NPs) with a mean diameter of ~110 nm for enhancing the localized curcumin delivery into the targeted brain nuclei via effective BBB opening in combination with ultrasound-targeted microbubble destruction (UTMD).Results: The liposomal nanohybrid cerasome exhibited superior stability towards PS 80 surfactant solubilization and longer circulation lifetime (t1/2 = 6.22 h), much longer than free curcumin (t1/2 = 0.76 h). The permeation was found to be 1.7-fold higher than that of CPC treatment only at 6 h after the systemic administration of CPC NPs. Notably, motor behaviors, dopamine (DA) level and tyrosine hydroxylase (TH) expression all returned to normal, thanks to α-synuclein (AS) removal mediated by efficient curcumin delivery to the striatum. Most importantly, the animal experiment demonstrated that the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice had notably improved behavior disorder and dopamine depletion during two-week post-observation after treatment with CPC NPs (15 mg curcumin/kg) coupled with UTMD.Conclusion: This novel CPC-UTMD formulation approach could be an effective, safe and amenable choice with higher therapeutic relevance and fewer unwanted complications than conventional chemotherapeutics delivery systems for PD treatment in the near future.

We have demonstrated that a typical nanothermometer was incorporated in a bovine serum albumin stabilized gold nanostar-indocyanine green (denoted as GNS-ICG-BSA) nanoprobe to realize surface-enhanced Raman scattering (SERS) imaging-based real-time sensitive monitoring of intracellular temperature in photothermal therapy (PTT), which significantly improved the spatial resolution compared to infrared thermal imaging. Herein, an exogenous thermosensitive molecule, ICG, acting as a tri-functional agent, was selected as the Raman reporter instead of direct cellular biochemical changes. The triggering of the obtained probe was unaffected by the cellular microenvironment, so it can act as a monitor of PTT in various cell types. High-resolution mass spectrometry (HRMS) was used to investigate the thermosensitive mechanism of ICG. The actively targeted GNS-ICG-BSA nanotags were used to induce SERS mapping-guided in vitro PTT of U87 glioma cells. Meanwhile, small temperature variations within a cell during PTT can be precisely monitored through the SERS fingerprint information, with a spatial resolution at the subcellular level and a sensitivity of 0.37 °C. Thus, the integrated GNS-ICG-BSA nanotags can be treated as a theranostic probe, a SERS imaging probe and an intracellular thermometer. Moreover, the good biocompatibility and the low cytotoxicity of GNS-ICG-BSA nanotags, together with their superior photothermal ablation effect on U87 glioma cells have been confirmed. This suggested that the implanted nanothermometry approach would be promising for a better understanding of the biological processes at subcellular level and provide new insights into the fabrication of a multifunctional nanoplatform. Furthermore, this study revealed that the SERS-based monitoring technique can offer great potential for theranostics as an emerging strategy.

The presence of blood‐brain barrier (BBB) greatly limits the availability of drugs and their efficacy against glioma. Focused ultrasound (FUS) can induce transient and local BBB opening for enhanced drug delivery. Here, we developed polysorbate 80‐modified paclitaxel‐loaded PLGA nanoparticles (PS‐80‐PTX‐NPs, PPNP) and examined the enhanced local delivery into the brain for glioma treatment by combining with FUS. Our result showed PPNP had good stability, fast drug release rate and significant toxicity to glioma cells. Combined with FUS, PPNP showed a stronger BBB permeation efficiency both in the in vitro and in vivo BBB models. Mechanism studies revealed the disrupted tight junction, reduced P‐glycoprotein expression and ApoE‐dependent PS‐80 permeation collectively contribute to the enhanced drug delivery, resulting in significantly stronger antitumour efficacy and longer survival time in the tumour‐bearing mice. Our study provided a new strategy to efficiently and locally deliver drugs into the brain to treat glioma.

The absence of effective therapeutic targets and tumor hypoxia are the main causes of failure in the treatment of triple-negative breast cancer (TNBC). Biomimetic nanotechnology and tumor microenvironment (TME)-responsiveness bring...

No abstract

BackgroundUltrasound-targeted microbubble destruction (UTMD) has been shown to be a promising noninvasive technique to change the tumor circulation, thus providing a potential method to increase reactive oxygen species (ROS) levels in tumors by inducing tumor tissue ischemia-reperfusion (IR). In this study, we investigated the feasibility of local tumor IR through UTMD to enhance the anti-tumor efficacy of doxorubicin (DOX) chemotherapy.MethodsUTMD was used to induce local tumor IR. After the major blood supply of the tumor was restored, DOX was intravenously injected into the tumor-bearing mice. The superoxide dismutase (SOD) and catalase (CAT) activity and ROS levels were examined, and the anti-tumor efficacy was evaluated.ResultsUTMD blocked the circulation to the tumor for 30 mins. Slow reperfusion began to occur after 30 mins, and major blood supply was restored after 1 hr. The blood perfusion of the tumor completely recovered at 2 hrs. The activity of SOD in the tumors was significantly decreased at 2 hrs and 1 day after IR treatment with or without DOX treatment. The CAT activity showed no obvious changes at 2 hrs after IR treatment, whereas a significant decrease was found after 1 day in both the IR and DOX/IR groups. Moreover, higher levels of ROS were produced in the IR group and IR/DOX group. In vivo anti-tumor study indicated that the local tumor IR strategy may significantly enhance the anti-tumor efficacy of DOX chemotherapy.ConclusionUTMD provides a novel, simple and non-invasive technique for tumor IR. In combination with chemotherapy, UTMD may have high great potential to improve the anti-tumor efficacy of chemotherapeutic drugs.

The absence of effective therapeutic targets and tumor hypoxia are the main causes of failure in the treatment of triple-negative breast cancer (TNBC). Biomimetic nanotechnology and tumor microenvironment (TME)-responsiveness bring hope and opportunity to address this problem. Here, we develop a core membrane nanoplatform (HM/D-I-BL) using hollow mesoporous manganese dioxide (HM) coated with biomimetic cancer cell membrane for enhanced chemotherapy/phototherapy via the strategy of precise drug delivery and hypoxia amelioration. Cancer cell membrane modification endows HM/D-I-BL with excellent homologous targeting and immune escape performance. The cellular uptake and fluorescence imaging studies confirmed that HM/D-I-BL can be accurately delivered to tumor sites. HM/D-I-BL also features efficient in situ O2 generation in tumor upon laser irradiation, and subsequently enhanced chemotherapy/phototherapy, pointing to its usefulness as a TME-responsive nanozyme to alleviate tumor hypoxia in the presence of H2O2. In addition, HM/D-I-BL showed good fluorescence and magnetic resonance imaging performances, which offers a reliable multimodal image-guided combination tumor therapy for precision theranostics in the future. In general, this intelligent biomimetic nanoplatform with its homotypic tumor targeting, in situ alleviation of tumor hypoxia and synergetic chemophototherapy would open up a new dimension for the precision treatment of TNBC.