No abstract

Chemo-immunotherapy holds the advantage of specific antitumor effects by activating T cell immune response. However, the efficiency of chemo-immunotherapy is restricted to the insufficient antigen presentation of dendritic cells (DCs) in the tumor immunosuppression microenvironment. Here, we rationally designed a simple yet versatile calcium ion nanogenerator to disrupt the autophagy inhibition condition within DCs, enrich damage-associated molecular patterns (DAMPs), and attenuate acidity in the tumor microenvironment. After chemotherapy, honeycomb calcium carbonate (CaCO3) nanoparticles (OVA@CaCO3, denoted as HOCN, ovalbumin (OVA) acted as skeleton) could preferentially accumulate in the tumor and display a series of benefits for disrupting multiple barriers in antigen cross-presentation of DCs: (i) recovering cell viability of DCs by HOCN-induced tumor acidity attenuating; (ii) disrupting the autophagy inhibition condition in DCs by generating Ca2+ in cells; (iii) improving maturation of DCs by Ca2+ overloading-mediated enhanced DAMP release from tumor cells. In addition, HOCN can also disrupt the immunosuppressive microenvironment by reducing the infiltration of immunosuppressive cells and factors. We believe regulation of the intratumoral Ca2+ offers an alternative strategy for improving cancer chemo-immunotherapy.

Despite advances in drug delivery systems (DDSs), the stimuli-responsive controlled release DDSs with high spatial/temporal resolution are still the best choice. Herein, a novel type of envelope-type mesoporous titanium dioxide nanoparticle (MTN) was developed for one-demand drug delivery platform. Docetaxel (DTX) was loaded in the pores of MTN with a high drug loading efficiency (∼26%). Then β-cyclodextrin (β-CD, a bulky gatekeeper) was attached to the outer surface of MTN via a reactive oxygen species (ROS) sensitive linker to block the pores (MTN@DTX-CD). MTN@DTX-CD could entrap the DTX in the pores and allow the rapid release until a focused ultrasound (US) emerged. A large number of ROS were generated by MTN under US radiation, leading to the cleavage of the ROS-sensitive linker; thus, DTX could be released rapidly since the gatekeepers (β-CD) were detached. Besides, the generation of ROS could also be used for tumor-specific sonodynamic therapy (SDT). Studies have shown the feasibility of MTN@DTX-CD for US-triggered DTX release and sonodynamic-chemotherapy. In the in vitro and in vivo studies, by integrating SDT and chemotherapy into one system, MTN@DTX-CD showed excellent antitumor efficacy. More importantly, this novel DDS significantly decreased the side effects of DTX by avoiding the spleen and hematologic toxicity to tumor-bearing mice.

Nucleating agents (NAs) are widely used for speeding up processing and tuning the final optical and mechanical properties. Despite their industrial importance, the search for highly efficient NAs is still mainly empirical. In this work, the heterogeneous nucleation process of isotactic polypropylene (i-PP) droplets containing nucleating agents (i.e., sodium benzoate (SB), (4,6-di-tert-butylphenyl)phosphate (NA-11), quinacridone quinone (QQ)) dispersed in an immiscible polystyrene matrix has been studied by differential scanning calorimetry (DSC) using an isothermal step crystallization protocol. When semicrystalline polymers are confined into isolated micro-or nanodomains, nucleation can kinetically control the overall crystallization. Differently, in a bulk polymer, the contributions of the nucleation and growth steps to the overall crystallization rate are commonly of similar importance. In the studied system, it is shown for the first time that the crystallization of nucleated i-PP droplets exhibits a first-order kinetics, with characteristic times much larger than those required for the crystals to grow and occupy the whole microdomain volume. Therefore, the kinetics of heterogeneous nucleation can be directly assessed. On the contrary, when neat i-PP droplets are self-nucleated, the crystallization kinetics shows a sigmoidal trend, with times comparable to those for the crystal space filling. This indicates the absence of any primary nucleation barrier for ideally self-nucleated PP melts, or at least that this nucleation barrier is negligible in comparison to the one for secondary nucleation/crystal growth. For the first time, it is evidenced that, as long as nucleation is the rate-determining step in the overall crystallization kinetics, a first-order kinetics can be obtained for both homo-or heterogeneously nucleated droplets in immiscible blends. A novel way to calculate an "intrinsic" nucleation efficiency, based on the derived freeenergy barriers of the different NAs, is proposed. This fundamental knowledge of heterogeneous nucleation can serve as a tool for a more rational search for new nucleating agents and can provide a method to unambiguously identify the origin of multiplecrystallization exotherms in fractionated crystallization of immiscible blends.