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Assessment of drug activation and subsequent interaction with targets in living tissues could guide nanomedicine design, but technologies enabling insight into how a drug reaches and binds its target are limited. We show that a Hoechst-based reporter system can monitor drug release and engagement from a nanoparticle delivery system in vitro and in vivo , elucidating differences in target-bound drug distribution related to drug-linker and nanoparticle properties. Drug engagement is defined as chemical detachment of drug or reporter from a nanoparticle and subsequent binding to a subcellular target, which in the case of Hoechst results in a fluorescence signal. Hoechst-based nanoreporters for drug activation contain prodrug elements such as dipeptide linkers, conjugation handles, and nanoparticle modifications such as targeting ligands to determine how nanomedicine design affects distribution of drug engaged with a subcellular target, which is tracked via cellular nuclear fluorescence in situ . Furthermore, the nanoplatform is amenable toward common maleimide-based linkers found in many prodrug-based delivery systems including polymer-, peptide-, and antibody-drug conjugates. Findings from the Hoechst reporter system were applied to develop highly potent, targeted, anticancer micelle nanoparticles delivering a monomethyl auristatin E (MMAE) prodrug comprising the same linkers employed in Hoechst studies. MMAE nanomedicine with the optimal drug-linker resulted in effective tumor growth inhibition in mice without associated acute toxicity, whereas the nonoptimal linker that showed broader drug activation in Hoechst reporter studies resulted in severe toxicity. Our results demonstrate the potential to synergize direct visualization of drug engagement with nanomedicine drug-linker design to optimize safety and efficacy.

The tumor microenvironment (TME) is featured with aberrant vasculatures, specific physiological parameters, viscoelastic extracellular matrix and stromal cells, which are important factors in tumor initiation, development and metastasis. The components in TME form physical/biological barriers for drug delivery and therapy, and also contribute to resistance to treatment and immunosuppression. The advances in nanobiotechnology have offered a myriad of nanoparticles for targeting and treating tumors through the passive or active targeting strategies. However, the barriers in TME always limit the drug delivery and therapeutic efficacy of nanoparticles. To cope with this, recent strategies have employed nanoparticles to target and remodel tumor microenvironment, while a variety of nanoparticles have been developed with different functions for this score. In this review, we have described the typical features of tumor microenvironment along with their roles in tumor progression, and then focused on recent progresses in development and application of nanoparticles to target and remodel TME for enhanced cancer therapy.

Targeted nanomedicines are a promising technology for treatment of disease; however, preparation and characterization of well-defined protein-nanoparticle systems remain challenging. Here, we describe a platform technology to prepare antibody binding fragment (Fab)-bearing nanoparticles and an accompanying real-time cell-based assay to determine their cellular uptake compared to monoclonal antibodies (mAbs) and Fabs. The nanoparticle platform was composed of core-cross-linked polyion complex (PIC) micelles prepared from azide-functionalized PEG-b-poly(amino acids), that is, azido-PEG-b-poly(l-lysine) [N3-PEG-b-PLL] and azido-PEG-b-poly(aspartic acid) [N3-PEG-b-PAsp]. These PIC micelles were 30 nm in size and contained approximately 10 polymers per construct. Fabs were derived from an antibody binding the EphA2 receptor expressed on cancer cells and further engineered to contain a reactive cysteine for site-specific attachment and a cleavable His tag for purification from cell culture expression systems. Azide-functionalized micelles and thiol-containing Fab were linked using a heterobifunctional cross-linker (FPM-PEG4-DBCO) that contained a fluorophenyl-maleimide for stable conjugation to Fabs thiols and a strained alkyne (DBCO) group for coupling to micelle azide groups. Analysis of Fab-PIC micelle conjugates by fluorescence correlation spectroscopy, size exclusion chromatography, and UV-vis absorbance determined that each nanoparticle contained 2-3 Fabs. Evaluation of cellular uptake in receptor positive cancer cells by real-time fluorescence microscopy revealed that targeted Fab-PIC micelles achieved higher cell uptake than mAbs and Fabs, demonstrating the utility of this approach to identify targeted nanoparticle constructs with unique cellular internalization properties.

Summary: Ferrous sulfides have high theoretical capacity in the electrochemical storage of Na‐ion and K‐ion, but its obvious volume change during the storage process greatly affects its cycling performance at high current density. In this regard, we construct a unique composites structure of Nitrogen‐doped carbon shell coated FeS nanoparticle with inner void spaces. As an anode in Na‐ion and K‐ion batteries, this structure could provide excellent cycling performance at high rate of charge/discharge process (560 mAh/g at 0.5 A/g for 300 cycles in Na‐ion battery and 322 mAh/g at 1 A/g for 300 cycles in K‐ion battery). Further research finds the inner void space could not only provide buffer space for the volume change of FeS nanoparticles, but also maintain a stable outer carbon shell during the electrochemical process. These behaviors greatly promote the reversibility of FeS at high rate charge transfer process. Consequently, the construction of inner void space in graphitized carbon shell in this work could be considered as an important reference for the promotion of electrochemical storage in other transitional metal compound system. [ABSTRACT FROM AUTHOR]

Antibodies and antigen-binding fragments (Fabs) can be used to modify the surface of nanoparticles for enhanced target binding. In our previous work, site-specific conjugation of Fabs to polymeric micelles using conventional methods was limited to approximately 30% efficiency, possibly due to steric hindrance related to macromolecular reactants. Here, we report a new method that enables conjugation of Fabs onto a micelle surface in a controlled manner with up to quantitative conversion of nanoparticle reactive groups. Variation of (i) PEG spacer length in a heterofunctionalized cross-linker and (ii) Fab/polymer feed ratios resulted in production of nanoparticles with a range of Fab densities on the surface up to the theoretical maximum value. The biological impact of variable Fab density was evaluated in vitro with respect to cell uptake and cytotoxicity of a drug-loaded (SN38) targeted polymeric micelle bearing anti-EphA2 Fabs. Fab conjugation increased cell uptake and potency compared with non-targeted micelles, although a Fab density of 60% resulted in decreased uptake and potency of the targeted micelles. Altogether, our findings demonstrate that conjugation strategies can be optimized to allow control of Fab density on the surface of nanoparticles and also that Fab density may need to be optimized for a given cell-surface target to achieve the highest bioactivity. [ABSTRACT FROM AUTHOR]

Summary: Ferrous sulfides have high theoretical capacity in the electrochemical storage of Na‐ion and K‐ion, but its obvious volume change during the storage process greatly affects its cycling performance at high current density. In this regard, we construct a unique composites structure of Nitrogen‐doped carbon shell coated FeS nanoparticle with inner void spaces. As an anode in Na‐ion and K‐ion batteries, this structure could provide excellent cycling performance at high rate of charge/discharge process (560 mAh/g at 0.5 A/g for 300 cycles in Na‐ion battery and 322 mAh/g at 1 A/g for 300 cycles in K‐ion battery). Further research finds the inner void space could not only provide buffer space for the volume change of FeS nanoparticles, but also maintain a stable outer carbon shell during the electrochemical process. These behaviors greatly promote the reversibility of FeS at high rate charge transfer process. Consequently, the construction of inner void space in graphitized carbon shell in this work could be considered as an important reference for the promotion of electrochemical storage in other transitional metal compound system. [ABSTRACT FROM AUTHOR]