An "AND" Logic-Gated Prodrug Micelle Locally Stimulates Antitumor Immunity.

Materials that can respond to multiple biomarkers simultaneously, acting as an "AND" gate, have the potential to enhance tumor-targeting for drug delivery. In this study, an "AND" logic-controlled release prodrug micelle is developed for codelivering the chemotherapeutic and the stimulator of interferon genes (STING) agonist, enabling precise combinatorial therapy. The drug release is programmed by tumor-enriched boramino acids (BAA) in the tumor microenvironment and intracellular reactive oxygen species (ROS), resulting in enhanced tumor targeting. STING agonist is successfully encapsulated into prodrug micelles through π-π stacking and hydrophobic interactions. These AND logic-gated prodrug micelles can achieve tumor-targeted delivery of STING agonist, leading to significantly enhanced immune activation and antitumor efficacy in vivo. It is expected that this clinically relevant nanoplatform will provide a rational design of an effective immunotherapy combination regimen to convert immunologically "cold" tumors to immunogenic "hot" tumors, addressing the major challenges faced by immunotherapies.

Radiopharmaceuticals heat anti-tumor immunity.

Radiopharmaceutical therapy (RPT) has proven to be an effective cancer treatment with minimal toxicity. With several RPT agents approved by FDA, the remarkable potential of this therapy is now being recognized, and the anti-tumor immunity induced by RPT is beginning to be noticed. This review evaluates the potential of RPT for immune activation, including promoting the release of danger associated-molecular pattern molecules that recruit inflammatory cells into the tumor microenvironment, and activating antigen-presenting cells and cytotoxic T cells. We also discuss the progress of combining RPT with immunotherapy to increase efficacy.

Radiotherapy-Induced Cleavage of Quaternary Ammonium Groups Activates Prodrugs in Tumors.

Cleavage chemistry offers a new chance to activate chemotherapeutic prodrugs in a tumor-selective manner, yet developing spatiotemporally controllable cleavage chemistry with deep tissue penetration is still a great challenge. Herein, we present a novel radiotherapy-triggered cleavage chemistry that enables controlled drug release in tumors. Quaternary ammonium groups are identified as masking groups that can be efficiently removed by hydrated electrons (e-aq ) from water radiolysis. The subsequently released tertiary amines can be anti-cancer toxins or readily release functional molecules via 1,6-elimination. This radiotherapy-induced cleavage works successfully in living cells and tumor-bearing mice, showing remarkable treatment efficacy when the mice are given carfilzomib prodrug and radiotherapy. This strategy provides a new perspective for combinational radiochemotherapy, which is the first-line treatment for over 50 % of cancer patients.

A Molecular Logic Gate for Developing "AND" Logic Probes and the Application in Hepatopathy Differentiation.

Accurate diagnosis and therapy are challenging because most diseases lack a single biomarker that distinguishes them from other disorders. A solution would enhance targeting accuracy by using AND-gated combinations of two disease-associated stimuli. Here, we report a novel "AND" molecular logic gate, enabling a double-controlled release of intact functional molecules. Benefiting from a significant difference in intramolecular cyclization rate, cargo release occurs notably faster with the presence of both stimuli. According to this finding, several AND logic probes have been developed that respond to a broad scope of stimuli and show remarkably improved signal-to-background contrast compared to those of monoresponsive probes. In addition, an AND logic probe that is responsive to monoamine oxidase (MAO) and leucine aminopeptidase (LAP) has been constructed for hepatopathy diagnosis. It works efficiently in living cells and mouse models. Of note, this probe can successfully differentiate cirrhotic from hepatitis B by testing the blood samples from patients.

Radiotherapy Reduces N-Oxides for Prodrug Activation in Tumors.

Precisely activating chemotherapeutic prodrugs in a tumor-selective manner is an ideal way to cure cancers without causing systemic toxicities. Although many efforts have been made, developing spatiotemporally controllable activation methods is still an unmet challenge. Here, we report a novel prodrug activation strategy using radiotherapy (X-ray). Due to its precision and deep tissue penetration, X-ray matches the need for altering molecules in tumors through water radiolysis. We first demonstrated that N-oxides can be effectively reduced by hydrated electrons (e-aq) generated from radiation both in tubes and living cells. A screening is performed to investigate the structure-reduction relationship and mechanism of the e-aq-mediated reductions. We then apply the strategy to activate N-oxide prodrugs. The anticancer drug camptothecin (CPT)-based N-oxide prodrug shows a remarkable anticancer effect upon activation by radiotherapy. This radiation-induced in vivo chemistry may enable versatile designs of radiotherapy-activated prodrugs, which are of remarkable clinical relevance, as over 50% of cancer patients take radiotherapy.

A Cationic Micelle as In Vivo Catalyst for Tumor-Localized Cleavage Chemistry.

The emerging strategies of accelerating the cleavage reaction in tumors through locally enriching the reactants is promising. Yet, the applications are limited due to the lack of the tumor-selectivity for most of the reactants. Here we explored an alternative approach to leverage the rate constant by locally inducing an in vivo catalyst. We found that the desilylation-induced cleavage chemistry could be catalyzed in vivo by cationic micelles, and accelerated over 1400-fold under physiological condition. This micelle-catalyzed controlled release platform is demonstrated by the release of a 6-hydroxyl-quinoline-2-benzothiazole derivative (HQB) in two cancer cell lines and a NIR dye in mouse tumor xenografts. Through intravenous injection of a pH-sensitive polymer micelles, we successfully applied this strategy to a prodrug activation of hydroxyl camptothecin (OH-CPT) in tumors. Its "decaging" efficiency is 42-fold to that without cationic micelles-mediated catalysis. This micelle-catalyzed desilylation strategy unveils the potential that micelle may act beyond a carrier but a catalyst for local perturbing or activation.

Ratiometric Fluorescent Mapping of pH and Glutathione Dictates Intracellular Transport Pathways of Micellar Nanoparticles.

Visualization of intracellular transport pathways is crucial to investigate the internalization mechanism and understand the intracellular behavior of nanomaterials. Herein, we rationalized the design of micellar nanoparticles (NPs) for ratiometric fluorescent mapping of intracellular pH and glutathione (GSH), two essential parameters for maintaining normal cellular functions. Specifically, pH-sensitive naphthalimide-based probe (NPI) and pH-inert rhodamine B (RhB) were covalently labeled to double hydrophilic block copolymers (DHBCs) using the thiolactone chemistry, enabling the covalent attachment of NPI and RhB to one molecule with a redox-responsive disulfide linkage. The dually labeled DHBCs exhibited blue/orange dual emissions in acidic pH, which was further converted into green/orange dual emissions in neutral pH because of the deprotonation of NPI moieties and the sole green emission in the presence of GSH at neutral pH because of the decreased Förster resonance energy transfer efficiency between an NPI donor and an RhB acceptor as a result of GSH-mediated cleavage of disulfide bonds. These remarkable ratiometric fluorescence changes allowed for not only the simultaneous mapping of the intracellular pH and GSH but also the intracellular transport pathways of internalized NPs.

Redox-responsive dextran based theranostic nanoparticles for near-infrared/magnetic resonance imaging and magnetically targeted photodynamic therapy.

Photodynamic therapy (PDT) is a site-specific treatment of cancer using much lower optical power densities with minimal nonspecific damage to normal tissues. To improve the therapeutic efficiency of PDT, we fabricated a multifunctional theranostic nanoparticle system (DSSCe6@Fe3O4 NPs) by loading Fe3O4 nanoparticles in redox-responsive chlorin e6 (Ce6)-conjugated dextran nanoparticles for near-infrared (NIR)/magnetic resonance (MR) dual-modality imaging and magnetic targeting. The obtained DSSCe6@Fe3O4 NPs demonstrated a uniform nanospherical morphology consisting of Fe3O4 clusters. The fluorescence signal of Ce6 of this theranostic system could turn "ON" from a self-quenching state in a reductive intracellular environment. T2-Weighted MR imaging revealed a high transverse relaxivity (r2) measured to be 194.4 S-1 mM-1, confirming that it was also a distinctive contrast agent in T2-weighted MR imaging. Confocal images and flow cytometry results showed that the cellular uptake of DSSCe6@Fe3O4 NPs was enhanced effectively under an extra magnetic field, which resulted in promoted PDT therapeutic efficiency. In vivo MR imaging showed that DSSCe6@Fe3O4 NPs effectively accumulated in tumors under an extra magnetic field. These results illustrated that the DSSCe6@Fe3O4 NPs could be a promising theranostic system for both NIR/MR imaging-guided PDT precision therapy.