Long-Lasting Reactive Oxygen Species Generation by Porous Redox Mediator-Potentiated Nanoreactor for Effective Tumor Therapy

The therapeutic efficiency of reactive oxygen species (ROS)-based nanotherapeutics is restrained by the rigorous production conditions of relatively sufficient and kinetically matching supply of intracellular substrates. The cumulative disruption of redox homeostasis and consequent pathology (e.g., Parkinson's disease) with low levels of substrates in living organisms may provide a promising model for ROS-based therapy. Herein, a catechol chemistry-mediated ternary nanostructure is prepared for long-lasting generation of oxidative •OH in weakly acidic, low H₂O₂ homeostasis conditions of tumor. This platform employs mesoporous polydopamine (MPDA) as the porous redox mediator, while PDA-induced sequential precipitation and biomineralization lead to hydroxy iron oxide (FeOOH) as the “iron reservoir,” and calcium phosphate (CaP) as the pH-sensitive sheddable shell. In weakly acidic conditions, the CaP layer can be degraded to expose the catalytic surface of Fe-dopamine interplay, where FeOOH dissolution, Fe(III) chelation, Fe(III) reduction, Fe(II) release take place sequentially and continuously for Fe(II) recycling and Fenton catalysis. Both in vitro and in vivo studies verify the significant inhibition of cancer cells and tumor regression, which can also be strengthened by the local photothermal heating. This work establishes the first paradigm of pathologically inspired nanohybrids of ROS generators with long-lasting efficacy for cancer therapy.     

Potent‐By‐Design: Amino Acids Mimicking Porous Nanotherapeutics with Intrinsic Anticancer Targeting Properties

Exogenous sources of amino acids are essential nutrients to fuel cancer growth. Here, the increased demand for amino acid displayed by cancer cells is unconventionally exploited as a design principle to replete cancer cells with apoptosis inducing nanoscopic porous amino acid mimics (Nano‐PAAM). A small library consisting of nine essential amino acids nanoconjugates (30 nm) are synthesized, and the in vitro anticancer activity is evaluated. Among the Nano‐PAAMs, l ‐phenylalanine functionalized Nano‐PAAM (Nano‐pPAAM) has emerged as a novel nanotherapeutics with excellent intrinsic anticancer and cancer‐selective properties. The therapeutic efficacy of Nano‐pPAAM against a panel of human breast, gastric, and skin cancer cells could be ascribed to the specific targeting of the overexpressed human large neutral amino acid transporter SLC7A5 (LAT‐1) in cancer cells, and its intracellular reactive oxygen species (ROS) inducing properties of the nanoporous core. At the mechanistic level, it is revealed that Nano‐pPAAM could activate both the extrinsic and intrinsic apoptosis pathways to exert a potent “double‐whammy” anticancer effect. The potential clinical utility of Nano‐pPAAM is further investigated using an MDA‐MB‐231 xenograft in NOD scid gamma mice, where an overall suppression of tumor growth by 60% is achieved without the aid of any drugs or application of external stimuli.     

Photosensitization Priming of Tumor Microenvironments Improves Delivery of Nanotherapeutics via Neutrophil Infiltration

Remodeling of tumor microenvironments enables enhanced delivery of nanoparticles (NPs). This study shows that direct priming of a tumor tissue using photosensitization rapidly activates neutrophil infiltration that mediates delivery of nanotherapeutics into the tumor. A drug delivery platform is comprised of NPs coated with anti‐CD11b antibodies (Abs) that target activated neutrophils. Intravital microscopy demonstrates that the movement of anti‐CD11b Abs‐decorated NPs (NPs‐CD11b) into the tumor is mediated by neutrophil infiltration induced by photosensitization (PS) because the systemic depletion of neutrophils completely abolishes the nanoparticle tumor deposition. The neutrophil uptake of NPs does not alter neutrophil activation and transmigration. For cancer therapy in mice, tumor PS and photothermal therapy of anti‐CD11b Abs‐linked gold nanorods (GNRs‐CD11b) are combined to treat the carcinoma tumor. The result indicates that neutrophil tumor infiltration enhances nanoparticle cancer therapy. The findings reveal that promoting tumor infiltration of neutrophils by manipulating tumor microenvironments could be a novel strategy to actively deliver nanotherapeutics in cancer therapies.     

Tumor‐Penetrating Nanotherapeutics Loading a Near‐Infrared Probe Inhibit Growth and Metastasis of Breast Cancer

The tumor growth and metastasis is the leading reason for the high mortality of breast cancer. Herein, it is first reported a deep tumor‐penetrating photothermal nanotherapeutics loading a near‐infrared (NIR) probe for potential photothermal therapy (PTT) of tumor growth and metastasis of breast cancer. The NIR probe of 1,1‐dioctadecyl‐3,3,3,3‐tetramethylindotricarbocyanine iodide (DiR), a lipophilicfluorescent carbocyanine dye with strong light‐absorbing capability, is entrapped into the photothermal nanotherapeutics for PTT application. The DiR‐loaded photothermal nanotherapeutics (DPN) is homogeneous nanometer‐sized particles with the mean diameter of 24.5 ± 4.1 nm. Upon 808 nm laser irradiation, DPN presents superior production of thermal energy than free DiR both in vitro and in vivo. The cell proliferation and migration activities of metastatic 4T1 breast cancer cells are obviously inhibited by DPN in combination with NIR irradiation. Moreover, DPN can induce a higher accumulation in tumor and penetrate into the deep interior of tumor tissues. The in vivo PTT measurements indicate that the growth and metastasis of breast cancer are entirely inhibited by a single treatment of DPN with NIR irradiation. Therefore, the deep tumor‐penetrating DPN can provide a promising strategy for PTT of tumor progression and metastasis of breast cancer.     

Mechanisms and Implications of Dual-Acting Methotrexate in Folate-Targeted Nanotherapeutic Delivery

The rational design of a nanoplatform in drug delivery plays a crucial role in determining its targeting specificity and efficacy in vivo. A conventional approach relies on the surface conjugation of a nanometer-sized particle with two functionally distinct types of molecules, one as a targeting ligand, and the other as a therapeutic agent to be delivered to the diseased cell. However, an alternative simplified approach can be used, in which a single type of molecule displaying dual function as both a targeting ligand and therapeutic agent is conjugated to the nanoparticle. In this review, we evaluate the validity of this new strategy by using methotrexate, which displays multifunctional mechanisms of action. Methotrexate binds to the folate receptor, a surface biomarker frequently overexpressed in tumor cells, and also inhibits dihydrofolate reductase, an enzyme critical for cell survival and division. Thus we describe a series of fifth generation poly(amido amine) dendrimers conjugated with methotrexate, and discuss several lines of evidence supporting the efficacy of this new platform strategy based on surface plasmon resonance spectroscopy, enzyme activity assays, and cell-based studies with folate receptor (+) KB cancer cells.     

A Homing Missile-Like Nanotherapeutic with Single-Atom Catalytic Sites for In Situ Elimination of Intracellular Bacterial Pathogens

Intracellular bacterial pathogens hiding in host cells tolerate the innate immune system and high-dose antibiotics, resulting in recurrent infections that are difficult to treat. Herein, a homing missile-like nanotherapeutic (FeSAs@Sa.M) composed of a single-atom iron nanozyme (FeSAs) core coated with infected macrophage membrane (Sa.M) is developed for in situ elimination of intracellular methicillin-resistant S. aureus (MRSA). Mechanically, the FeSAs@Sa.M initially binds to the extracellular MRSA via the bacterial recognition ability of the Sa.M component. Subsequently, the FeSAs@Sa.M can be transported to the intracellular MRSA-located regions in the host cell like a homing missile under the guidance of the extracellular MRSA to which it is attached, generating highly toxic reactive oxygen species (ROS) for intracellular MRSA killing via the enzymatic activities of the FeSAs core. The FeSAs@Sa.M is far superior to FeSAs in killing intracellular MRSA, proposing a feasible strategy for treating intracellular infections by in situ generating ROS in bacterial residing regions.