Multifunctional Nanoplatform for NIR-II Imaging-Guided Synergistic Oncotherapy.

Tumors are a major public health issue of concern to humans, seriously threatening the safety of people's lives and property. With the increasing demand for early and accurate diagnosis and efficient treatment of tumors, noninvasive optical imaging (including fluorescence imaging and photoacoustic imaging) and tumor synergistic therapies (phototherapy synergistic with chemotherapy, phototherapy synergistic with immunotherapy, etc.) have received increasing attention. In particular, light in the near-infrared second region (NIR-II) has triggered great research interest due to its penetration depth, minimal tissue autofluorescence, and reduced tissue absorption and scattering. Nanomaterials with many advantages, such as high brightness, great photostability, tunable photophysical properties, and excellent biosafety offer unlimited possibilities and are being investigated for NIR-II tumor imaging-guided synergistic oncotherapy. In recent years, many researchers have tried various approaches to investigate nanomaterials, including gold nanomaterials, two-dimensional materials, metal sulfide oxides, polymers, carbon nanomaterials, NIR-II dyes, and other nanomaterials for tumor diagnostic and therapeutic integrated nanoplatform construction. In this paper, the application of multifunctional nanomaterials in tumor NIR-II imaging and collaborative therapy in the past three years is briefly reviewed, and the current research status is summarized and prospected, with a view to contributing to future tumor therapy.

Oleoylethanolamide ameliorates motor dysfunction through PPARα-mediates oligodendrocyte differentiation and white matter integrity after ischemic stroke.

BACKGROUND AND AIM: Our previous study has revealed that OEA promotes motor function recovery in the chronic stage of ischemic stroke. However, the neuroprotective mechanism of OEA on motor function recovery after stroke still is unexplored. Therefore, the aim of this study was to explore the effects of OEA treatment on angiogenesis, neurogenesis, and white matter repair in the peri-infarct region after cerebral ischemia. EXPERIMENTAL PROCEDURE: The adult male rats were subjected to 2 h of middle cerebral artery occlusion. The rats were treated with 10 and 30 mg/kg OEA or vehicle daily starting from day 2 after ischemia induction until they were sacrificed. KEY RESULTS AND CONCLUSIONS: The results revealed that OEA increased cortical angiogenesis, neural progenitor cells (NPCs) proliferation, migration, and differentiation. OEA treatment enhanced the survival of newborn neurons and oligodendrogenesis, which eventually repaired the cortical neuronal injury and improved motor function after ischemic stroke. Meanwhile, OEA treatment promoted the differentiation of oligodendrocyte progenitor cells (OPCs) and oligodendrogenesis by activating the PPARα signaling pathway. Our results showed that OEA restores motor function by facilitating cortical angiogenesis, neurogenesis, and white matter repair in rats after ischemic stroke. Therefore, we demonstrate that OEA facilitates functional recovery after ischemic stroke and propose the hypothesis that the long-term application of OEA mitigates the disability after stroke.

Biomimetic dual-responsive bioengineered nanotheranostics for intracellular cascade-synthesizing chemo-drugs and efficient oncotherapy.

Intracellular-synthesized chemo-drugs based on the inherent characteristics of the tumor microenvironment (TME) have been extensively applied in oncotherapy. However, combining other therapeutic strategies to convert nontoxic small molecules into toxic small-molecule chemo-drugs in the TME is still a huge challenge. To address this issue, herein we have developed a biomimetic dual-responsive bioengineered nanotheranostics system via the supramolecular co-assembly of the nontoxic small-molecule 1,5-dihydroxynaphthalene (DHN) and small-molecule photosensitizer indocyanine green (ICG) followed by surface cloaking through red blood cell membranes (RBCs) for intracellular cascade-synthesizing chemo-drugs and efficient oncotherapy. Such nanotheranostics with a suitable diameter, core-shell structure, ultrahigh dual-drug payload rate, and excellent stability can efficiently accumulate in tumor regions and then internalize into tumor cells. Under the dual stimulations of near-infrared laser irradiation and acidic lysosomes, the nanotheranostics system exhibited exceptional instability under heat-primed membrane rupture and pH decrease, thereby achieving rapid disassembly and on-demand drug release. Furthermore, the released ICG can efficiently convert 3O2 into 1O2. After that, the generated 1O2 can efficiently oxidize the released nontoxic DHN into the highly toxic chemo-drug juglone, thereby realizing intracellular cascade-synthesizing chemo-drugs and synergistic photodynamic-chemotherapy while reducing detrimental side effects on normal cells or tissues. Overall, it is envisioned that RBC-cloaked nanotheranostics with intracellular cascade-synthesizing chemo-drugs can provide a promising strategy for intracellular chemo-drug synthesis-based oncotherapy.

Shuttle-Shape Carrier-Free Platinum-Coordinated Nanoreactors with O2 Self-Supply and ROS Augment for Enhanced Phototherapy of Hypoxic Tumor.

The synergistic nanotheranostics of reactive oxygen species (ROS) augment or phototherapy has been a promising method within synergistic oncotherapy. However, it is still hindered by sophisticated design and fabrication, lack of a multimodal synergistic effect, and hypoxia-associated poor photodynamic therapy (PDT) efficacy. Herein, a kind of porous shuttle-shape platinum (IV) methylene blue (Mb) coordination polymer nanotheranostics-loaded 10-hydroxycamptothecin (CPT) is fabricated to address the abovementioned limitations. Our nanoreactors possess spatiotemporally controlled O2 self-supply, self-sufficient singlet oxygen (1O2), and outstanding photothermal effect. Once they are taken up by tumor cells, nanoreactors as a cascade catalyst can efficiently catalyze degradation of the endogenous hydrogen peroxide (H2O2) into O2 to alleviate tumor hypoxia. The production of O2 can ensure enhanced PDT. Subsequently, under both stimuli of external red light irradiation and internal lysosomal acidity, nanoreactors can achieve the on-demand release of CPT to augment in situ mitochondrial ROS and highly efficient tumor ablation via phototherapy. Moreover, under the guidance of near-infrared (NIR) fluorescent imaging, our nanoreactors exhibit strongly synergistic potency for treatment of hypoxic tumors while reducing damages against normal tissues and organs. Collectively, shuttle-shape platinum-coordinated nanoreactors with augmented ROS capacity and enhanced phototherapy efficiency can be regarded as a novel tumor theranostic agent and further promote the research of synergistic oncotherapy.

Selective antitumor activity of drug-free TPGS nanomicelles with ROS-induced mitochondrial cell death.

D-a-tocopheryl polyethylene glycol succinate (TPGS) as a FDA-approved safe adjuvant has shown an excellent application in the targeting delivery of antitumor drugs and overcoming multidrug resistance. Beside, TPGS can result in apoptogenic activity toward many tumor types because it can induce mitochondrial dysfunction. Therefore, TPGS can serve as an antineoplastic agent. However, the current research on the selective antitumor activity of TPGS is ignored. To reveal the issue, herein we develop a mitochondria-targeting drug-free TPGS nanomicelles with the hydrodynamic diameter of about 100 nm and outstanding serum stability by weak interaction-driven self-assembly of the amphiphilic TPGS polymer. Moreover, such drug-free TPGS nanomicelles intravenously injected into tumor-bearing mice exhibit long blood circulation time, superior tumor enrichment, and inhibit the tumor growth via inducing excessive reactive oxygen species (ROS) generation within tumor cells. Further in vitro and in vivo researches jointly demonstrate that drug-free TPGS nanomicelles have more significant antitumor effect on HeLa cells compared with that of other tumor cells. On the contrary, drug-free TPGS nanomicelles display the low toxicity toward normal cells and tissues. Taken together, these new findings confirm that TPGS drug-free nanomicelles represent simple, multifunctional, safe, and efficient antineoplastic agents, which can be expected to bring new light on the development of drug-free polymers for tumor therapy.

Self-recognizing and stimulus-responsive carrier-free metal-coordinated nanotheranostics for magnetic resonance/photoacoustic/fluorescence imaging-guided synergistic photo-chemotherapy.

Carrier-free nanotheranostics directly assembled by using clinically used photosensitizers and chemotherapeutic drugs are a promising alternative to tumor theranostics. However, the weak interaction-driven assembly still suffers from low structural stability against disintegration, lack of targeting specificity, and poor stimulus-responsive property. Moreover, almost all exogenous ligands possess no therapeutic effect. Enlightened by the concept of metal-organic frameworks, we developed a novel self-recognizing metal-coordinated nanotheranostic agent by the coordination-driven co-assembly of photosensitizer indocyanine green (ICG) and chemo-drug methotrexate (MTX, also served as a specific "targeting ligand" towards folate receptors), in which ferric (FeIII) ions acted as a bridge to tightly associate ICG with MTX. Such carrier-free metal-coordinated nanotheranostics with high dual-drug payload (∼94 wt%) not only possessed excellent structural and physiological stability, but also exhibited prolonged blood circulation. In addition, the nanotheranostics could achieve the targeted on-demand drug release by both stimuli of internal lysosomal acidity and external near-infrared laser. More importantly, the nanotheranostics could self-recognize the cancer cells and selectively target the tumors, and therefore they decreased toxicity to normal tissues and organs. Consequently, the nanotheranostics showed strongly synergistic potency for tumor photo-chemotherapy under the precise guidance of magnetic resonance/photoacoustic/fluorescence imaging, thereby achieving highly effective tumor curing efficiency. Considering that ICG and bi-functional MTX are approved by the Food and Drug Administration, and FeIII ions have high biosafety, the self-recognizing and stimulus-responsive carrier-free metal-coordinated nanotheranostics may hold potential applications in tumor theranostics.

Design of light/ROS cascade-responsive tumor-recognizing nanotheranostics for spatiotemporally controlled drug release in locoregional photo-chemotherapy.

Carrier-free nanotheranostics with high drug loading and no carrier-related toxicity are highly promising cancer therapy agents. However, the limited tumor accumulation and poorly controlled drug release of these nanotheranostics continue to be major challenges that restrict clinical applications. In this study, we develop a tumor-recognizing carrier-free nanotheranostic with light/reactive oxygen species (ROS) cascade-responsiveness for spatiotemporally selective photo-chemotherapy. The nanotheranostic is constructed by co-assembly of the indocyanine green (ICG) photosensitizer and the mannose-thioketal-doxorubicin conjugate (MAN-TK-DOX) (abbreviated as IMTD), efficiently preventing premature DOX leakage during blood circulation while reducing nonspecific damage to normal tissues/cells. Once accumulated in tumor tissues, IMTD rapidly diffuses into cancer cells via lectin receptors-mediated endocytosis. Photoacoustic/fluorescence-imaging-guided laser irradiation induces local hyperthermia and ROS generation in tumor cells, thereby promoting apoptosis. Together, the ICG-generated ROS and the endogenous ROS in cancer cells synergistically enhance DOX release, resulting in more efficient chemotherapeutic effects. The in vitro and in vivo results consistently demonstrate that IMTD achieves superior tumor accumulation, highly controllable drug release, and synergetic photo-chemotherapy. Therefore, the co-assembly of an ROS-sensitive targeting ligand-chemodrug conjugate and a photosensitizer could be used to develop spatiotemporally light-activatable nanotheranostics for precision cancer therapy. STATEMENT OF SIGNIFICANCE: Synergistic phototherapy and chemotherapy have been considered as a promising cancer treatment modality to maximize the therapeutic efficacy. Unfortunately, most nanodrugs consisting of chemotherapeutic drug and photosensitizer suffer from suboptimal tumor accumulation and poorly controlled drug release, which results in reduced therapeutic outcome. In this study, Mannose (MAN) was conjugated to the anticancer drug doxorubicin (DOX) by a ROS-sensitive thioketal linker (TK), the obtained amphiphilic MAN-TK-DOX could serve as an ideal self-carrier material to deliver photosensitizer, thus to achieve high-efficient tumor-targeting, spatiotemporal controlled drug release, and superior antitumor effect. We believe that the ROS-sensitive amphiphilic targeting ligand-chemodrug conjugate could be developed as a universal approach for designing tumor-targeted nanodrugs with precisely controlled drug release.

Light/pH-Triggered Biomimetic Red Blood Cell Membranes Camouflaged Small Molecular Drug Assemblies for Imaging-Guided Combinational Chemo-Photothermal Therapy.

Nanoparticles camouflaged by red blood cell (RBC) membranes have attracted considerable attention owing to reservation of structure of membrane and surface proteins, endowing prominent cell-specific function including biocompatibility, prolonged circulation lifetime, and reduced reticular endothelial system (RES) uptake ability. Considering the drawbacks of carrier-free nanomedicine including the serious drug burst release, poor stability, and lack of immune escape function, herein we developed and fabricated a novel RBC membranes biomimetic combinational therapeutic system by enveloping the small molecular drug coassemblies of 10-hydroxycamptothecin (10-HCPT) and indocyanine green (ICG) in the RBC membranes for prolonged circulation, controlled drug release, and synergistic chemo-photothermal therapy (PTT). The self-reorganized RBCs@ICG-HCPT nanoparticles (NPs) exhibited a diameter of ∼150 nm with core-shell structure, high drug payload (∼92 wt %), and reduced RES uptake function. Taking advantage of the stealth functionality of RBC membranes, RBCs@ICG-HCPT NPs remarkably enhanced the accumulation at the tumor sites by passive targeting followed by cellular endocytosis. Upon the stimuli of near-infrared laser followed by acidic stimulation, RBCs@ICG-HCPT NPs showed exceptional instability by heat-mediated membrane disruption and pH change, thereby triggering the rapid disassembly and accelerated drug release. Consequently, compared with individual treatment, RBCs@ICG-HCPT NPs under dual-stimuli accomplished highly efficient apoptosis in cancer cells and remarkable ablation of tumors by chemo-PTT. This biomimetic nanoplatform based on carrier-free, small molecular drug coassemblies integrating imaging capacity as a promising theranostic system provides potential for cancer diagnosis and combinational therapy.

Design of pH-sensitive methotrexate prodrug-targeted curcumin nanoparticles for efficient dual-drug delivery and combination cancer therapy.

AIM: We designed acid-labile methotrexate (MTX) targeting prodrug self-assembling nanoparticles loaded with curcumin (CUR) drug for simultaneous delivery of multi-chemotherapeutic drugs and combination cancer therapy. METHODS: A dual-acting MTX, acting as both an anticancer drug and as a tumor-targeting ligand, was coupled to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[aldehyde(polyethylene glycol)-2000] via Schiff's base reaction. The synthesized prodrug conjugate (DSPE-PEG-Imine-MTX) could be self-assembled into micellar nanoparticles (MTX-Imine-M) in aqueous solution, which encapsulated CUR into their core by hydrophobic interactions (MTX-Imine-M-CUR). RESULTS: The prepared MTX-Imine-M-CUR nanoparticles were composed of an inner hydrophobic DSPE/CUR core and an outside hydrophilic bishydroxyl poly (ethyleneglycol) (PEG) shell with a self-targeting MTX prodrug corona. The imine linker between 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[aldehyde(polyethyleneglycol)-2000] and MTX, as a dynamic covalent bond, was strong enough to remain intact in physiological pH, even though it is rapidly cleaved in acidic pH. The MTX-Imine-M-CUR could codeliver MTX and CUR selectively and efficiently into the cancer cells via folate receptor-mediated endocytosis followed by the rapid intracellular release of CUR and the active form of MTX via the acidity of endosomes/lysosomes. Moreover, the MTX-Imine-M-CUR resulted in significantly higher in vitro and in vivo anticancer activity than pH-insensitive DSPE-PEGAmide-MTX assembling nanoparticles loaded with CUR (MTX-Amide-M-CUR), MTX unconjugated DSPE-PEG assembling micellar nanoparticles loaded with CUR (M-CUR), combination of both free drugs, and individual free drugs. CONCLUSION: The smart system provided a simple, yet feasible, drug delivery strategy for targeted combination chemotherapy.