Ming-Kang Zhang

Enhanced Immunotherapy Based on Photodynamic Therapy for Both Primary and Lung Metastasis Tumor Eradication

Metastasis and recurrence are two unavoidable and intractable problems in cancer therapy, despite various robust therapeutic approaches. Currently, it seems that immunotherapy is an effective approach to solve these problems, but the high heterogeneity of tumor tissue, inefficient presentation of tumor antigen, and deficient targeting ability of therapy usually blunt the efficacy of immunotherapy and hinder its clinical application. Herein, an approach based on combining photodynamic and immunological therapy was designed and developed. We synthesized a chimeric peptide, PpIX-1MT, which integrates photosensitizer PpIX with immune checkpoint inhibitor 1MT via a caspase-responsive peptide sequence, Asp-Glu-Val-Asp (DEVD), to realize a cascaded synergistic effect. The PpIX-1MT peptide could form nanoparticles in PBS and accumulate in tumor areas via the enhanced penetration retention effect. Upon 630 nm light irradiation, the PpIX-1MT nanoparticles produced reactive oxygen species, induced apoptosis of cancer cells, and thus facilitated the expression of caspase-3 and the production of tumor antigens, which could trigger an intense immune response. The subsequently released 1MT upon caspase-3 cleavage could further strengthen the immune system and help to activate CD8+ T cells effectively. This cascaded synergistic effect could inhibit both primary and lung metastasis tumor effectively, which may provide the solution for solving tumor recurrence and metastasis clinically.

A biomimetic theranostic O2-meter for cancer targeted photodynamic therapy and phosphorescence imaging

In this report, a biomimetic theranostic oxygen (O2)-meter (cancer cell membrane@Pt(II) porphyrinic-metal organic framework, designated as mPPt) was constructed for cancer targeted and phosphorescence image-guided photodynamic therapy (PDT). mPPt presents high photosensitizers (PSs) loading and evitable self-quenching behaviors for favorable biological O2 sensing and PDT. Besides, endowed by the surface functionalization of cancer cell membrane, the homotypic targeting and immune escape abilities of mPPt could dramatically enhance its cancer targeting ability. Importantly, the O2-dependent phosphorescence responsibility of mPPt could be employed to pre-evaluate the real time O2 level in situ and guide the PDT under light irradiation. A significant anticancer effect is observed after intravenous injection of mPPt and subsequent treatment with PDT with no obvious side effects. As a versatile platform for cell imaging, O2 fluctuation monitoring as well as PDT, this biomimetic O2-meter exhibits great potential for biological analysis and personalized cancer theranostics.

π-Extended Benzoporphyrin-Based Metal–Organic Framework for Inhibition of Tumor Metastasis

We report on the benzoporphyrin-based metal-organic framework (TBP-MOF), with 10-connected Zr6 cluster and much improved photophysical properties over the traditional porphyrin-based MOFs. It was found that TBP-MOF exhibited red-shifted absorption bands and strong near-infrared luminescence for bioimaging, whereas the π-extended benzoporphyrin-based linkers of TBP-MOF facilitated 1O2 generation to enhance O2-dependent photodynamic therapy (PDT). It was demonstrated that poly(ethylene glycol)-modified nanoscale TBP-MOF (TBP-nMOF) can be used as an effective PDT agent under hypoxic tumor microenvironment. We also elucidated that the low O2-dependent PDT of TBP-nMOF in combination with αPD-1 checkpoint blockade therapy can not only suppress the growth of primary tumor, but also stimulate an antitumor immune response for inhibiting metastatic tumor growth. We believe this TBP-nMOF has great potential to serve as an efficient photosensitizer for PDT and cancer immunotherapy.

Universal Porphyrinic Metal–Organic Framework Coating to Various Nanostructures for Functional Integration

A universal strategy was reported that enables functional group-capped nanostructures with various morphologies and compositions to be coated by porphyrin metal-organic framework (MOF). Based on the nanostructure-induced heterogeneous nucleation, the controlled growth of MOF shell on the surface of nanostructures can be realized. It was demonstrated that this modification strategy can realize controlled growth of porphyrin MOF on a series of organic and inorganic nanostructures, such as polydopamine (PDA) nanoparticles, PDA@Pt nanoparticles, graphene oxide sheets, and Au nanorods. The as-prepared composites exhibit excellent catalytic and optical properties that originate from the nanostructure as well as the coated porphyrin MOF. We further explored the potential applications of PDA@MOF and PDA@Pt@MOF in nanomedicine and photocatalysis.

Metal Ion/Tannic Acid Assembly as a Versatile Photothermal Platform in Engineering Multimodal Nanotheranostics for Advanced Applications

This study reports a family of photothermal materials, metal ion/tannic acid assemblies (MITAs). MITAs from FeIII, VIII, and RuIII afford excellent photothermal efficiency (η ≈ 40%). Sharply differing from the currently existing photothermal agents, MITAs are highlighted by merits including green synthesis, facile incorporation of diagnostic metal ions, and particularly topology-independent adhesion. Owing to the adhesion nature of MITAs, various kinds of MITA-based nanoengineerings are readily available via the self-adhesion of MITAs onto diverse templates, enabling MITAs well suited as a photothermal platform for versatile combination with other therapy approaches and imaging techniques. As a proof of concept, polymeric/inorganic nanoparticle/nanovesicle-supported FeIII-tannic acid (FeIIITA) is fabricated. The photothermal effect is shown to be unaffected by the template origin and type and FeIIITA thickness on the templates. We validate the potency of nanovesicle-supported FeIIITA (PNV@FeIIITA) for tumor-specific photoactivated utilizations, including NIR photothermal therapy with complete tumor elimination, photothermal imaging (PTI), and photoacoustic imaging (PAI) in addition to T1-MRI imaging. PNV@FeIIITA can be simultaneously equipped with functionalities, including T2-MRI imaging by additionally doping MnII and NIR fluorescence imaging by encapsulating a hydrophilic NIR fluoroprobe. MITA demonstrates unparalleled superiority as a photothermal platform in engineering multimodal theranostics for advanced applications.

Real-Time Imaging of Free Radicals for Mitochondria-Targeting Hypoxic Tumor Therapy

Free radicals have emerged as new-type and promising candidates for hypoxic tumor treatment, and further study of their therapeutic mechanism by real-time imaging is of great importance to explore their biomedical applications. Herein, we present a smart free-radical generator AuNC-V057-TPP for hypoxic tumor therapy; the AuNC-V057-TPP not only exhibits good therapeutic effect under both hypoxic and normoxic conditions but also can monitor the release of free radicals in real-time both in vitro and in vivo. What is more, with the mitochondria-targeting ability, the AuNC-V057-TPP is demonstrated with improved antitumor efficacy through enhanced free radical level in mitochondria, which leads to mitochondrial membrane damage and ATP production reduction and finally induces cancer cell apoptosis.

A Universal Approach to Render Nanomedicine with Biological Identity Derived from Cell Membranes

Biomimetic nanoengineering built through integrating the specific cell membrane with artificially synthetic nanomedicines represents one of the most promising directions for the actualization of personalized therapy. For addressing the technical hurdle against the development of this biomimetic technology, the present report describes the in-depth exploration and optimization over each critical preparation step, including establishment of a nanoparticle-stabilized dispersion system, cargo loading, membrane coating, and product isolation. Magnetic iron oxide nanoparticles loaded with DOX is used as a typical model for the coating with cancer cell membranes, providing compact DNP@CCCM nanostructure well-characterized by various techniques. Furthermore, the feasibility of this optimized approach in constructing biomimetic membrane-coated nanomedicines has been validated on the basis of the remarkably improved biofunctions, such as the targetability, magnetic property, hemolysis risk, macrophage evasion, in vitro cytotoxicity, in vivo circulation duration, and in vivo principal component analysis postinjection. We hope this study regarding technique optimization will prompt the advancement of biomembrane-camouflaged nanoparticles as a newly emerging biomimetic technology.

Aggressive Man‐Made Red Blood Cells for Hypoxia‐Resistant Photodynamic Therapy

Extreme hypoxia of tumors represents the most notable barrier against the advance of tumor treatments. Inspired by the biological nature of red blood cells (RBCs) as the primary oxygen supplier in mammals, an aggressive man-made RBC (AmmRBC) is created to combat the hypoxia-mediated resistance of tumors to photodynamic therapy (PDT). Specifically, the complex formed between hemoglobin and enzyme-mimicking polydopamine, and polydopamine-carried photosensitizer is encapsulated inside the biovesicle that is engineered from the recombined RBC membranes. The mean corpuscular hemoglobin of AmmRBCs reaches about tenfold as high as that of natural RBCs. Owing to the same origin of outer membranes, AmmRBCs share excellent biocompatibility with parent RBCs. The introduced polydopamine plays the role of the antioxidative enzymes existing inside RBCs to effectively prevent the oxygen-carrying hemoglobin from the oxidation damage during the circulation. This biomimetic engineering can accumulate in tumors, permit in situ efficient oxygen supply, and impose strong PDT efficacy toward the extremely hypoxic tumor with complete tumor elimination. The man-made pseudo-RBC shows potentials as a universal oxygen-self-supplied platform to sensitize hypoxia-limited tumor treatment means, including but not limited to PDT. Meanwhile, this study offers ideas to the production of artificial substitutes of packed RBCs for clinical blood transfusion.

MnO2 Motor: A Prospective Cancer-Starving Therapy Promoter

Here, a tumor-targeted MnO2 motor nanosystem (designed as MG/HA) was constructed by the assembly of glucose oxidase (GOD), manganese dioxide (MnO2), and glycoprotein CD44-targeting polymer hyaluronic acid (HA) to elevate cancer-starving therapy efficacy in solid tumor. Upon the specific uptake of MG/HA by CD44 overexpressed cancer cells, GOD catalyzed the oxidation of glucose into gluconic acid and hydrogen peroxide (H2O2) accompanying the consumption of oxygen (O2). Meanwhile, MnO2 would react with H2O2 and acid to generate O2, which is in turn supplied to the glucose-depletion process, running like a loop. As a result, MnO2 is displayed as a motor to promote the rate of glucose depletion that contributed to the starving therapy. In contrast to G/HA, MG/HA could not only achieve effective glucose consumption to depress cancer progression, but also alleviate hypoxia and reduce the expression of Glut1 to inhibit the metabolism for further restraining the tumor aggressiveness and metastasis. The concept of MnO2 motor shows a promising prospect to overcome the restriction of the starving therapy.