Recently, diverse functional materials that take subcellular structures as therapeutic targets are playing increasingly important roles in cancer therapy. Here, particular emphasis is placed on four ...kinds of therapies, including chemotherapy, gene therapy, photodynamic therapy (PDT), and hyperthermal therapy, which are the most widely used approaches for killing cancer cells by the specific destruction of subcellular organelles. Moreover, some non‐drug‐loaded nanoformulations (i.e., metal nanoparticles and molecular self‐assemblies) with a fatal effect on cells by influencing the subcellular functions without the use of any drug molecules are also included. According to the basic principles and unique performances of each treatment, appropriate strategies are developed to meet task‐specific applications by integrating specific materials, ligands, as well as methods. In addition, the combination of two or more therapies based on multifunctional nanostructures, which either directly target specific subcellular organelles or release organelle‐targeted therapeutics, is also introduced with the intent of superadditive therapeutic effects. Finally, the related challenges of critical re‐evaluation of this emerging field are presented.
The rapid development in the field of subcellular targeted cancer therapy is reviewed systemically and comprehensively on account of six sets of treatment modalities: chemotherapy, gene therapy, PDT, hyperthermia, non‐drug‐loaded nanoformulations, and synergistic combined therapy.
Immunotherapy that can activate immunity or enhance the immunogenicity of tumors has emerged as one of the most effective methods for cancer therapy. Nevertheless, single‐mode immunotherapy is still ...confronted with several critical challenges, such as the low immune response, the low tumor infiltration, and the complex immunosuppression tumor microenvironment. Recently, the combination of immunotherapy with other therapeutic modalities has emerged as a powerful strategy to augment the therapeutic outcome in fighting against cancer. In this review, recent research advances of the combination of immunotherapy with chemotherapy, phototherapy, radiotherapy, sonodynamic therapy, metabolic therapy, and microwave thermotherapy are summarized. Critical challenges and future research direction of immunotherapy‐based cancer therapeutic strategy are also discussed.
Immunotherapy‐involved combination cancer therapy: the rapid development in the combination of immunotherapy with other therapeutic modalities for cancer therapy are systematically reviewed, and the critical challenges and future directions are also discussed.
This paper presents an airborne piezoelectric micromachined ultrasonic transducers (PMUTs) operated at low frequency (40-50 kHz) for long-range detection, where the acoustic absorption loss in air is ...relatively low (0.8-1 dB/m). The PMUTs made with single-crystal Lead Zirconate Titanate (PZT) enables a high piezoelectric coefficient (<inline-formula> <tex-math notation="LaTeX">{e} _{31, f} \approx ~16 </tex-math></inline-formula>- 24 C/<inline-formula> <tex-math notation="LaTeX">\text{m}^{{2}} </tex-math></inline-formula>), and a low dielectric constant (<inline-formula> <tex-math notation="LaTeX">\varepsilon _{\mathrm {r}}~\approx ~308 </tex-math></inline-formula>), achieving high PMUT transceiver efficiency. The <inline-formula> <tex-math notation="LaTeX">2\times 2 </tex-math></inline-formula> PMUT array achieves a very high sound pressure level (SPL) output of 109.4 dB at 26 cm distance. Different from conventional PZT PMUTs, this study utilized single-crystal PZT with a low permittivity to achieve a good acoustic reception, demonstrating the sensitivity of 2 mV/Pa. This work reports the PMUT design, modeling, fabrication, characterization, enabling a long-range detection of 4.8 meters in a pulse-echo experiment, which was conducted by a pair of <inline-formula> <tex-math notation="LaTeX">2\times 2 </tex-math></inline-formula> PMUT arrays with the matched resonances. 2020-0270
Poor tumor selectivity and short life span of reactive oxygen species (ROS) are two major challenges in photodynamic therapy (PDT). In this study, a self‐transformable pH‐driven membrane anchoring ...photosensitizer (pHMAPS) is used to realize tumor‐specific accumulation and in situ PDT on tumor cell membrane to maximize the therapeutic potency. It is found that pHMAPS was able to form α‐helix structure under acidic condition (pH 6.5 or 5.5), while remain random coil at normal pH of 7.4. This pH‐driven secondary structure switch enables the successful insertion of pHMAPS into membrane lipid bilayer, especially for cancerous cell membrane in the acidic tumor microenvironment. Under laser irradiation, cytotoxic ROS is generated in the immediate vicinity of cell membrane, resulting in superior cell killing effect in vitro and significant inhibition of tumor growth in vivo. Importantly, benefited from this membrane‐specific PDT, tumor growth‐induced hepatic, pulmonary, as well as osseous metastases of breast cancer cells are also retarded after PDT treatment. Thus, the membrane localized PDT by pHMAPS provides a simple but effective strategy to enhance the medical performance of photosensitizing agents in cancer therapy.
Membrane‐anchoring photodynamic therapy: A pH‐driven membrane‐anchoring photodynamic therapy is developed to inhibit tumor growth and metastasis. With the formation of α‐helix structure in tumor acidic microenvironment, pH‐driven membrane anchoring photosensitizer can rapidly insert into tumor cell membrane and the membrane localized photodynamic therapy (PDT) directly induces significant membrane damage, giving rise to superior cell killing effect and enhanced PDT.
Nucleic acid–modified UiO‐68 metal–organic framework nanoparticles, NMOFs, are loaded with the anticancer drug camptothecin (or drug models), and the loaded NMOFs are capped with sequence‐specific ...duplex units. The NMOFs are unlocked by the biocatalytic decomposition of the duplex capping units that result in the release of the drug (or drug models). The enzymes used are DNase I, a nicking enzyme (Nt.BbvCI), an endonuclease (EcoRI), and an exonuclease III (Exo III). Camptothecin‐loaded NMOFs, capped by tailored hairpin nucleic acids being cooperatively unlocked by adenosine triphosphate (ATP), that is overexpressed in cancer cells, and Exo III are prepared. The camptothecin‐loaded NMOFs reveal that selective cytotoxicity toward MDA‐MB‐231 cancer cells and ≈55% apoptosis of the cancer cells is observed after 5 days of treatment with the NMOFs, while only ≈15% apoptosis of epithelial MCF‐10A breast cells is observed.
Nucleic acid–capped drug‐loaded metal–organic framework nanoparticles (NMOFs) are unlocked by the biocatalytic degradation of the nucleic acid capping units, resulting in the release of the drug. By the capping of drug‐loaded NMOFs with hairpin units that include adenosine triphosphate (ATP)–aptamer sequences, the unlocking of the capping units, in the presence of ATP, proceeds. The drug‐loaded NMOFs reveal selective cytotoxicity toward MDA‐MB‐231 cancer cells.
UiO‐68 metal–organic framework nanoparticles (NMOFs) are loaded with a doxorubicin drug (fluorescent dye analogs) and locked by means of structurally engineered duplex nucleic acid structures, where ...one strand is covalently linked to the NMOFs and the second strand is hybridized with the anchor strand. Besides the complementarity of the second strand to the anchor sequence, it includes the complementary sequence to the microRNAs (miRNA)‐21 or miRNA‐221 that is specific miRNA biomarker for MCF‐7 breast cancer cells or OVCAR‐3 ovarian cancer cells. In the presence of the respective miRNA biomarkers, the miRNA‐induced displacement of the strand associated with the anchor strand proceeds, resulting in the release of DNA/miRNA duplexes. The released duplexes are, however, engineered to be digested in the presence of exonuclease III, Exo III, a process that recycles the miRNAs and provides the autonomous amplified unlocking of the NMOFs and the release of the doxorubicin load (or the fluorescent dye analogs) even at low concentrations of miRNA. Preliminary cell experiments reveal that the respective NMOFs are unlocked by the miRNA‐21 or miRNA‐221, resulting in selective cytotoxicity toward MCF‐7 breast cancer cells or OVCAR‐3 ovarian cancer cells.
miRNA‐responsive NMOFs: UiO‐68 metal–organic framework nanoparticles are loaded with doxorubicin and gated with specific miRNA‐responsive nucleic acid locks. In the presence of miRNA‐21 (a breast cancer biomarker) or miRNA‐221 (an ovarian cancer biomarker), the gates are unlocked, leading to the release of the drug. Selective cytotoxicity toward respective cancer cells is demonstrated.
Significance Whether infinitely fast spinning vortices can develop in initially smooth, incompressible inviscid flow fields in finite time is one of the most challenging problems in fluid dynamics. ...Besides being a difficult mathematical question that has remained open for more than 250 years, the problem also attracts great attention in the physics and engineering communities due to its potential connection to the onset of turbulence in viscous flows. This paper attempts to provide an affirmative answer to this long-standing open question from a numerical point of view, by describing a class of rotationally symmetric flows from which infinitely fast spinning vortices can form in finite time. It suggests, after decades of controversies, a promising direction to the resolution of the problem.
Spheroid-based three-dimensional (3D) liver culture models, offering a desirable biomimetic microenvironment, are useful for recapitulating liver functions in vitro. However, a user-friendly, robust ...and specially optimized method has not been well developed for a convenient, highly efficient, and safe in situ perfusion culture of spheroid-based 3D liver models. Here, we have developed a biomimetic and reversibly assembled liver-on-a-chip (3D-LOC) platform and presented a proof of concept for long-term perfusion culture of 3D human HepG2/C3A spheroids for building a 3D liver spheroid model. On the basis of a fast and reversible seal of concave microwell-based PDMS-membrane-PDMS sandwich multilayer chips, it enables a high-throughput and parallel perfusion culture of 1080 cell spheroids in a high mass transfer and low fluid shear stress biomimetic microenvironment as well as allowing the convenient collection and analysis of the cell spheroids. In terms of reducing spheroid loss and maintaining cell morphology and viability in long-term perfusion culture, the cell spheroids in the 3D-LOC were more safe and efficient. Notably, the polarisation, liver-specific functions, and metabolic activity of the cell spheroids in 3D-LOC were also remarkably improved and exhibited better long-term maintenance over conventional perfusion methods. Additionally, a robust micromilling method that incorporates secondary PDMS coating techniques (SPCs) for fabricating V-shaped concave microwells was also developed. The V-shaped concave microwell arrays exhibited a higher distribution density and aperture ratio, making it easy to form large-scale and uniform-sized cell spheroids with minimum cell loss. In summary, the proposed 3D-LOC could provide a convenient and robust solution for the long-term safe perfusion culture of hepatic spheroids and be beneficial for a variety of potential applications including development of bio-artificial livers, disease modeling, and drug toxicity screening.
Abstract Supramolecular photosensitizers (supraPSs) have emerged as effective photodynamic therapy (PDT) agents. Here, we propose the assembling capacity of supraPSs as a new strategy to construct ...theranostic nanoplatform with versatile functions aming at high-performance tumor therapy. By coating tirapazamine (TPZ)-loaded mesoporous silica nanoparticles (MSNs) with layer-by-layer (LbL) assembled multilayer, the versatile nanoplatform (TPZ@MCMSN-Gd3+ ) was obtained with the formation of supraPSs via host-guest interaction and the chelation with paramagnetic Gd3+ . The TPZ@MCMSN-Gd3+ could be specifically uptaken by CD44 receptor overexpressed tumor cells and respond to hyaluronidase (HAase) to trigger the release of therapeutics. As confirmed by in vivo studies, TPZ@MCMSN-Gd3+ showed preferential accumulation in tumor site and significantly inhibited the tumor progression by the collaboration of PDT and bioreductive chemotherapy under NIR fluorescence/MR imaging guidance. Taken together, this supraPSs based strategy paves a new paradigm of the way for the construction of theranostic nanoplatform.
To integrate treatments of photothermal therapy, photodynamic therapy (PDT), and chemotherapy, this study reports on a multifunctional nanocomposite based on mesoporous silica‐coated gold nanorod for ...high‐performance oncotherapy. Gold nanorod core is used as the hyperthermal agent and mesoporous silica shell is used as the reservoir of photosensitizer (Al(III) phthalocyanine chloride tetrasulfonic acid, AlPcS4). The mesoporous silica shell is modified with β‐cyclodextrin (β‐CD) gatekeeper via redox‐cleavable Pt(IV) complex for controlled drug release. Furthermore, tumor targeting ligand (lactobionic acid, LA) and long‐circulating poly(ethylene glycol) chain are introduced via host–guest interaction. It is found that the nanocomposite can specifically target to hepatoma cells by virtue of the LA targeting moiety. Due to the abundant existence of reducing agents within tumor cells, β‐CD can be removed by reducing the Pt(IV) complex to active cisplatin drug for chemotherapy, along with the releasing of entrapped AlPcS4 for effective PDT. As confirmed by in vitro and in vivo studies, the nanocomposite exhibits an obvious near‐infrared induced thermal effect, which significantly improves the PDT and chemotherapy efficiency, resulting in a superadditive therapeutic effect. This collaborative strategy paves the way toward high‐performance nanotherapeutics with a superior antitumor efficacy and much reduced side effects.
Collaborative tumor‐targeted therapy: A highly integrated nanocomposite is constructed based on mesoporous silica‐coated gold nanorods for tumor‐targeted therapy by virtue of the GNR‐mediated PTT, PS‐mediated PDT, and platinum‐based chemotherapy. In vitro and in vivo results confirm that this multifunctional nanocomposite can serve as an ideal platform for tri‐model high‐performance tumor therapy.
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