Fast‐Clearable Nanocarriers Conducting Chemo/Photothermal Combination Therapy to Inhibit Recurrence of Malignant Tumors

Inhomogeneous heating by photothermal therapy (PTT) during cancer treatment often results in the recurrence of tumors. Thus, integrating PTT with chemotherapy (CHT) may provide a complementary treatment for enhanced therapeutic efficiency. Herein, this study develops a hollow structured polymer–silica nanohybrid (HPSN) as a nanocarrier to simultaneously deliver the anticancer drug paclitaxel and photothermal agent palladium phthalocyanine to tumors through enhanced permeation and the retention effect. A combinational CHT/PTT therapy on mice bearing aggressive tumor grafts is conducted. The highly malignant tumor model, which recurs after sole treatment of PTT, can be eradicated by the combined CHT/PTT treatment. In addition, most of the off‐targeted HPSN nanocarriers can be excreted through a hepatobiliary pathway in about 10 d. Serology results show that the fast‐clearable HPSN can significantly reduce the side effect of the loaded paclitaxel drug. The present work provides an alternative approach for combinational cancer treatment with high therapeutic efficiency.     

Peptide Nanotube‐Templated Biomineralization of Cu2−xS Nanoparticles for Combination Treatment of Metastatic Tumor

1D peptide nanostructures (i.e., peptide nanotubes, PNTs) exhibit tunable chemo‐physical properties and functions such as improved tissue adhesion, increased cellular uptake, and elongated blood circulation. In this study, the application of PNTs as a desirable 1D template for biomineralization of Cu_2?xS nanoparticles (Cu_2?xS NPs, x = 1–2) is reported. Monodisperse Cu_2?xS NPs are uniformly coated on the peptide nanotubes owing to the specific high binding affinity of Cu ions to the imidazole groups exposed on the surface of nanotubes. The Cu_2?xS NP–coated PNTs are further covalently grafted with an oxaliplatin prodrug (Pt–CuS–PNTs) to construct a versatile nanoplatform for combination cancer therapy. Upon 808 nm laser illumination, the nanoplatform induces significant hyperthermia effect and elicits reactive oxygen species generation through electron transfer and Fenton‐like reaction. It is demonstrated that the versatile nanoplatform dramatically inhibits tumor growth and lung metastasis of melanoma in a B16‐F10 melanoma tumor‐bearing mouse model by combined photo‐ and chemotherapy. This study highlights the ability of PNTs for biomineralization of metal ions and the promising potential of such nanoplatforms for cancer treatment.     

Albumin‐Templated Manganese Dioxide Nanoparticles for Enhanced Radioisotope Therapy

Although nanoparticle‐based drug delivery systems have been widely explored for tumor‐targeted delivery of radioisotope therapy (RIT), the hypoxia zones of tumors on one hand can hardly be reached by nanoparticles with relatively large sizes due to their limited intratumoral diffusion ability, on the other hand often exhibit hypoxia‐associated resistance to radiation‐induced cell damage. To improve RIT treatment of solid tumors, herein, radionuclide ¹³¹I labeled human serum albumin (HSA)‐bound manganese dioxide nanoparticles (¹³¹I‐HSA‐MnO₂) are developed as a novel RIT nanomedicine platform that is responsive to the tumor microenvironment (TME). Such ¹³¹I‐HSA‐MnO₂ nanoparticles with suitable sizes during blood circulation show rather efficient tumor passive uptake owing to the enhanced permeability and retention effect, as well as little retention in other normal organs to minimize radiotoxicity. The acidic TME can trigger gradual degradation of MnO₂ and thus decomposition of ¹³¹I‐HSA‐MnO₂ nanoparticles into individual ¹³¹I‐HSA with sub‐10 nm sizes and greatly improves intratumoral diffusion. Furthermore, oxygen produced by MnO₂‐triggered decomposition of tumor endogenous H₂O₂ would be helpful to relieve hypoxia‐associated RIT resistant for those tumors. As the results, the ¹³¹I‐HSA‐MnO₂ nanoparticles appear to be a highly effective RIT agent showing great efficacy in tumor treatment upon systemic administration.     

Cancer‐Cell Targeting and Photoacoustic Therapy Using Carbon Nanotubes as “Bomb” Agents

A unique approach using the large photoacoustic effect of single‐walled carbon nanotubes (SWNTs) for targeting and selective destruction of cancer cells is demonstrated. SWNTs exhibit a large photoacoustic effect in suspension under the irradiation of a 1064‐nm Q‐switched millisecond pulsed laser and trigger a firecracker‐like explosion at the nanoscale. By using such an explosion, a photoacoustic agent is developed by functionalizing the SWNTs with folate acid (FA) that can selectively bind to cancer cells overexpressing folate receptor on the surface of the cell membrane and kill them through SWNT explosion inside the cells under the excitation of millisecond pulsed laser. The uptake pathway of folate‐conjugated SWNTs into cancer cells is investigated via fluorescence imaging and it is found that the FA‐SWNTs can enter into cancer cells selectively with a high targeting capability of 17–28. Under the treatment of 1064‐nm millisecond pulsed laser, 85% of cancer cells with SWNT uptake die within 20 s, while 90% of the normal cells remain alive due to the lack of SWNTs inside cells. Temperature changes during laser treatment are monitored and no temperature increases of more than ± 3 °C are observed. With this approach, the laser power used for cancer killing is reduced 150–1500 times and the therapy efficiency is improved. The death mechanism of cancer cells caused by the photoacoustic explosion of SWNTs is also studied and discussed in detail. These discoveries provide a new way to use the photoacoustic properties of SWNTs for therapeutic applications.     

Cell Membrane Camouflaged Hydrophobic Drug Nanoflake Sandwiched with Photosensitizer for Orchestration of Chemo‐Photothermal Combination Therapy

Many candidate anticancer drugs have suffered from their intrinsic hydrophobicity, which poses several obstacles for clinical application. To overcome this challenge and further improve the performance, herein a nanocrystal‐based biomimetic formulation with a sandwich structure is developed. As the core, flake shaped nanocrystals (NCs) with high loading of the hydrophobic drug hydroxycamptothecin (HCPT) are synthesized via a mild nanoprecipitation process by exploring the template effect of serum albumin. Meanwhile, the camouflaged cancer cell membrane (CM) composed of plentiful membrane proteins endows the NCs with homotypic targeting capacity at tumor sites. In addition, the photosensitizer indocyanine green sandwiched between NCs and CM not only converts near infrared light to heat for photothermal treatment but also improves the dissolution of HCPT NCs for chemotherapy. These features corporately achieve the orchestration of chemo‐photothermal combination therapy and completely inhibit tumor growth with few adverse effects, showing promise as a new modality for the utilization of hydrophobic drugs to treat cancer.     

Sniffing the Unique “Odor Print” of Non‐Small‐Cell Lung Cancer with Gold Nanoparticles

A highly sensitive and fast‐response array of sensors based on gold nanoparticles, in combination with pattern recognition methods, can distinguish between the odor prints of non‐small‐cell lung cancer and negative controls with 100% accuracy, with no need for preconcentration techniques. Additionally, preliminary results indicate that the same array of sensors might serve as a better tool for understanding the biochemical source of volatile organic compounds that might occur in cancer cells and appear in the exhaled breath, as compared to traditional spectrometry techniques. The reported results provide a launching pad to initiate a bedside tool that might be able to screen for early stages of lung cancer and allow higher cure rates. In addition, such a tool might be used for the immediate diagnosis of fresh (frozen) tissues of lung cancer in operating rooms, where a dichotomic diagnosis is crucial to guide surgeons.     

Supramolecular Protein Nanodrugs with Coordination‐ and Heating‐Enhanced Photothermal Effects for Antitumor Therapy

Supramolecular protein nanodrugs provide opportunities for improving antitumor therapeutic efficiency and lowering toxicity. However, protein nanodrugs that have robust structural stability and enhanced therapeutic efficiency are still in infancy. In this study, photothermal protein nanodrugs are constructed through a supramolecular approach along with heating by using proteins, photosensitizers, and metal ions as the building blocks. The metal coordination and heating improve not only the structural stability but also photothermal performance of the resulting nanodrugs. By virtue of the first integration of coordination‐ and heating‐enhanced photothermal effects, the nanodrugs show superior photothermal conversion efficiency, enhanced tumor accumulation, and improved tumor inhibition. Metal coordination and heating are versatile to be applied for various protein nanodrugs. Hence, this study provides insights for the construction of highly efficient photothermal nanodrugs and thus will be beneficial to precision theranostics.     

Sub‐10‐nm Pd Nanosheets with Renal Clearance for Efficient Near‐Infrared Photothermal Cancer Therapy

Efficient renal clearance is of fundamentally important property of nanoparticles for their in vivo biomedical applications. In this work, we report the successful synthesis of ultra‐small Pd nanosheets (SPNS) with an average diameter of 4.4 nm and their application in photothermal cancer therapy using a near infrared laser. The ultra‐small Pd nanosheets have strong optical absorption in the NIR region and high photothermal conversion efficiency (52.0%) at 808 nm. After being surface‐functionalized with reduced glutathione (GSH), the SPNS‐GSH was administered to mice to investigate the biodistribution, photothermal efficacy and tumor ablation in vivo. The in vivo photothermal therapy studies clearly demonstrate that surface modification with GSH allows the nanosheets to exhibit prolonged blood circulation and thus high accumulation in tumors. Upon 808 nm NIR irradiation, the tumors can be completely ablated. More importantly, with the size below the renal filtration limit (<10 nm), the GSHylated Pd nanosheets can be nicely cleared from body through the renal excretion route and into urine. Together with the high efficacy of NIR photothermal therapy, the unique renal clearance properties make the ultra‐small Pd nanosheets promising for practical use in photothermal cancer therapy.     

Core–Satellite Polydopamine–Gadolinium‐Metallofullerene Nanotheranostics for Multimodal Imaging Guided Combination Cancer Therapy

Integration of magnetic resonance imaging (MRI) and other imaging modalities is promising to furnish complementary information for accurate cancer diagnosis and imaging‐guided therapy. However, most gadolinium (Gd)–chelator MR contrast agents are limited by their relatively low relaxivity and high risk of released‐Gd‐ions‐associated toxicity. Herein, a radionuclide‐⁶⁴Cu‐labeled doxorubicin‐loaded polydopamine (PDA)–gadolinium‐metallofullerene core–satellite nanotheranostic agent (denoted as CDPGM) is developed for MR/photoacoustic (PA)/positron emission tomography (PET) multimodal imaging‐guided combination cancer therapy. In this system, the near‐infrared (NIR)‐absorbing PDA acts as a platform for the assembly of different moieties; Gd₃N@C₈₀, a kind of gadolinium metallofullerene with three Gd ions in one carbon cage, acts as a satellite anchoring on the surface of PDA. The as‐prepared CDPGM NPs show good biocompatibility, strong NIR absorption, high relaxivity (r ₁ = 14.06 mM^?1 s^?1), low risk of release of Gd ions, and NIR‐triggered drug release. In vivo MR/PA/PET multimodal imaging confirms effective tumor accumulation of the CDPGM NPs. Moreover, upon NIR laser irradiation, the tumor is completely eliminated with combined chemo‐photothermal therapy. These results suggest that the CDPGM NPs hold great promise for cancer theranostics.     

Lipase‐Triggered Water‐Responsive “Pandora's Box” for Cancer Therapy: Toward Induced Neighboring Effect and Enhanced Drug Penetration

Insufficient drug release as well as poor drug penetration are major obstacles for effective nanoparticles (NPs)‐based cancer therapy. Herein, the high aqueous instability of amorphous calcium carbonate (ACC) is employed to construct doxorubicin (DOX) preloaded and monostearin (MS) coated “Pandora's box” (MS/ACC–DOX) NPs for lipase‐triggered water‐responsive drug release in lipase‐overexpressed tumor tissue to induce a neighboring effect and enhance drug penetration. MS as a solid lipid can prevent potential drug leakage of ACC–DOX NPs during the circulatory process, while it can be readily be disintegrated in lipase‐overexpressed SKOV3 cells to expose the ACC–DOX core. The high aqueous instability of ACC will lead to burst release of the encapsulated DOX to induce apoptosis and cytotoxicity to kill the tumor cells. The liberated NPs from the dead or dying cells continue to respond to the ubiquitous aqueous environment to sufficiently release DOX once unpacked, like the “Pandora's box”, leading to severe cytotoxicity to neighboring cells (neighboring effect). Moreover, the continuously released free DOX molecules can readily diffused through the tumor extracellular matrix to enhance drug penetration to deep tumor tissue. Both effects contribute to achieve elevated antitumor benefits.     

Cationic Bovine Serum Albumin Based Self‐Assembled Nanoparticles as siRNA Delivery Vector for Treating Lung Metastatic Cancer

It is generally believed that intravenous application of cationic vectors is limited by the binding of abundant negatively charged serum components, which may cause rapid clearance of the therapeutic agent from the blood stream. However, previous studies show that systemic delivery of cationic gene vectors mediates specific and efficient transfection within the lung, mainly as a result of interaction of the vectors with serum proteins. Based on these findings, a novel and charge‐density‐controllable siRNA delivery system is developed to treat lung metastatic cancer by using cationic bovine serum albumin (CBSA) as the gene vector. By surface modification of BSA, CBSA with different isoelectric points (pI) is synthesized and the optimal cationization degree of CBSA is determined by considering the siRNA binding and delivery ability, as well as toxicity. The CBSA can form stable nanosized particles with siRNA and protect siRNA from degradation. CBSA also shows excellent abiliies to intracellularly deliver siRNA and mediate significant accumulation in the lung. When Bcl2‐specific siRNA is introduced to this system, CBSA/siRNA nanoparticles exhibit an efficient gene‐silencing effect that induces notable cancer cell apoptosis and subsequently inhibits the tumor growth in a B16 lung metastasis model. These results indicate that CBSA‐based self‐assembled nanoparticles can be a promising strategy for a siRNA delivery system for lung targeting and metastatic cancer therapy.     

An “On‐Site Transformation” Strategy for Treatment of Bacterial Infection

To date, numerous nanosystems have been developed as antibiotic replacements for bacterial infection treatment. However, these advanced systems are limited owing to their nontargeting accumulation and the consequent side effects. Herein, transformable polymer–peptide biomaterials have been developed that enable specific accumulation in the infectious site and long‐term retention, resulting in enhanced binding capability and killing efficacy toward bacteria. The polymer–peptide conjugates are composed of a chitosan backbone and two functional peptides, i.e., an antimicrobial peptide and a poly(ethylene glycol)‐tethered enzyme‐cleavable peptide (CPC‐1). The CPC‐1 initially self‐assembles into nanoparticles with pegylated coronas. Upon the peptides are cleaved by the gelatinase secreted by a broad spectrum of bacterial species, the resultant compartments of nanoparticles spontaneously transformed into fibrous nanostructures that are stabilized by enhanced chain–chain interaction, leading to exposure of antimicrobial peptide residues for multivalent cooperative electrostatic interactions with bacterial membranes. Intriguingly, the in situ morphological transformation also critically improves the accumulation and retention of CPC‐1 in infectious sites in vivo, which exhibits highly efficient antibacterial activity. This proof‐of‐concept study demonstrates that pathological environment‐driven smart self‐assemblies may provide a new idea for design of high‐performance biomaterials for disease diagnostics and therapeutics.     

A Hypoxia‐Responsive Albumin‐Based Nanosystem for Deep Tumor Penetration and Excellent Therapeutic Efficacy

Uncontrolled cancer cell proliferation, insufficient blood flow, and inadequate endogenous oxygen lead to hypoxia in tumor tissues. Herein, a unique type of hypoxia‐responsive human serum albumin (HSA)‐based nanosystem (HCHOA) is reported, prepared by cross‐linking the hypoxia‐sensitive azobenzene group between photosensitizer chlorin e6 (Ce6)‐conjugated HSA (HC) and oxaliplatin prodrug‐conjugated HSA (HO). The HCHOA nanosystem is stable under normal oxygen partial pressure with a size of 100–150 nm. When exposed to the hypoxic tumor microenvironment, the nanosystem can quickly dissociate into ultrasmall HC and HO therapeutic nanoparticles with a diameter smaller than 10 nm, significantly enabling their enhanced intratumoral penetration. After the dissociation, the quenched fluorescence of Ce6 in the produced HC nanoparticles can be recovered for bioimaging. At the same time, the production of singlet oxygen is increased because of the enhancement in the photoactivity of the photosensitizer. On account of these improvements, combined photodynamic therapy and chemotherapy is realized to display superior antitumor efficacy in vivo. Based on this simple strategy, it is possible to achieve the dissociation of hypoxic‐responsive nanosystem to enhance the tumor penetration and therapeutic effect.     

A “Missile‐Detonation” Strategy to Precisely Supply and Efficiently Amplify Cerenkov Radiation Energy for Cancer Theranostics

Cerenkov radiation (CR) from radionuclides can act as a built‐in light source for cancer theranostics, opening a new horizon in biomedical applications. However, considerably low tumor‐targeting efficiency of existing radionuclides and radionuclide‐based nanomedicines limits the efficacy of CR‐induced theranostics (CRIT). It remains a challenge to precisely and efficiently supply CR energy to the tumor site. Here, a “missile‐detonation” strategy is reported, in which a high dose of p‐SCN‐Bn‐deferoxamine‐porphyrin‐PEG nanocomplex (Df‐PPN) is first adminstered as a CR energy receiver/missile to passively target to tumor, and then a low dose of the ⁸⁹Zr‐labeled Df‐PPN is administrated as a CR energy donor/detonator, which can be visualized and quantified by Cerenkov energy transfer imaging, positron‐emission tomography, and fluorescence imaging. Based on homologous properties, the colocalization of Df‐PPN and ⁸⁹Zr‐Df‐PPN in the tumor site is maximized and efficient CR energy transfer is enabled, which maximizes the tumor‐targeted CRIT efficacy in an optimal spatiotemporal setting while also reducing adverse off‐target effects from CRIT. This precise and efficient CRIT strategy causes significant tumor vascular damage and inhibited tumor growth.