Recent progress in MoS2 nanostructures for biomedical applications: Experimental and computational approach.

In the category of 2D materials, MoS2 a transition metal dichalcogenide, is a novel and intriguing class of materials with interesting physicochemical properties, explored in applications ranging from cutting-edge optoelectronic to the frontiers of biomedical and biotechnology. MoS2 nanostructures an alternative to heavy toxic metals exhibit biocompatibility, low toxicity and high stability, and high binding affinity to biomolecules. MoS2 nanostructures provide a lot of opportunities for the advancement of novel biosensing, nanodrug delivery system, electrochemical detection, bioimaging, and photothermal therapy. Much efforts have been made in recent years to improve their physiochemical properties by developing a better synthesis approach, surface functionalization, and biocompatibility for their safe use in the advancement of biomedical applications. The understanding of parameters involved during the development of nanostructures for their safe utilization in biomedical applications has been discussed. Computational studies are included in this article to understand better the properties of MoS2 and the mechanism involved in their interaction with biomolecules. As a result, we anticipate that this combined experimental and computational studies of MoS2 will inspire the development of nanostructures with smart drug delivery systems, and add value to the understanding of two-dimensional smart nano-carriers.

Drug repurposing-based nanoplatform via modulating autophagy to enhance chemo-phototherapy against colorectal cancer.

Multi-modal combination therapy is regarded as a promising approach to cancer treatment. Combining chemotherapy and phototherapy is an essential multi-modal combination therapy endeavor. Ivermectin (IVM) is a potent antiparasitic agent identified as having potential antitumor properties. However, the fact that it induces protective autophagy while killing tumor cells poses a challenge to its further application. IR780 iodide (IR780) is a near-infrared (NIR) dye with outstanding photothermal therapy (PTT) and photodynamic therapy (PDT) effects. However, the hydrophobicity, instability, and low tumor uptake of IR780 limit its clinical applications. Here, we have structurally modified IR780 with hydroxychloroquine, an autophagy inhibitor, to synthesize a novel compound H780. H780 and IVM can form H780-IVM nanoparticles (H-I NPs) via self-assembly. Using hyaluronic acid (HA) to modify the H-I NPs, a novel nano-delivery system HA/H780-IVM nanoparticles (HA/H-I NPs) was synthesized for chemotherapy-phototherapy of colorectal cancer (CRC). Under NIR laser irradiation, HA/H-I NPs effectively overcame the limitations of IR780 and IVM and exhibited potent cytotoxicity. In vitro and in vivo experiment results showed that HA/H-I NPs exhibited excellent anti-CRC effects. Therefore, our study provides a novel strategy for CRC treatment that could enhance chemo-phototherapy by modulating autophagy.

Dual-Functionalized Nanoliposomes Achieve a Synergistic Chemo-Phototherapeutic Effect.

The enhancement of photodynamic therapy (PDT) effectiveness by combining it with other treatment modalities and improved drug delivery has become an interesting field in cancer research. We have prepared and characterized nanoliposomes containing the chemotherapeutic drug irinotecan (CPT11lip), the photodynamic agent protoporphyrin IX (PpIXlip), or their combination (CPT11-PpIXlip). The effects of individual and bimodal (chemo-phototherapeutic) treatments on HeLa cells have been studied by a combination of biological and photophysical studies. Bimodal treatments show synergistic cytotoxic effects on HeLa cells at relatively low doses of PpIX/PDT and CPT11. Mechanistic cell inactivation studies revealed mitotic catastrophe, apoptosis, and senescence contributions. The enhanced anticancer activity is due to a sustained generation of reactive oxygen species, which increases the number of double-strand DNA breaks. Bimodal chemo-phototherapeutic liposomes may have a very promising future in oncological therapy, potentially allowing a reduction in the CPT11 concentration required to achieve a therapeutic effect and overcoming resistance to individual cancer treatments.

Biodegradable Nanocomposite with Dual Cell-Tissue Penetration for Deep Tumor Chemo-Phototherapy.

Chemo-phototherapy, as a promising cancer combination therapy strategy, has attracted widespread attention. However, the complex tumor microenvironment restricts the penetration depth of chemo-phototherapy agents in the tumor region. Here, biodegradable amphiphilic gelatin (AG) wrapped nanocomposite (PRDCuS@AG) composed of doxorubicin and copper sulfide (CuS)-loaded dendrimer is designed for deep tumor chemo-phototherapy. PR in PRDCuS@AG represents arginine-conjugated polyamidoamine dendrimer. PRDCuS@AG can rapidly biodegrade into PRDCuS by matrix metalloproteinases under near-infrared light irradiation. The resulted PRDCuS harbors dual cell-tissue penetration ability, which can effectively penetrate deep into the tumor tissue. In particular, PRDCuS@AG achieves photoacoustic imaging-guided synergistic chemo-phototherapy with 97% of tumor inhibition rate. Moreover, PRDCuS@AG can further degrade into 3 nm ultrasmall CuS, which can be eliminated from the body after treatment to avoid side effects. This strategy provides an insight that the development of chemo-phototherapy agents with high penetration ability to overcome the limitation of current deep tumor therapy.

Chemo-photothermal nanoplatform with diselenide as the key for ferroptosis in colorectal cancer.

Colorectal cancer (CRC) is a prevalent clinical malignancy of the gastrointestinal system, and its clinical drug resistance is the leading cause of poor prognosis. Mechanistically, CRC cells possess a specific oxidative stress defense mechanism composed of a significant number of endogenous antioxidants, such as glutathione, to combat the damage produced by drug-induced excessive reactive oxygen species (ROS). We report on a new anti-CRC nanoplatform, a multifunctional chemo-photothermal nanoplatform based on Camptothecin (CPT) and IR820, an indocyanine dye. The implementation of a GSH-triggered ferroptosis-integrated tumor chemo-photothermal nanoplatform successfully addressed the poor targeting ability of CPT and IR820 while exhibiting significant growth inhibitory effects on CRC cells. Mechanistically, to offset the oxidative stress created by the broken SeSe bonds, endogenous GSH was continuously depleted, which inactivated GPX4 to accumulate lipid peroxides and induce ferroptosis. Concurrently, exogenously administered linoleic acid was oxidized under photothermal conditions, resulting in an increase in LPO accumulation. With the breakdown of the oxidative stress defense system, chemotherapeutic efficacy could be effectively enhanced. In combination with photoacoustic imaging, the nanoplatform could eradicate solid tumors by means of ferroptosis-sensitized chemotherapy. This study indicates that chemotherapy involving a ferroptosis mechanism is a viable method for the treatment of CRC.

A Multifunctional Bimetallic Nanoplatform for Synergic Local Hyperthermia and Chemotherapy Targeting HER2-Positive Breast Cancer.

Anti-HER2 (human epidermal growth factor receptor 2) therapies significantly increase the overall survival of patients with HER2-positive breast cancer. Unfortunately, a large fraction of patients may develop primary or acquired resistance. Further, a multidrug combination used to prevent this in the clinic places a significant burden on patients. To address this issue, this work develops a nanotherapeutic platform that incorporates bimetallic gold-silver hollow nanoshells (AuAg HNSs) with exceptional near-infrared (NIR) absorption capability, the small-molecule tyrosine kinase inhibitor pyrotinib (PYR), and Herceptin (HCT). This platform realizes targeted delivery of multiple therapeutic effects, including chemo-and photothermal activities, oxidative stress, and immune response. In vitro assays reveal that the HCT-modified nanoparticles exhibit specific recognition ability and effective internalization by cells. The released PYR inhibit cell proliferation by downregulating HER2 and its associated pathways. NIR laser application induces a photothermal effect and tumor cell apoptosis, whereas an intracellular reactive oxygen species burst amplifies oxidative stress and triggers cancer cell ferroptosis. Importantly, this multimodal therapy also promotes the upregulation of genes related to TNF and NF-κB signaling pathways, enhancing immune activation and immunogenic cell death. In vivo studies confirm a significant reduction in tumor volume after treatment, substantiating the potential effectiveness of these nanocarriers.

Targeted chemo-phototherapy in red light with novel doxorubicin and iron(III) complex-functionalized gold nanoconjugate (Dox-Fe@FA-AuNPs).

The anticancer efficacy of doxorubicin, an anthracycline-based and FDA-approved chemotherapeutic drug, is significantly hindered by acquired chemoresistance and severe side effects, despite its potent anticancer properties. To overcome these challenges, we developed an innovative therapeutic formulation that integrates targeted chemotherapy and phototherapy within a single platform using gold nanoparticles (AuNPs). This novel nanoconjugate, designated as Dox-Fe@FA-AuNPs, is co-functionalized with folic acid, doxorubicin, and an iron(III)-phenolate/carboxylate complex, enabling cancer-specific drug activation. Here, we report the synthesis, characterization, and comprehensive physico-chemical and biological evaluations of Dox-Fe@FA-AuNPs. The nanoconjugate exhibited excellent solubility, stability, and enhanced cellular uptake in folate receptor-positive cancer cells. The nanoconjugate was potently cytotoxic against HeLa and MDA-MB-231 cancer cells (HeLa: 105.5 ± 16.52 µg mL-1; MDA-MB-231: 112.0 ± 12.31 µg mL-1; MDA-MB-231 (3D): 156.31 ± 19.35 µg mL-1) while less cytotoxic to the folate(-) cancer cells (MCF-7, A549 and HepG2). The cytotoxicity was attributed to the pH-dependent release of doxorubicin, which preferentially occurs in the acidic tumor microenvironment. Additionally, under red light irradiation, the nanoconjugate generated ROS, inducing caspase-3/7-dependent apoptosis with a photo-index (PI) >50, and inhibited cancer cell migration. Our findings underscore the potential of Dox-Fe@FA-AuNPs as a highly effective and sustainable platform for targeted chemo-phototherapy.

Dual-targeted delivery of paclitaxel and indocyanine green with aptamer-modified ferritin for synergetic chemo-phototherapy.

The combination of phototherapy and chemotherapy has become attractive and effective cancer treatment. However, the accurate delivery of both chemo-phototherapy drugs to the target site as well as the development of high-efficient phototherapy and chemotherapy drugs remain major challenges. In this study, indocyanine green (ICG) and paclitaxel (PTX)-loaded aptamer ferritin (HAS1411-PTX-ICG) was developed as a biocompatible nanoplatform for combined chemo/photothermal/photodynamic (PTT/PDT) therapy that was safe and highly effective against tumors. HAS1411 was prepared by coupling aptamer AS1411 to the surface of human H chain ferritin (HFtn) by the carbon diimide method to further enhance the targeting of HFtn. Both ICG and PTX were effectively encapsulated in the HAS1411 by incubation at 60 â„ƒ. Moreover, under near-infrared (NIR) light irradiation, HAS1411 enhanced the photothermal effect and cell internalization of ICG, as well as the production of reactive oxygen species in cancer cells. HAS1411-PTX-ICG displayed effective cytotoxicity and a significant tumor spheroids inhibitory effect owning to the improved internalization of PTX and ICG mediated by TfR1 and nucleolin dual receptors. Co-loaded PTX combined with ICG can produce chemo/PTT/PDT under near-infrared (NIR) light irradiation, enhancing the anti-tumor effect. The dual-targeting HAS1411 nanocarrier developed in this study can be a promising delivery system for cancer therapy and the fabricated HAS1411-PTX-ICG possesses potential application in chemo-phototherapy.

Self-Assembled Nanodelivery System with Rapamycin and Curcumin for Combined Photo-Chemotherapy of Breast Cancer.

Nanodelivery systems combining photothermal therapy (PTT) and chemotherapy (CT), have been widely used to improve the efficacy and biosafety of chemotherapeutic agents in cancer. In this work, we constructed a self-assembled nanodelivery system, formed by the assembling of photosensitizer (IR820), rapamycin (RAPA), and curcumin (CUR) into IR820-RAPA/CUR NPs, to realize photothermal therapy and chemotherapy for breast cancer. The IR820-RAPA/CUR NPs displayed a regular sphere, with a narrow particle size distribution, a high drug loading capacity, and good stability and pH response. Compared with free RAPA or free CUR, the nanoparticles showed a superior inhibitory effect on 4T1 cells in vitro. The IR820-RAPA/CUR NP treatment displayed an enhanced inhibitory effect on tumor growth in 4T1 tumor-bearing mice, compared to free drugs in vivo. In addition, PTT could provide mild hyperthermia (46.0 °C) for 4T1 tumor-bearing mice, and basically achieve tumor ablation, which is beneficial to improving the efficacy of chemotherapeutic drugs and avoiding damage to the surrounding normal tissue. The self-assembled nanodelivery system provides a promising strategy for coordinating photothermal therapy and chemotherapy to treat breast cancer.

Aptamer and Peptide-Engineered Polydopamine Nanospheres for Target Delivery and Tumor Perfusion in Synergistic Chemo-Phototherapy of Pancreatic Cancer.

Pancreatic cancer (PC) is the fourth leading cause of cancer death, and the 5 year survival rate is only 4%. Chemotherapy is the treatment option for the majority of PC patients diagnosed at an advanced stage, whereas the desmoplastic stroma of PC could block the perfusion of chemotherapeutic agents to tumor tissues and contribute generally to chemoresistance. Therefore, the clinical status of PC calls for an urgent exploration in the effective treatment strategy. Chemo-phototherapy is an emerging modality against malignant tumors, but owing to the low targeting ability of theranostic agents or unspecific accumulation in the tumor region, majority of chemo-phototherapy techniques have disappointing therapeutic efficiencies. Herein, we have explored CD71-specific targeting aptamers and paclitaxel (PTX)-modified polydopamine (PDA) nanospheres with the conjugation of peptidomimetic AV3 (termed Apt-PDA@PTX/AV3 bioconjugates) to specifically target and combat PC in vivo by synergistic chemo-phototherapy. After the delivery of nanotheranostic agents to the tumor microenvironment (TME) or subsequent endocytic uptake by PC cells, a simultaneous release of AV3 and PTX from Apt-PDA@PTX/AV3 bioconjugates via near-infrared (NIR) irradiation can decrease desmoplastic stroma to enhance tumor perfusion and tumor-killing effects. Meanwhile, PDA cores utilize NIR laser to create unendurable hyperthermia within TME to "cook" tumors. Taken together, the current study finally suggests that our Apt-PDA@PTX/AV3 bioconjugates could act as a novel therapeutic approach by synergistic chemo-phototherapy for the programmable inhibition of PC.

Anti-Glioma Activity Achieved by Dual Blood-Brain Barrier/Glioma Targeting Naive Chimeric Peptides-Based Co-Assembled Nanophototheranostics.

Peptide monomers can either self-assemble with themselves enacting a solo-component assembly or they can co-assemble by interacting with other suitable partners to mediate peptide co-assembly. Peptide co-assemblies represent an innovative class of naive, multifunctional, bio-inspired supramolecular constructs that result in the production of nanostructures with widespread functional, structural, and chemical multiplicity. Herein, the co-assembly of novel chimeric peptides (conjugates of T7 (HAIYPRH)/t-Lyp-1 (CGNKRTR) peptides and aurein 1.2 (GLFDIIKKIAESF)) has been explored as a means to produce glioma theranostics exhibiting combinatorial chemo-phototherapy. Briefly, we have reported here the design and solid phase synthesis of a naive generation of twin-functional peptide drugs incorporating the blood-brain barrier (BBB) and glioma dual-targeting functionalities along with anti-glioma activity (G-Anti G and B-Anti G). Additionally, we have addressed their multicomponent co-assembly and explored their potential application as glioma drug delivery vehicles. Our naive peptide drug-based nanoparticles (NPs) successfully demonstrated a heightened glioma-specific delivery and anti-glioma activity. Multicomponent indocyanine green (ICG)-loaded peptide co-assembled NPs (PINPs: with a hydrodynamic size of 348 nm and a zeta-potential of 5 mV) showed enhanced anti-glioma responses in several cellular assays involving C6 cells. These included a mass demolition with no wound closure (i.e., a 100% cell destruction) and around 63% collaborative chemo-phototoxicity (with both a photothermal and photodynamic effect) after near infrared (NIR) 808 laser irradiation. The dual targeting ability of peptide bioconjugates towards both the BBB and glioma cells, presents new opportunities for designing tailored and better peptide-based nanostructures or nanophototheranostics for glioma.

Real-time SERS monitoring anticancer drug release along with SERS/MR imaging for pH-sensitive chemo-phototherapy.

In situ and real-time monitoring of responsive drug release is critical for the assessment of pharmacodynamics in chemotherapy. In this study, a novel pH-responsive nanosystem is proposed for real-time monitoring of drug release and chemo-phototherapy by surface-enhanced Raman spectroscopy (SERS). The Fe3O4@Au@Ag nanoparticles (NPs) deposited graphene oxide (GO) nanocomposites with a high SERS activity and stability are synthesized and labeled with a Raman reporter 4-mercaptophenylboronic acid (4-MPBA) to form SERS probes (GO-Fe3O4@Au@Ag-MPBA). Furthermore, doxorubicin (DOX) is attached to SERS probes through a pH-responsive linker boronic ester (GO-Fe3O4@Au@Ag-MPBA-DOX), accompanying the 4-MPBA signal change in SERS. After the entry into tumor, the breakage of boronic ester in the acidic environment gives rise to the release of DOX and the recovery of 4-MPBA SERS signal. Thus, the DOX dynamic release can be monitored by the real-time changes of 4-MPBA SERS spectra. Additionally, the strong T2 magnetic resonance (MR) signal and NIR photothermal transduction efficiency of the nanocomposites make it available for MR imaging and photothermal therapy (PTT). Altogether, this GO-Fe3O4@Au@Ag-MPBA-DOX can simultaneously fulfill the synergistic combination of cancer cell targeting, pH-sensitive drug release, SERS-traceable detection and MR imaging, endowing it great potential for SERS/MR imaging-guided efficient chemo-phototherapy on cancer treatment.

NIR and Reduction Dual-Sensitive Polymeric Prodrug Nanoparticles for Bioimaging and Combined Chemo-Phototherapy.

The combination of chemotherapy, photothermal therapy (PTT) and photodynamic therapy (PDT) based on a single nanosystem is highly desirable for cancer treatment. In this study, we developed a versatile Pt(IV) prodrug-based nanodrug, PVPt@Cy NPs, to realize synchronous chemotherapy, PDT and PTT and integrate cancer treatment with bioimaging. To construct PVPt@Cy NPs, the amphiphilic Pt(IV)-based polymeric prodrug PVPt was synthesized by a facile one-pot coupling reaction, and then it was used to encapsulate an optotheranostic agent (HOCyOH, Cy) via hydrophobic interaction-induced self-assembly. These NPs would disaggregate under acidic, reductive conditions and NIR irradiation, which are accompanied by photothermal conversion and reactive oxygen species (ROS) generation. Moreover, the PVPt@Cy NPs exhibited an enhanced in vitro anticancer efficiency with 808-nm light irradiation. Furthermore, the PVPt@Cy NPs showed strong NIR fluorescence and photothermal imaging in H22 tumor-bearing mice, allowing the detection of the tumor site and monitoring of the drug biodistribution. Therefore, PVPt@Cy NPs displayed an enormous potential in combined chemo-phototherapy.

Lipid-based nanoparticles for photosensitive drug delivery systems.

Background: Numerous drug delivery strategies have been studied, but many hurdles exist in drug delivery rates to the target site. Recently, researchers have attempted to remotely control the in vivo behavior of drugs with light to overcome the shortcomings of conventional drug delivery systems. Photodynamic and photothermal systems are representative strategies wherein a photosensitive material is activated in response to a specific wavelength of light. Area covered: Photosensitive materials generally exhibit poor solubility and low biocompatibility. Additionally, their low photostability negatively affects delivery performance. A formulation of lipid-based nanoparticles containing photosensitive substances can help achieve photosensitive drug delivery with improved biocompatibility. The lipid bilayer structure, which can be assembled and disassembled by modulating the surrounding conditions (temperature, pH, etc.), can also be crucial for controlled release of drugs. Expert opinion: To the best of our knowledge, translation research on photoresponsive nanoparticles is scarce. However, as various drugs based on lipid nanoparticles have been clinically approved, the development potential of the lipid-based photoresponsive nanoparticles seems high. Thus, the identification of valid indications and development of optimum medical devices will increase the interest in photoresponsive material-based nanoparticles.

Biomimetic polyphenol-coated nanoparticles by Co-assembly of mTOR inhibitor and photosensitizer for synergistic chemo-photothermal therapy.

Rapamycin (RAPA) functions as effectively clinical immunosuppressive agent, its significant tumor growth suppression effect via various pathways in diverse cancers, especially combined with photothermal therapy, is gaining a burgeoning attention. However, its critical defects, low solubility and poor stability, have severely hampered its further application. Herein, RAPA, indocyanine green (ICG) and epigallocatechin gallate (EGCG) serving as chemotherapeutic drug, photosensitizer and biomimetic coatings, respectively, were co-assembled into carrier-free, high biocompatible ICG-RAPA-EGCG nanoparticles (IRE NPs) for synergistic cancer therapy. Particularly, the bioinspired EGCG coatings not only improved the stability of IRE NPs under physiological conditions to avert NPs disassembly and drug release, but also maintained the photostability of ICG to achieve excellent photothermal response. The results indicated that the as-prepared IRE NPs displayed good monodispersity and enhanced stability at various stored media after introducing of EGCG. Compared with monotherapy of RAPA or ICG, IRE NPs showed higher dose-dependent toxicity in MCF-7 cells, HepG2 cells and HeLa cells, especially plus near-infrared laser irradiation. Furthermore, IRE NPs exhibited quicker uptake in cells, higher accumulation in tumor region (even in 48 h) than free ICG and effectively inhibited tumor growth without side effect in H22 tumor-bearing mice. Collectively, the carrier-free IRE NPs provided a simply alternative approach to fabricate RAPA/photosensitizer co-loaded nanoparticles for combinatorial tumor therapy.

Imaging-Guided Biomimetic M1 Macrophage Membrane-Camouflaged Magnetic Nanorobots for Photothermal Immunotargeting Cancer Therapy.

Biohybrid micro/nanorobots have demonstrated improved therapeutic outcomes for targeting and treating diseases in preclinical trials. However, in vivo applications remain challenging due to a lack of sufficient targeting. Based on evidence that immune cells play a role in the immune modulation in the tumor microenvironment, we developed M1 macrophage membrane-coated magnetic photothermal nanocomplexes (MPN) for photoacoustic (PA) imaging-guided tumor therapy. The MPN were able to inherit the protein from the original macrophage cells and exert a targeted immunosuppression role. Integrating black phosphorus quantum dots and DOX also greatly enhanced reactive oxygen species generation and chemo-phototherapy efficacy. The results suggest that the MPN can be employed as an excellent tumor immunotargeting nanorobotic platform for modulating the tumor microenvironment under PA imaging and magnetic guidance and, thus, exert synergistic therapeutic efficacies.

Construction and evaluation of red blood cells-based drug delivery system for chemo-photothermal therapy.

In this study, a novel tumor-targeting drug delivery system (DDS) based on red blood cells (RBCs) were fabricated for combinational chemo-phototherapy against cancer. Cyclic peptide (cRGD) and indocyanine green (ICG) were applied to the surface of RBCs to increase the targeting and photothermal effect, respectively. Doxorubicin (DOX) as a model drug was loaded into RBCs by the hypotonic dialysis method. A series of tests have been carried out to evaluate the RBCs-based DDS and these tasks include physicochemical properties, cellular uptake, targeting ability, and combination therapeutic efficiency. As a result, the DOX was successfully loaded into RBCs and the drug loading amount was 0.84 ±â€¯0.09 mg/mL. There was no significant change of particle size after surface modification of RBCs. The RBCs-based DDS could target to the surface of cancer cells, which delivery DOX to the lesions efficiently and accurately. Meanwhile, due to the combined treatment effect, the RBCs-based DDS can effectively inhibit tumor growth. The RBCs-based DDS constructed in this research may have promising applications in cancer therapy due to their highly synergistic efficient therapy and to investigate its possibility for tumor therapy.

Metal-doped and hybrid carbon dots: A comprehensive review on their synthesis and biomedical applications.

Carbon dots (CDs) are the most promising candidates of the carbon family with superior properties like ultra-small size, high aqueous solubility, low cytotoxicity, and inherent photoluminescence which makes them suitable for diverse biomedical applications. Methods have been developed to enhance their applications. Doping/surface passivation of CDs improves their physicochemical properties, visible light absorption probability, and quantum yield by controlling their size, morphology, structure, and band-gap energy. Recently, metal-doped CDs have emerged as an important class of nanomaterials with numerous biomedical applications. Additionally, the conjugation of CDs with semiconductor metal-oxide nanoparticles (NPs) enhances their free radical production rates under visible light irradiation. Conjugation of fluorescent CDs with magnetic NPs leads to the development of multimodal imaging platforms. Similarly, ternary conjugates composed of fluorescent CDs, near-infrared (NIR) responsive, and magnetic NPs are useful for multi-modal imaging-guided, and NIR-responsive synergistic chemo-phototherapy. However, no comprehensive review is published yet which covers metal-doped and hybrid CDs. Therefore, herein we provide detailed information about their synthesis and important biomedical applications. Firstly, we have covered various synthesis methods for CD conjugation including the critical analysis of the effects of the reaction conditions and doping/conjugation on the structure and properties of the CDs. Then we have extensively reviewed their biomedical applications as antimicrobial, antioxidant, and bioimaging agents, and in the field of cancer phototherapy with special emphasis on their mechanisms of actions. Finally, the future directions of research and the applications of the metal-doped and hybrid CDs have been discussed. We believe that this review article will enrich the understanding of different synthetic routes of CD-nanocomposites and their biomedical applications.

Perfluorocarbon Nanodroplets with Deep Tumor Penetration and Controlled Drug Delivery for Ultrasound/Fluorescence Imaging Guided Breast Cancer Therapy.

Some impediments, including insufficient drug release, poor tumor penetration, and lack of real-time imaging guidance, still limited the therapeutic efficiency of nanotechnology-based drug delivery systems. Here, light-responsive perfluoropentane (PFP) based nanodroplets as doxorubicin (DOX) nanocarriers that could achieve deep tumor delivery under multimodal imaging guidance were developed. Triggered by laser irradiation, the liquid PFP with low boiling point could go through small-to-big size change and liquid-to-gas phase transformation. At the same time, the accompanied cavitation effect led to not only the disruption of dense extracellular matrix for deep penetration but also the disruption of endo-/lysosome for nucleus delivery of released DOX. Furthermore, different from many imaging approaches which were always "on", only upon laser stimulation could the nanodroplets act as ultrasound/fluorescence probes due to the echogenic PFP bubbles and the recovered fluorescence of DOX itself after released from nanodroplets, which was highly desirable to indicate the DOX state in real time. Therefore, such PFP nanodroplets with phase/size tunable properties enable site-specific drug delivery efficiently and exhibit their potent in cancer theranostics.

4-in-1 Fe3O4/g-C3N4@PPy-DOX nanocomposites: Magnetic targeting guided trimode combinatorial chemotherapy/PDT/PTT for cancer.

At present, cancer has become a major disease threatening human health worldwide. Therefore, developing targeting guided multimode synergetic therapy has become one of the hot spots in current antitumor research and is also a great challenge. Herein, a new Fe3O4/g-C3N4@PPy-DOX nanocomposite containing magnetic iron oxide (Fe3O4) nanoparticles (NPs), lamellar structure of graphite-like carbon nitride (g-C3N4) and polypyrrole (PPy) shell with the loaded anti-tumor drug doxorubicin hydrochloride (DOX) was designed and prepared. The monodisperse Fe3O4 nanoparticles (NPs) with the diameter of 20 nm endowed the nanocomposite with the magnetic targeting ability, reducing damage to normal tissues. It is very interesting that the Fe3O4 NPs also possessed photosensitizer function for photodynamic therapy (PDT). The g-C3N4 sheets as the photocatalysis towards the degradation of water for generating O2 could effectively improve the hypoxia of solid tumors and increase the efficiency of PDT. In addition, PPy has high light-to-heat conversion efficiency, so was chosen for the cancer photothermal therapy (PTT). Finally, an anticancer drug (DOX) was loaded on the nanocomposite because the presence of mesoporous structure. Thus, the prepared Fe3O4/g-C3N4@PPy-DOX nanocomposites exhibit synergetic chemotherapy/PTT/enhanced PDT antitumor effect. This study provides an inspiration for combining targeting and multimodality to improve the anticancer efficiency.