S-nitrosothiols loaded mini-sized Au@silica nanorod elicits collagen depletion and mitochondrial damage in solid tumor treatment.

To a large extent, the dense extracellular matrix (ECM), which tightly connects tumor cells to arm the tumor into an intractable fortress, significantly decreases the nanoparticles delivery efficacy and overall performance in cancer treatments. Therefore, it is necessary to transform the dense stroma of solid tumors to loose state, which could realize deep penetration of nanomedicine and enhance cancer treatment effects. Here, we fabricated a protein-free collagen nanosweeper, triphenylphosphonium bromide (TPP) coated and S-nitrosothiols loaded mini-sized Au@silica nanorod (Au@SiO2-SNO/PEG/TPP, GSNP-TPP), to clear the transport barriers of nanoparticles as well as elevate enhanced permeability and retention (EPR) effect, thus alleviating the diffusion resistance and realizing further penetration of nanoparticles. Methods: By modifying the Au@silica with thermo-sensitive S-nitrosothiols, the carrier could release the nitric oxide (NO) due to the surface overheat as well as perform photothermal therapy (PTT) under near-infrared (NIR) laser irradiation. The level of collagen depletion was observed via western blotting and immunofluorescent staining. In addition, the dual-imaging and antitumor efficiency of GSNP-TPPs were evaluated with the HeLa tumor-bearing mouse model. Results: On one hand, the released NO could deplete collagen by activating matrix metalloproteinases (MMPs) to break collagen fibers, thus loosening the dense ECM to enhance the cellular internalization. On the other hand, with the mitochondrial-targeted effect of TPP, the diffusible NO in tumor might rapidly interact with superoxide anion (O2Y-) to produce highly toxic and powerful reactive nitrogen species (RNS) -- peroxynitrite (ONOO-), which resulted in mitochondrial damage to induce cell apoptosis. With the unique properties of mini-sized gold nanorods, the formulated nanoparticles exhibited good computed tomography (CT) and multi-spectral optoacoustic tomography (MSOT) imaging effects in precisely locating and monitoring tumor. Moreover, the antitumor efficacy of GSNP-TPPs + laser group was further confirmed by ex-vivo histological analysis of tumor tissue. Conclusion: This work points out a strategy to overcome the obstacle standing in nanoparticles penetration, and opens the door of further exploitation of NO-related theranostic systems.

Boosted photocatalytic activity induced NAMPT-Regulating therapy based on elemental bismuth-humic acids heterojunction for inhibiting tumor proliferation/migration/inflammation.

Due to the highly complex biological formation procedure, tumor is still difficult to be treated efficiently and always associated with proliferation, migration and inflammation during treatment. Herein, a novel strategy of boosted photocatalytic activity induced NAMPT-regulating therapy is used for tumors inhibition based on FK866 loaded bismuth-humic acids heterojunction (Bi-HA/FK866). With the reduction function of HA, Bi (Ⅲ) can be reduced to elemental Bi, which can be excited by NIR laser to form electron-hole pair due to the narrow bandgap. Moreover, the coated HA and Bi could form a heterojunction structure, which could decrease the electron-hole recombination, and further boost the photocatalytic activity, leading to highly efficient ROS generation and GSH depletion. The resulted ROS could induce DNA damage of the tumor cells, thus enhancing the sensitivity to the inhibitor of NAMPT (FK866) to downregulate NAD/ERK/NF-κB signal pathways, and eventually simultaneously prevent cancer progression. Moreover, the decreased NAD could downregulate NADPH and further suppress the innate antioxidant defense system by inhibiting reduction of GSSG. The boosted photocatalytic activity induced NAMPT-regulating therapy offers a promising way to address the important issue of penetration depth limitation induced cancer relapse and migration, providing more possibilities toward successful clinical application.

Ultra-small Bi2S3 nanodot-doped reversible Fe(ii/iii)-based hollow mesoporous Prussian blue nanocubes for amplified tumor oxidative stress-augmented photo-/radiotherapy.

Improving the generation of reactive oxygen species (ROS) while consuming glutathione (GSH) is the main method for amplifying intracellular oxidative stress. However, in previous studies, it was normally necessary to combine two or more materials to achieve the effect of destroying the intracellular redox homeostasis. This made the preparation process relatively complicated. Herein, we designed ultra-small bismuth sulfide quantum dot (Bi2S3 QD)-doped hollow mesoporous Prussian blue (HMPB) (HMPB/Bi2S3) nanocubes for amplified tumor oxidative stress to augment photo-/radiotherapy. In addition to being photothermal materials, Prussian blue can be used as both a catalyst for the Fenton reaction and a consumer of GSH due to the multivalent state of iron. Ferrous ions (Fe(ii)) can produce toxic ROS-hydroxyl radicals (˙OH) with abundant hydrogen peroxide in the tumor cells by the Fenton reaction. Meanwhile, ferric ions (Fe(iii)) can oxidize the intracellular GSH to GSSG, thus depleting the concentration of GSH inside tumors. As a result, oxidative stress imbalance could be induced by the reversible redox property of Fe(ii/iii), thereby causing DNA damage and increasing the cell membrane permeability to realize enhanced photo-/radiotherapy. As a sensitizer for radiotherapy, ultra-small Bi2S3 QDs (3-5 nm) are doped in HMPB, thus improving the therapeutic effect by prolonging blood circulation and reducing systemic toxicity via kidney metabolism. Therefore, such a reversible HMPB/Bi2S3 nanocube is a promising therapeutic agent for amplified tumor oxidative stress to augment photo-/radiotherapy, which might show further applications in nanomedical science.

Oxygen-supplementing mesoporous polydopamine nanosponges with WS2 QDs-embedded for CT/MSOT/MR imaging and thermoradiotherapy of hypoxic cancer.

Multifunctional nanoplatforms with flexible architectures and tumor microenvironment response are highly anticipated within the field of thermoradiotherapy. Herein, the multifunctional nanoplatforms for thermoradiotherapy have been successfully constructed by the embedding of tungsten disulfide quantum dots (WS2 QDs) into mesoporous polydopamine nanosponges (MPDA NSs), followed by integration with manganese dioxide (MnO2). MPDA-WS2@MnO2, the resultant nanoplatforms, exhibit radiosensitization enhanced behavior and a capacity for responsive oxygen self-supplementation. The ingenious mesoporous structure of MPDA NSs serves as reservoir for the assembly of WS2 QDs to form MPDA-WS2 nanoparticles (NPs), in which WS2 QDs provide the radiation enhancement effect, whereas the MPDA NSs framework endows the MPDA-WS2@MnO2 with an excellent photothermal capability. Additionally, the integration of the MnO2 component works to decompose the tumor-overexpressed H2O2 and alleviate tumor hypoxia subsequently, which has been demonstrated to enhance radiotherapy performance considerably. Meanwhile, the prepared MPDA-WS2@MnO2 nanoplatforms have been evaluated as trimodality contrast agents for computed tomography (CT), multispectral optoacoustic tomography (MSOT), and tumor microenvironment-responsive T1-weighted magnetic resonance (MR) imaging that have the potential for real-time guidance and monitoring during cancer therapy. More importantly, when subjected to near infrared (NIR) laser irradiation and X-ray exposure, the tumor is found to be inhibited significantly through the process of combined thermoradiotherapy. The design concepts of embedding WS2 QDs into MPDA NSs and oxygen self-supplementing hold great potential for multimodal imaging-guided thermoradiotherapy of hypoxic cancer.

Biomodal Tumor-Targeted and Redox-Responsive Bi2 Se3 Hollow Nanocubes for MSOT/CT Imaging Guided Synergistic Low-Temperature Photothermal Radiotherapy.

Hyperthemia (>50 °C) induced heating damage of nearby normal organs and inflammatory diseases are the main challenges for photothermal therapy (PTT) of cancers. To overcome this limitation, a redox-responsive biomodal tumor-targeted nanoplatform is synthesized, which can achieve multispectral optoacoustic tomography/X-ray computed tomography imaging-guided low-temperature photothermal-radio combined therapy (PTT RT). In this study, Bi2 Se3 hollow nanocubes (HNCs) are first fabricated based on a mild cation exchange way and Kirkendall effect and then modified with hyaluronic acid (HA) through redox-cleavable linkage (-s-s-), thus enabling the HNC to target cancer cells overexpressing CD-44 and control the cargo release profile. Finally, gambogic acid (GA), a type of heat-shock protein (HSP) inhibitor, which is vital to cells resisting heating-caused damage is loaded, into Bi2 Se3 HNC. Such HNC-s-s-HA/GA under a mild NIR laser irradiation can induce efficient cancer cell apoptosis, achieving PTT under relatively low temperature (≈43 °C) with remarkable cancer cell damage efficiency. Furthermore, enhanced radiotherapy (RT) can also be experienced without depth limitation based on RT sensitizer Bi2 Se3 HNC. This research designs a facile way to synthesize Bi2 Se3 HNC-s-s-HA/GA possessing theranostic functionality and cancer cells-specific GSH, but also shows a low-temperature PTT RT method to cure tumors in a minimally invasive and highly efficient way.

Glutathione-Mediated Clearable Nanoparticles Based on Ultrasmall Gd2O3 for MSOT/CT/MR Imaging Guided Photothermal/Radio Combination Cancer Therapy.

Recently, multifunctional clearable inorganic theranostic nanoparticles have been attracting more and more attention. Protein-based nanoparticles can be cleared by the hepatobiliary system efficiently. In this work, ultrasmall gadolinium oxide (Gd2O3) nanoparticles, which possess the advantage of high longitudinal relaxation rate, were coated with bovine serum albumin (BSA). After the Gd2O3/BSA nanoparticles were linked with two-dimensional photothermal MoS2 nanomaterials, the nanoparticles were also modified with hyaluronic acid (HA) through the disulfide bonds for tumor-targeting effect. As indicated by in vitro and in vivo studies, these Gd2O3/BSA@MoS2-HA nanoparticles could be rapidly degraded and excreted after reacting with glutathione (GSH) by the redox response, thus avoiding long-term toxicity. In addition, the cellular uptake study and in vivo multispectral optoacoustic tomography (MSOT), X-ray computed tomography (CT), and magnetic resonance (MR) triple-modal images demonstrated that Gd2O3/BSA@MoS2-HA nanoparticles exhibited a high tumor uptake effect after intravenous injection. Consequently, such clearable theranostic nanoparticles with multiple functions, which are applicable in multimodal imaging-guided cancer therapy, might show promise for applications in nanomedical science.

Ultrasmall MoS2 Nanodots-Doped Biodegradable SiO2 Nanoparticles for Clearable FL/CT/MSOT Imaging-Guided PTT/PDT Combination Tumor Therapy.

Recently, we developed ultrasmall molybdenum disulfide (MoS2) quantum dots for computed tomography (CT) and multispectral optoacoustic tomography (MSOT) imaging-guided photothermal therapy (PTT). But, due to rapid body elimination and limited blood circulation time, the tumor uptake of the dots is low. In our study, this problem was solved via designing an amino-modified biodegradable nanomaterial based on MoS2 quantum-dots-doped disulfide-based SiO2 nanoparticles (denoted MoS2@ss-SiO2) for multimodal application. By integrating the MoS2 quantum dots into clearable SiO2 nanoparticles, this nanoplatform with an appropriate particle size can not only degrade and excrete in a reasonable period induced by redox responsiveness of glutathione but also exhibit a high tumor uptake due to the longer blood circulation time. Moreover, hyaluronic acid and chlorin e6 (Ce6) were adsorbed on the outer shell for tumor-targeting effect and photodynamic therapy, respectively. So, this biodegradable and clearable theranostic nanocomposite, which is applicable in integrated fluorescence/CT/MSOT imaging-guided combined photothermal therapy (PTT) and photodynamic therapy, is very promising in biomedical applications in the future.

Rodlike MSN@Au Nanohybrid-Modified Supermolecular Photosensitizer for NIRF/MSOT/CT/MR Quadmodal Imaging-Guided Photothermal/Photodynamic Cancer Therapy.

Recently, rodlike nanomaterials with specific aspect ratio for efficient cellular uptake have received enormous attention. For functional nanomaterials, such as photothermal agents, large surface areas for their rod-shaped exterior that increase the amount of light absorbed would lead to a higher absorption coefficient as well as drug-loading property. In this project, we coated rodlike mesoporous silica with gold nanoshells (MSNR@Au hybrid), modifying them with ultrasmall gadolinium (Gd)-chelated supramolecular photosensitizers, TPPS4 (MSNR@Au-TPPS4(Gd)), which could be applied to near-infrared fluorescence/multispectral optoacoustic tomography/computed tomography/magnetic resonance imaging and imaging-guided remotely controlled photothermal (PTT)/photodynamic (PDT) combined antitumor therapy. Gold nanoshells, as a perfect PTT agent, were used to assemble the rodlike mesoporous silica nanoparticles with larger superficial area and higher drug loading, thus obtaining the MSNR@Au hybrid. HS-ß-CD, which was used as the host, was adsorbed on the gold nanoshell (MSNR@Au-ß-CD) to link TPPS4(Gd) through the host-guest reaction, thus forming CD-TPPS4 supramolecular photosensitizers (supraPSs). Compared with conventional PSs, supraPSs have host screens, which could reduce the self-aggregation of TPPS4, and consequently generate 1O2 with high efficiency. The in vivo quadmodal imaging of MSNR@Au-TPPS4(Gd) nanoparticles revealed an intensive tumor uptake effect after injection. The in vivo antitumor efficacy further testified that the synergistic therapy, which was more efficient than any other monotherapy, exhibited an excellent tumor inhibition therapeutic effect. As a result, this encourages to further explore multifunctional theranostic nanoparticles based on gold shells for combined cancer therapy.

Photothermally activatable PDA immune nanomedicine combined with PD-L1 checkpoint blockade for antimetastatic cancer photoimmunotherapy.

Photothermal therapy (PTT) has shown promising potential and bright prospects in damaging primary tumors; however, it is limited to metastatic and recrudescent tumors as PTT requires straightforward light irradiation. Moreover, metastatic and recrudescent tumor immunosuppression due to host T-cell antitumor activity is dramatically impeded because of programmed cell death 1 ligand (PD-L1) and programmed cell death receptor 1 (PD-1) pathways and immune checkpoint blockade (ICB) therapy. In this work, we demonstrate that PTT combined with ICB could not only eliminate primary tumors, but also prevent tumor metastasis to the lungs/liver. In particular, we have designed immunoadjuvant nanomedicine carriers on the basis of polydopamine (PDA) simultaneously loaded with resiquimod (R848)-a kind of toll-like receptor 7 (TLR7) agonist-and carbon dots (CDs)-a fluorescent agent. This nanomedicine is defined as PDA-PEG-R848-CD nanoparticle (NP). The multitasking PDA-PEG-R848-CD NPs can destroy 4T1 breast tumors by PTT under near-infrared laser irradiation in addition to generating tumor-associated antigens. Moreover, the PTT effect triggered the release of R848, thereby inducing a strong antitumor immune response. Meanwhile, this synergistic therapy also shows the abscopal effects by completely inhibiting the growth of untreated distant tumors by effectively triggering the tumors infiltrated by CD3/CD8. Such findings suggest that PDA-PEG-R848-CD NPs could significantly potentiate the systemic therapeutic efficiency of PD-L1 checkpoint blockade therapy by activating both innate and adaptive immune systems in the body.

One-Pot Synthesis of a Bismuth Selenide Hexagon Nanodish Complex for Multimodal Imaging-Guided Combined Antitumor Phototherapy.

For integrating therapy and diagnosis into a single nanoparticle for higher antitumor efficiency and lower toxicity, our group designed a smart theranostic nanoplatform based on a hyaluronic acid-doped polypyrrole-coated bismuth selenide loading with a zinc phthalocyanine nanodish complex (Bi2Se3@HA-doped PPy/ZnPc) for multimodal imaging-guided combined phototherapy. Moreover, we expect that the HA-doped PPy smart shell for the surface functionalization will also be applied to a variety of 2D nanomaterials sharing a similar structure with Bi2Se3 to broaden their applications in biomedicine. The Bi2Se3 hexagon nanodish was synthesized via a simple and safe solution-based method compared to the commonly adopted ones. A one-pot synthesis of the naoncomplex was carried out by adding HA during the polypyrrole coating on the Bi2Se3 process, and then it was further loaded with ZnPc. Besides the good ability for infrared thermal, photoacoustic, fluorescence, and X-ray computed tomography imaging, the nanodish complex has its own high photoheat conversion efficiency for photothermal therapy, and it has remarkable optical absorption of the coefficient for photodynamic therapy. With the EPR effect of nanoparticles and the CD44-targeted effect of HA, the tumor-growth inhibition ratio of Bi2Se3@HA-doped PPy/ZnPc for PTT/PDT was as high as 96.4%, compared with that of the PTT (68.0%) or PDT (24.3%) alone, showing an excellent combined therapeutic effect. Moreover, no obvious toxicity in vivo was caused by the nanoparticles. Thus, such a Bi2Se3@HA-doped PPy/ZnPc nanodish complex has promise for real-time monitoring and precise, high-efficiency antitumor treatment.

Polymer-based gadolinium oxide nanocomposites for FL/MR/PA imaging guided and photothermal/photodynamic combined anti-tumor therapy.

Recently, ultrasmall gadolinium oxide (Gd2O3) nanoparticles with high longitudinal relaxation rate have received enormous attention. However, it can't be concentrated in tumor site through intravenous administration due to its ultrasmall size. In this project, we coated ultrasmall Gd2O3 nanoparticles with a near-infrared (NIR) light-absorbing polymer polypyrrole (PPy), modifying with hyaluronic acid (HA) and loaded aluminum phthalocyanine (AlPc), the Gd2O3@PPy/AlPc-HA nanoparticles could be used for fluorescence (FL)/magnetic resonance (MR)/photoacoustic (PA) imaging guided as well as remotely controlled PTT/PDT combined anti-tumor therapy. Polymerized PPy with high photothermal conversion efficiency was introduced to assemble the ultrasmall Gd2O3 nanoparticles which have high longitudinal relaxation rate and signal-to-noise ratio, thus obtaining Gd2O3@PPy nanoparticles which possess a larger particle size and can be more suitable for tumor targeting based on the EPR effect. HA and AlPc were adsorbed on PPy for HA-mediated tumor targeting and photodynamic therapy respectively. The in vivo triple-modal imaging revealed that Gd2O3@PPy/AlPc-HA nanoparticles possess enhanced tumor uptake effect after intravenous injection. More importantly, the nanoparticles exhibited an obvious photothermal effect, which can trigger the release and de-quench of AlPc. The anti-tumor efficiency further corroborated that the combined therapy achieved an excellent tumor inhibition therapeutic effect which was much better than any other mono-therapy. Consequently, our work encouraged further exploration of polymer-based multifunctional theranostic nanoparticles for cancer combination therapy under remote near-infrared (NIR) light controls.

All-in-One Theranostic Nanoplatform Based on Hollow MoSx for Photothermally-maneuvered Oxygen Self-enriched Photodynamic Therapy.

Photodynamic therapy (PDT) kills cancer cells by converting tumor-dissolved oxygen into reactive singlet oxygen (1O2) using a photosensitizer under laser irradiation. However, pre-existing hypoxia in tumors and oxygen consumption during PDT can result in an inadequate oxygen supply, which in turn hampers PDT efficacy. Herein, an O2 self-sufficient nanotheranostic platform based on hollow MoSx nanoparticles (HMoSx) with oxygen-saturated perfluorohexane (O2@PFH) and surface-modified human serum albumin (HSA)/chloride aluminium phthalocyanine (AlPc) (O2@PFH@HMoSx-HSA/AlPc), has been designed for the imaging and oxygen self-enriched photodynamic therapy (Oxy-PDT) of cancer. METHODS: The in vitro anti-cancer activity and intracellular 1O2 generation performance of the nanoparticles were examined using 4T1 cells. We also evaluated the multimodal imaging capabilities and anti-tumor efficiency of the prepared nanoparticles in vivo using a 4T1 tumor-bearing nude mouse model. RESULTS: This nanoplatform could achieve the distinct in vivo fluorescence (FL)/photoacoustic (PA)/X-ray computed tomography (CT) triple-model imaging-guided photothermally-maneuvered Oxy-PDT. Interestingly, the fluorescence and Oxy-PDT properties of O2@PFH@HMoSx-HSA/AlPc were considerably quenched; however, photothermal activation by 670 nm laser irradiation induced a significant increase in temperature, which empowered the Oxy-PDT effect of the nanoparticles. In this study, O2@PFH@HMoSx-HSA/AlPc demonstrated a great potential to image and treat tumors both in vitro and in vivo, showing complete tumor-inhibition over 16 days after treatment in the 4T1 tumor model. CONCLUSION: O2@PFH@HMoSx-HSA/AlPc is promising to be used as novel multifunctional theranostic nanoagent for triple-modal imaging as well as single wavelength NIR laser triggered PTT/Oxy-PDT synergistic therapy.

Magnetically-targeted and near infrared fluorescence/magnetic resonance/photoacoustic imaging-guided combinational anti-tumor phototherapy based on polydopamine-capped magnetic Prussian blue nanoparticles.

In recent years, Prussian blue (PB)-based nanoagents have become a new platform in photothermal cancer treatment. However, there is little research for PB-based nanoagents to achieve synergistic phototherapy guided by multimodal imaging diagnosis and monitoring. Herein, a novel single wavelength near infrared (NIR) laser-induced magnetically targeted theranostic nanoplatform has been successfully designed and synthesized for the first time based on polydopamine (PDA)/aluminum phthalocyanine (AlPc)/bovine serum albumin (BSA) coated magnetic Prussian blue nanoparticles (Fe3O4@PB NPs) for multiple imaging-guided combinatorial cancer therapy. The resultant multifunctional Fe3O4@PB@PDA/AlPc/BSA nanocomposites show excellent stability and superparamagnetism, facilitating them to achieve superior photothermal therapy in physiological environments under magnetic guidance. In addition, the delivery vehicles can remarkably increase tumor accumulation of AlPc, thus leading to an enhanced photodynamic therapy efficacy. Furthermore, Fe3O4@PB@PDA/AlPc/BSA can be utilized as a multimodality nanoprobe for simultaneous diversified imaging, including near-infrared fluorescence imaging (NIRFI), magnetic resonance imaging (MRI), and photoacoustic imaging (PAI). Most importantly, without noticeable dark toxicity, the obtained Fe3O4@PB@PDA/AlPc/BSA nanocomposites are able to significantly suppress tumor growth via combined photothermal and photodynamic therapies upon a single 660 nm laser irradiation, achieving a superior synergetic manner compared to monotherapy both in vitro and in vivo. Therefore, our strategy provides Fe3O4@PB@PDA/AlPc/BSA nanocomposites for trimodality cancer imaging-guided synergistic therapy, with a great potential for new generation theranostics nanoagents.

NIRF/PA/CT multi-modality imaging guided combined photothermal and photodynamic therapy based on tumor microenvironment-responsive nanocomposites.

In this study, we developed a novel chitosan (CS)-controlled and aluminum phthalocyanine chloride (AlPc)-loaded molybdenum disulfide (MoS2) nanocomposite as a single nanoplatform (AlPc-MoS2@SiO2-CS) for near-infrared fluorescence (NIRF), photoacoustic (PA), and X-ray computed tomography (CT) multi-modality imaging-guided photothermal and photodynamic combination therapy of tumors. The MoS2 nanodot was used as the PA/CT contrast as well as hyperthermal agent. The MoS2@SiO2 nanoparticles prepared by a facile one-pot approach can serve as drug-delivery vehicles to transport the NIR absorbing photosensitizer AlPc within the mesoporous cavities. Meanwhile, a natural cationic polysaccharide, CS, was introduced as a gatekeeper to avoid the premature release of loaded AlPc. What's more, CS as a tumor microenvironment-responsive agent can control the release of loaded drugs to the acidic local environment in the tumor. The in vivo multimodal imaging uncovered that the AlPc-MoS2@SiO2-CS nanocomposites showed enhanced tumor uptake and diagnosis abilities after intravenous injection. More importantly, the nanocomposites exhibited an evident near-infrared induced photothermal effect in the in vitro and in vivo experiments, which remarkably improved the photodynamic therapy efficiency by accelerating the blood flow and subsequently increasing oxygen supply in the tumor. Taken together, our current work demonstrated a nanoplatform for multimodal imaging guided targeted dual-therapy, which revealed a potential strategy for tumor treatment.

Theranostic Nanoplatform: Triple-Modal Imaging-Guided Synergistic Cancer Therapy Based on Liposome-Conjugated Mesoporous Silica Nanoparticles.

Mesoporous silica nanoparticles (MSNs) have long since been investigated to provide a versatile drug-delivery platform due to their multitudinous merits. Presently, gadolinium (Gd), a T1 magnetic resonance imaging (MRI) contrast agent, was doped into MSNs as a newly emerging theranostic nanocomposite, which has received much research attention. However, it is still concerned about the dispersibility and drug leakage of MSNs. Hence, in this project, we constructed an near-infrared (NIR) irradiation-triggered, triple-modal imaging-guided nanoplatform based on doxorubicin (DOX)@Gd-doped MSNs, conjugating with indocyanine green (ICG)-loaded thermosensitive liposomes (designated as DOX@GdMSNs-ICG-TSLs). In this platform, ICG could contribute to both photodynamic therapy and photothermal therapy effects; meanwhile, it could also give play to near-infrared fluorescence imaging (NIRFI) as well as photoacoustic imaging (PAI). Consequently, NIRFI and PAI from ICG combined with the MRI function of Gd, devoted to triple-modal imaging with success. At the same time, folic acid-modified thermosensitive liposomes were explored to be coated onto the surface of DOX@GdMSNs, to solve the DOX leakage as well as improve cellular uptake. Under NIR irradiation, ICG could generate heat, thus leading to the rupture of ICG-TSLs and the release of DOX. Accordingly, the multifunctional nanocomposite appeared to be a promising meritorious theranostic nanoplatform to pave a way for treating cancer.

BSA-Bioinspired Gadolinium Hybrid-Functionalized Hollow Gold Nanoshells for NIRF/PA/CT/MR Quadmodal Diagnostic Imaging-Guided Photothermal/Photodynamic Cancer Therapy.

Multimodal imaging-guided synergistic therapy promises a more accurate diagnosis and higher therapeutic efficiency than single imaging modality or their simple "mechanical" combination. In this research, we have constructed an innovative multifunctional drug delivery platform by gadolinium (Gd)-based bovine serum albumin (BSA) hybrid-coated hollow gold nanoshells (Au@BSA-Gd). The obtained nanoparticles exhibited excellent photothermal effect and computed tomography (CT)/photoacoustic (PA) activity. Besides, the BSA-bioinspired gadolinium complex endowed the nanoparticles with an excellent T1 contrast agent for magnetic resonance imaging (MRI). In addition, the near-infrared (NIR) absorbing phototherapeutic agent [indocyanine green (ICG)] was loaded into the Au@BSA-Gd nanoparticles because of their unique, hollow, and porous structures, thus possessing photodynamic/photothermal property and near-infrared fluorescence (NIRF)/PA imaging capability. As a result, a combined cancer therapy containing the photothermal therapy of Au@BSA-Gd and the synchronous photodynamic/photothermal therapy of ICG was constructed. Furthermore, the well-designed nanocomposites with multiple integrated modalities enabled them to be an ideal nanotheranostic agent for NIRF/PA/CT/MR quadmodal imaging. Therefore, the ICG-loaded albumin-bioinspired gadolinium hybrid-functionalized hollow gold nanoshells (ICG-Au@BSA-Gd) hold great promise as a theranostic platform for simultaneous therapeutic monitoring and precise cancer therapy.

Hollow Au-Cu Nanocomposite for Real-Time Tracing Photothermal/Antiangiogenic Therapy.

High absorption in the near-infrared (NIR) region is essential for a photoabsorbing agents to realize efficient photothermal therapy (PTT) for cancer. Here, a novel hollow Au-Cu nanocomposite (HGCNs) is developed, which displays a significantly enhanced NIR surface plasmon resonance absorption and photothermal transduction efficiency. Besides, fluorescent polymer dots poly(9,9-dioctylfluorene-2,7-diyl-co-benzothiadiazole) (PFBT) and chemotherapeutic mammalian target of rapamycin (mTOR) inhibitor agent rapamycin (RAPA) are attached onto the HGCNs (RAPA/PFBT-HGCNs) for real-time NIR fluorescence tracing and combined PTT/antiangiogenesis therapy. In particular, due to the fluorescence resonance energy transfer effect, RAPA/PFBT-HGCNs can act as NIR-activatable on/off probe system for real-time tracing of tumor tissues. A standard in vitro cellular uptake study, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, dual-staining study, and flow cytometry assay reveal that the RAPA/PFBT-HGCNs combined with NIR laser exhibit higher drug accumulation and cytotoxicity in both tumor cells and epithelial cells. Moreover, the margins of tumor and normal tissue can be accurately indicated by NIR-stimulated dequenched PFBT after 24 h intravenous administration. Further, tumor growth can be considerably hampered by the optimal formulation plus laser treatment with relatively lower side effects. Consequently, the work highlights the real-time tracing and enhanced PTT/antiangiogenesis therapy prospects of the established HGCNs with tremendous potential for treatment of cancer.

A triple-synergistic strategy for combinational photo/radiotherapy and multi-modality imaging based on hyaluronic acid-hybridized polyaniline-coated WS2 nanodots.

In this study, we report a strategy for integrating hyaluronic acid (HA), polyaniline (PANI), WS2 nanodots (WS2), and chlorin e6 (Ce6) into a single nanoplatform (HA-WS2@PANI/Ce6) for fluorescence, photoacoustic, and computed tomography multi-modality imaging-guided trimodal photothermal/radiation/photodynamic combination therapy of tumors. The WS2 nanodot core is used as the radiosensitizer with the PANI shell as the hyperthermal agent and the photosensitizer reservoir. HA and Ce6 were adsorbed on the outer shell for tumor targeting and photodynamic therapy, respectively. The in vivo trimodal imaging uncovered that HA-WS2@PANI/Ce6 nanoparticles showed enhanced tumor uptake and diagnosis effects after intravenous injection. More importantly, in the in vitro and in vivo experiments, the nanoparticles exhibited an evident near-infrared induced photothermal effect, which remarkably improved the radiation and photodynamic therapy efficiency by accelerating the blood flow and subsequently increasing oxygen supply in the tumor. The nanohybrids were found to be safe to cells in vitro and organs in vivo. Taken together, our current work demonstrates a nanoplatform for multimodal imaging guided targeted triple-therapy, which reveals a potential strategy for tumor treatment.

A photoresponsive and rod-shape nanocarrier: Single wavelength of light triggered photothermal and photodynamic therapy based on AuNRs-capped & Ce6-doped mesoporous silica nanorods.

Rod-shape nanocarriers have attracted great interest because of their better cell internalization capacity and higher drug loading properties. Besides, the combination of photodynamic therapy (PDT) and photothermal therapy (PTT) holds great promise to overcome respective limitations of the anti-cancer treatment. In this work, we first report Au nanorods-capped and Ce6-doped mesoporous silica nanorods (AuNRs-Ce6-MSNRs) for the single wavelength of near infrared (NIR) light triggered combined phototherapy. AuNRs-Ce6-MSNRs are not only able to generate hyperthermia to perform PTT effect based on the AuNRs, but also can produce singlet oxygen (1O2) for PDT effect based on Ce6 after uncapping of AuNRs under the single NIR wavelength irradiation. In addition, the combined therapy can be dual-imaging guided by taking the photoacoustic (PA) and NIR fluorescence (NIRF) imaging of AuNRs and Ce6, respectively. What's more, by utilizing the special structure of MSNRs, this nanocarrier can serve as a drug delivery platform with high drug loading capacity and enhanced cellular uptake efficiency. The multi-functional nanocomposite is designed to integrate photothermal and photodynamic therapy, in vivo dual-imaging into one system, achieving synergistic anti-tumor effects both in vitro and in vivo.

A single-light triggered and dual-imaging guided multifunctional platform for combined photothermal and photodynamic therapy based on TD-controlled and ICG-loaded CuS@mSiO2.

Near-infrared (NIR)-responsive drug delivery systems have received enormous attention because of their good biocompatibility and high biological penetration. In this work, we report a novel 1-tetradecanol (TD)-controlled and indocyanine green (ICG)-loaded CuS@mSiO2 phototherapy nanoplatform (CuS@mSiO2-TD/ICG). The CuS@mSiO2 nanoparticles prepared by a facile one-pot approach can serve as drug-delivery vehicles to transport the NIR absorbing phototherapeutic agent (ICG) within the mesoporous cavities. Meanwhile a phase-change molecule (PCM), TD, is introduced as a thermosensitive gatekeeper to avoid the premature release of loaded ICG. Noticeably, the combined therapy is irradiated at an 808 nm single-light wavelength, thus performing the photothermal therapy (PTT) based on CuS@mSiO2 as well as simultaneously triggering the photodynamic (PDT)/PTT effect based on ICG. Furthermore, ICG also has the function of dual in vivo fluorescence imaging and photoacoustic (PA) imaging. This dual imaging-guided and gatekeeper-controlled nanoplatform for the single-light triggered PTT/PDT treatment holds significant promise for future cancer therapy due to their markedly improved therapeutic efficacy and decreased systemic toxicity.