An albumin-based theranostic nano-agent for dual-modal imaging guided photothermal therapy to inhibit lymphatic metastasis of cancer post surgery

A large variety of cancers are associated with a high incidence of lymph node metastasis, which leads to a high risk of cancer death. Herein, we demonstrate that multimodal imaging guided photothermal therapy can inhibit tumor metastasis after surgery by burning the sentinel lymph nodes (SLNs) with metastatic tumor cells. A near-infrared dye, IR825, is absorbed onto human serum albumin (HSA), which is covalently linked with diethylenetriamine pentaacetic acid (DTPA) molecules to chelate gadolinium. The formed HSA-Gd-IR825 nanocomplex exhibits strong fluorescence together with high near-infrared (NIR) absorbance, and in the mean time could serve as a T1 contrast agent in magnetic resonance (MR) imaging. In vivo bi-modal fluorescence and MR imaging uncovers that HSA-Gd-IR825 after being injected into the primary tumor would quickly migrate into tumor-associated SLNs through lymphatic circulation. Utilizing the strong NIR absorbance of HSA-Gd-IR825, SLNs with metastatic cancer cells can be effectively ablated under exposure to a NIR laser. Such treatment when combined with surgery to remove the primary tumor offers remarkable therapeutic outcomes in greatly inhibiting further metastatic spread of cancer cells and prolonging animal survival. Our work presents an albumin-based theranostic nano-probe with functions of multimodal imaging and photothermal therapy, together with a ‘photothermal ablation assisted surgery’ strategy, promising for future clinical cancer treatment.     

Near-infrared dye bound albumin with separated imaging and therapy wavelength channels for imaging-guided photothermal therapy

Development of theranostic agent for imaging-guided photothermal therapy has been of great interest in the field of nanomedicine. However, if fluorescent imaging and photothermal ablation are conducted with the same wavelength of light, the requirements of the agent's quantum yield (QY) for imaging and therapy are controversial. In this work, our synthesized near-infrared dye, IR825, is bound with human serum albumin (HSA), forming a HSA-IR825 complex with greatly enhanced fluorescence under 600 nm excitation by as much as 100 folds compared to that of free IR825, together with a rather high absorbance but low fluorescence QY at 808 nm. Since high QY that is required for fluorescence imaging would result in reduced photothermal conversion efficiency, the unique optical behavior of HSA-IR825 enables imaging and photothermal therapy at separated wavelengths both with optimized performances. We thus use HSA-IR825 for imaging-guided photothermal therapy in an animal tumor model. As revealed by in vivo fluorescence imaging, HSA-IR825 upon intravenous injection shows high tumor uptake likely owing to the enhanced permeability and retention effect, together with low levels of retentions in other organs. While HSA is an abundant protein in human serum, IR825 is able to be excreted by renal excretion as evidenced by high-performance liquid chromatography (HPLC). In vivo tumor treatment experiment is finally carried out with HSA-IR825, achieving 100% of tumor ablation in mice using a rather low dose of IR825. Our work presents a safe, simple, yet imageable photothermal nanoprobe, promising for future clinical translation in cancer treatment.     

Two-dimensional magnetic WS2@Fe3O4 nanocomposite with mesoporous silica coating for drug delivery and imaging-guided therapy of cancer

Integrating multiple imaging and therapy functionalities into one single nanoscale platform has been proposed to be a promising strategy in cancer theranostics. In this work, WS₂ nanosheets with their surface pre-adsorbed with iron oxide (IO) nanoparticles via self-assembly are coated with a mesoporous silica shell, on to which polyethylene glycol (PEG) is attached. The obtained WS₂-IO@MS-PEG composite nanoparticles exhibit many interesting inherent physical properties, including high near-infrared (NIR) light and X-ray absorbance, as well as strong superparamagnetism. In the mean time, the mesoporous silica shell in WS₂-IO@MS-PEG could be loaded with a chemotherapy drug, doxorubicin (DOX), whose intracellular release afterwards may be triggered by NIR-induced photothermal heating for enhanced cancer cell killing. Upon systemic administration of such drug-loaded nano-theranostics, efficient tumor homing of WS₂-IO@MS-PEG/DOX is observed in tumor-bearing mice as revealed by three-modal fluorescence, magnetic resonance (MR), and X-ray computed tomography (CT) imaging. In vivo combined photothermal & chemotherapy is then carried out with WS₂-IO@MS-PEG/DOX, achieving a remarkably synergistic therapeutic effect superior to the respective mono-therapies. Our study highlights the promise of developing multifunctional nanoscale theranostics based on two-dimensional transition metal dichalcogenides (TMDCs) such as WS₂ for multimodal imaging-guided combination therapy of cancer.     

Protein modified upconversion nanoparticles for imaging-guided combined photothermal and photodynamic therapy

In this work, we develop a multifunctional nano-platform by coating upconversion nanoparticles (UCNPs) with bovine serum albumin (BSA), obtaining UCNP@BSA nanoparticles with great solubility and stability in physiological environments. Two types of dye molecules, including a photosensitizer, Rose Bengal (RB), and an NIR-absorbing dye, IR825, can be simultaneously loaded into the BSA layer of the UCNP@BSA nanoparticles. In this carefully designed UCNP@BSA-RB&; IR825 system, RB absorbs green light emitted from UCNPs under 980-nm excitation to induce photodynamic cancer cell killing, while IR825 whose absorbance shows no overlap with upconversion excitation and emission wavelengths, offers nanoparticles a strong photothermal perform under 808-nm laser irradiation. Without showing noticeable dark toxicity, the obtained dual-dye loaded nanoparticles are able to kill cancer via combined photothermal and photodynamic therapies, both of which are induced by NIR light with high tissue penetration, by a synergetic manner both in vitro and in vivo. In addition, the intrinsic paramagnetic and optical properties of Gd³⁺-doped UCNPs can further be utilized for in vivo dual modal imaging. Our study suggests that UCNPs with well-designed surface engineering could serve as a multifunctional nano-platform promising in cancer theranostics.     

A tumor-targeting near-infrared laser-triggered drug delivery system based on GO@Ag nanoparticles for chemo-photothermal therapy and X-ray imaging

In this study, a GO@Ag nanocomposite was synthesized by chemical deposition of Ag nanoparticles onto graphene oxide (GO) through a hydro thermal reaction, and doxorubicin (DOX), one of the most effective drugs against a wide range of cancers, was employed as the model drug and linked to GO@Ag via ester bonds with a very high drug loading efficiency (∼82.0%, weight ratio of DOX/GO@Ag), then GO@Ag-DOX was functionalized by DSPE-PEG2000-NGR, giving GO@Ag-DOX with active tumor-targeting capacity and excellent stability in physiological solutions. The release profiles of DOX from GO@Ag-DOX-NGR showed strong dependences on near-infrared (NIR) laser and the SPR effect of Ag nanoparticles. Compared with free DOX in an in vivo murine tumor model, GO@Ag-DOX-NGR afforded much higher antitumor efficacy without obvious toxic effects to normal organs owing to 8.4-fold higher DOX uptake of tumor and 1.7-fold higher DOX released in tumor with NIR laser than the other tissues. Besides, in this work, GO@Ag-DOX-NGR not only served as a powerful tumor diagnostic X-ray contrast agent, but also as a strong agent for photothermal ablation of tumor, the ability of GO@Ag-DOX-NGR nanoparticles to combine the local specific chemotherapy with external photothermal therapy (PTT) significantly improved the therapeutic efficacy. GO@Ag-DOX-NGR showed excellent chem-photothermal therapeutic efficacy, tumor-targeting property, NIR laser-controlled drug releasing function and X-ray imaging ability, demonstrating that there is a great potential of GO@Ag-DOX-NGR for cancer diagnosis and therapy.     

Immunostimulatory oligonucleotides-loaded cationic graphene oxide with photothermally enhanced immunogenicity for photothermal/immune cancer therapy

Graphene oxide (GO) has attracted tremendous research interest due to its excellent electrical, thermal, and mechanical properties. Here, we apply the polyethylene glycol (PEG) and polyethylenimine (PEI) dual-polymer-functionalized GO (GO-PEG-PEI) as the carrier for efficient CpG delivery. GO-PEG-PEI can significantly promote the production of proinflammatory cytokines and enhance the immunostimulatory effect of CpG. In addition, the NIR optical absorbance of GO-PEG-PEI has been further applied to control the immunostimulatory activity of CpG ODNs, showing remarkably enhanced immunostimulation responses under NIR laser irradiation, owing to the photothermally induced local heating that accelerated intracellular trafficking of nanovectors. This is the first demonstration of using the photothermally enhanced intracellular transportation of nanocarriers for light-controllable CpG delivery. In vivo assay demonstrates that the GO-PEG-PEI-CpG complex provides synergistic photothermal and immunological effects under laser irradiation for cancer treatment, which shows the highest efficiency in tumor reduction, implying the excellent therapeutic efficacy of the GO-PEG-PEI-CpG complex in cancer therapy.     

Synergistic effect of chemo-photothermal therapy using PEGylated graphene oxide

Graphene has shown great potential both in photothermal therapy and drug delivery. Herein, we developed doxorubicin-loaded PEGylated nanographene oxide (NGO-PEG-DOX) to facilitate combined chemotherapy and photothermal therapy in one system. In this work, we studied the ablation of tumor both in vivo and in vitro by the combination of photothermal therapy and chemotherapy using this functional graphene oxide. The ability of the NGO-PEG-DOX nanoparticle to combine the local specific chemotherapy with external near-infrared (NIR) photothermal therapy significantly improved the therapeutic efficacy of cancer treatment. Compared with chemotherapy or photothermal therapy alone, the combined treatment demonstrated a synergistic effect, resulting in higher therapeutic efficacy. Furthermore, lower systematic toxicity of NGO-PEG-DOX than DOX was proved by the pathologic examination of main organs in our toxicity study.     

A multi-stimuli responsive gold nanocage–hyaluronic platform for targeted photothermal and chemotherapy

Noninvasive and pinpointed intracellular drug release that responds to multiple stimulus is still a formidable challenge for cancer therapy. Herein, we reported a multi-stimuli responsive platform based on drug loaded gold nanocages @ hyaluronic acid (AuNCs-HA) for pinpointed intracellular drug release. These well-prepared nanohybrids could specifically recognize cancer cells via HA-CD44 interactions and be efficiently endocytosed by receptor-mediated process. Subsequently, the coated HA molecules could be degraded in lysosomes, resulting in the release of encapsulated drug. In addition, by taking advantage of the excellent photothermal properties, the AuNCs could accelerate the release of encapsulated drug and induce a higher therapeutic efficacy upon near-infrared (NIR) irradiation. In vitro results confirmed that the encapsulated drug could only be pinpointedly released in intracellular environments, which permitted high therapeutic efficacy against cancer cells and minimized the side effects. Importantly, as compared to that of the two therapies independently, a complete inhibition of tumor growth treated with the combination of chemotherapy and photothermal therapy was observed in vivo. Taken together, our present study provides new insights into developing pinpointed, multi-stimuli responsive intracellular drug release systems for synergistic cancer therapy.     

Rose-bengal-conjugated gold nanorods for in vivo photodynamic and photothermal oral cancer therapies

Gold nanorods (GNRs) conjugated with rose bengal (RB) molecules exhibit efficient singlet oxygen generation when illuminated by 532 nm green light and high photothermal efficiency under 810 nm near-infrared (NIR) irradiation. In vitro experiments show that reactive oxygen species generated by green light and hyperthermia produced by NIR light constitute two different mechanisms for cancer cell death. The RB-GNRs also exhibit improved photodynamic efficacy by enhancing the uptake of RB by cancer cells. In vivo experiments are conducted on hamster cheek pouches to resemble the human oral cancer conditions more accurately to assess the therapeutic effectiveness. Compared to the single photodynamic therapy (PDT) or photothermal therapy (PTT), the RB-GNRs with combined PDT-PTT capabilities provide better therapeutic effects against oral cancer and have large potential in cancer treatment.     

PEGylated Prussian blue nanocubes as a theranostic agent for simultaneous cancer imaging and photothermal therapy

Theranostic agents with both imaging and therapeutic functions have attracted enormous interests in cancer diagnosis and treatment in recent years. In this work, we develop a novel theranostic agent based on Prussian blue nanocubes (PB NCs), a clinically approved agent with strong near-infrared (NIR) absorbance and intrinsic paramagnetic property, for in vivo bimodal imaging-guided photothermal therapy. After being coated with polyethylene glycol (PEG), the obtained PB-PEG NCs are highly stable in various physiological solutions. In vivo T₁-weighted magnetic resonance (MR) and photoacoustic tomography (PAT) bimodal imaging uncover that PB-PEG NCs after intravenous (i.v.) injection show high uptake in the tumor. Utilizing the strong and super stable NIR absorbance of PB, in vivo cancer treatment is then conducted upon i.v. injection of PB-PEG NCs followed by NIR laser irradiation of the tumors, achieving excellent therapeutic efficacy in a mouse tumor model. Comprehensive blood tests and careful histological examinations reveal no apparent toxicity of PB-PEG NCs to mice at our tested dose, which is two-fold of the imaging/therapy dose, within two months. Our work highlights the great promise of Prussian blue with well engineered surface coating as a multifunctional nanoprobe for imaging-guided cancer therapy.     

Fluorescent porous carbon nanocapsules for two-photon imaging,NIR/pH dual-responsive drug carrier,and photothermal therapy

An efficient nanomedical platform that can combine two-photon cell imaging, near infrared (NIR) light and pH dual responsive drug delivery, and photothermal treatment was successfully developed based on fluorescent porous carbon-nanocapsules (FPC-NCs, size ∼100 nm) with carbon dots (CDs) embedded in the shell. The stable, excitation wavelength (λ_ex)-tunable and upconverted fluorescence from the CDs embedded in the porous carbon shell enable the FPC-NCs to serve as an excellent confocal and two-photon imaging contrast agent under the excitation of laser with a broad range of wavelength from ultraviolet (UV) light (405 nm) to NIR light (900 nm). The FPC-NCs demonstrate a very high loading capacity (1335 mg g⁻¹) toward doxorubicin drug benefited from the hollow cavity structure, porous carbon shell, as well as the supramolecular π stacking and electrostatic interactions between the doxorubicin molecules and carbon shell. In addition, a responsive release of doxorubicin from the FPC-NCs can be activated by lowering the pH to acidic (from 7.4 to 5.0) due to the presence of pH-sensitive carboxyl groups on the FPC-NCs and amino groups on doxorubicin molecules. Furthermore, the FPC-NCs can absorb and effectively convert the NIR light to heat, thus, manifest the ability of NIR-responsive drug release and combined photothermal/chemo-therapy for high therapeutic efficacy.     

The influence of surface chemistry and size of nanoscale graphene oxide on photothermal therapy of cancer using ultra-low laser power

Photothermal therapy as a physical treatment approach to destruct cancer has emerged as an alternative of currently used cancer therapies. Previously we have shown that polyethylene glycol (PEG) functionalized nano-graphene oxide (nGO-PEG) with strong optical absorption in the near-infrared (NIR) region was a powerful photothermal agent for in vivo cancer treatment. In this work, by using ultra-small reduced graphene oxide (nRGO) with non-covalent PEG coating, we study how sizes and surface chemistry affect the in vivo behaviors of graphene, and remarkably improve the performance of graphene-based in vivo photothermal cancer treatment. Owing to the enhanced NIR absorbance and highly efficient tumor passive targeting of nRGO-PEG, excellent in vivo treatment efficacy with 100% of tumor elimination is observed after intravenous injection of nRGO-PEG and the followed 808 nm laser irradiation, the power density (0.15 W/cm², 5 min) of which is an order of magnitude lower than that usually applied for in vivo tumor ablation using many other nanomaterials. All mice after treatment survive over a period of 100 days without a single death or any obvious sign of side effect. Our results highlight that both surface chemistry and sizes are critical to the in vivo performance of graphene, and show the promise of using optimized nano-graphene for ultra-effective photothermal treatment, which may potentially be combined with other therapeutic approaches to assist our fight against cancer.     

NIR photothermal therapy using polyaniline nanoparticles

Developing a biocompatible and efficient photothermal coupling agent with appropriate size is a prerequisite for the development of near-infrared (NIR) light-induced photothermal therapy (PTT). In the present study, polyaniline nanoparticles (PANPs) with a size of 48.5 ± 1.5 nm were fabricated and exhibited excellent dispersibility in water by a hydrothermal method and further surface functionalization by capping with F127. The developed F127-modified PANPs (F-PANPs) had a high molar extinction coefficient of 8.95 × 10⁸ m⁻¹ cm⁻¹, and high NIR photothermal conversion efficiency of 48.5%. Furthermore, combined with NIR irradiation at 808 nm and injection of F-PANP samples, in vivo photothermal ablation of tumor with excellent treatment efficacy was achieved. In vitro transmission electron microscopy (TEM) images of cells, methyl thiazolyl tetrazolium (MTT) assay, histology, and hematology studies revealed that the F-PANPs exhibit low toxicity to living systems. Therefore, F-PANPs could be used as PTT agents for ablating cancer, and the concept of developing polyaniline-based nanoparticles can serve as a platform technology for the next generation of in vivo PTT agents.     

Multifunctional PEG-GO/CuS nanocomposites for near-infrared chemo-photothermal therapy

The synergistic therapy, the combination of photothermal therapy and chemotherapy, has become a potential treatment in the battles with cancer. Here, we developed a synergistic therapy tool that based on CuS nanoparticles-decorated graphene oxide functionalized with polyethylene glycol (PEG-GO/CuS) for cervical cancer treatment. The as-synthesized PEG-GO/CuS nanocomposites with excellent biocompatibility was revealed to have high storage capacity for anticancer drug of doxorubicin (Dox) and high photothermal conversion efficiency, and were effectively employed for the ablation of tumor. In addition, the therapeutic efficacy of Dox-loaded PEG-GO/CuS (PEG-GO/CuS/Dox) nanocomposites was evaluated in vitro and in vivo for cervical cancer therapy. In vitro cell cytotoxicity tests of PEG-GO/CuS/Dox demonstrate about 1.3 and 2.7-fold toxicity than PEG-GO/CuS and free Dox under 5 min irradiation with NIR laser at 1.0 W/cm², owing to both PEG-GO/CuS-mediated photothermal ablation and cytotoxicity of light-triggered Dox release. In mouse models, mouse cervical tumor growth was found to be significantly inhibited by the chemo-photothermal effect of PEG-GO/CuS/Dox nanocomposites, resulting in effective tumor reduction. Overall, compared with chemotherapy or photothermal therapy alone, the combined treatment demonstrates better therapeutic efficacy of cancer in vitro and in vivo. These findings highlight the promise of the highly versatile multifunctional nanoparticles in biomedical application.     

Tumor microenvironment sensitive doxorubicin delivery and release to glioma using angiopep-2 decorated gold nanoparticles

Glioma is still hard to be treated due to their complex microenvironment. In this study, a gold nanoparticle-based delivery system was developed. The system, An-PEG-DOX-AuNPs, was loaded with doxorubicin (DOX) through hydrazone, an acid-responsive linker, and was functionalized with angiopep-2, a specific ligand of low density lipoprotein receptor-related protein-1 (LRP1), which could mediate the system to penetrate blood brain barrier and target to glioma cells. The particle size of An-PEG-DOX-AuNPs was 39.9 nm with a zeta potential of −19.3 mV, while the DOX loading capacity was 9.7%. In vitro, the release of DOX from DOX-AuNPs was pH-dependent. At lower pH values, especially 5.0 and 6.0, release of DOX was much quicker than that at pH 6.8 and 7.4. After coating with PEG, the acid-responsive release of DOX from PEG-DOX-AuNPs was almost the same as that from DOX-AuNPs. Cellular uptake study showed obviously higher intensity of intracellular An-PEG-DOX-AuNPs compared with PEG-DOX-AuNPs. In vivo, An-PEG-DOX-AuNPs could distribute into glioma at a higher intensity than that of PEG-DOX-AuNPs and free DOX. Correspondingly, glioma-bearing mice treated with An-PEG-DOX-AuNPs displayed the longest median survival time, which was 2.89-fold longer than that of saline. In conclusion, An-PEG-DOX-AuNPs could specifically deliver and release DOX in glioma and significantly expand the median survival time of glioma-bearing mice.     

FeS nanoplates as a multifunctional nano-theranostic for magnetic resonance imaging guided photothermal therapy

In this work, we develop magnetic iron sulfide (FeS) nanoplates as a theranostic agent for magnetic resonance (MR) imaging-guided photothermal therapy of cancer. FeS nanoplates are synthesized via a simple one-step method and then functionalized with polyethylene glycol (PEG). The obtained PEGylated FeS (FeS-PEG) nanoplates exhibit high NIR absorbance together with strong superparamagnetism. The r2 relaxivity of FeS-PEG nanoplates is determined to be 209.8 mm-1S-1, which appears to be much higher than that of iron oxide nanoparticles and several types of clinical approved T2-contrast agents. After intravenous (i.v.) injection, those nanoplates show high accumulation in the tumor as revealed by MR imaging. Highly effective photothermal ablation of tumors is then achieved in a mouse tumor model upon i.v. injection of FeS-PEG at a moderate dose (20 mg/kg) followed by 808-nm NIR laser irradiation. Importantly, it has been found that PEGylated FeS nanoplates after systemic administration could be gradually excreted from major organs of mice, and show no appreciable toxicity to the treated animals even at a dose (100 mg/kg) 5 times as high as that used for imaging & treatment. Our results demonstrate that PEGylated FeS nanoplates may be a promising class of theranostic nano-agents with a good potential for future clinical translation.     

Mulberry-like dual-drug complicated nanocarriers assembled with apogossypolone amphiphilic starch micelles and doxorubicin hyaluronic acid nanoparticles for tumor combination and targeted therapy

A comprehensive strategy for the preparation of mulberry-like dual-drug complicated nanocarriers (MLDC NCs) with high drug loading and adjustable dual-drug ratio was developed. First, apogossypolone (ApoG2) amphiphilic starch micelles (AASt MCs) were prepared by self-assembly process, and doxorubicin (DOX) hyaluronic acid nanoparticles (DHA NPs) were prepared by DOX absorption with excess HA by electrostatic absorption. MLDC NCs were obtained by adsorption of 8–9 DHA NPs around one AASt MC via electrostatic interaction. UV–visible and fluorescence spectrophotometers were used to measure the entrapment efficiency and loading efficiency of the two drugs. Transmission electron microscope and dynamic light scattering method were used to observe the size distribution and morphology of the particles. The tumor-targeting feature caused by HA-receptor mediation was confirmed by in vitro cell uptake and in vivo near-infrared fluorescence imaging. MLDC NCs were found to possess a mulberry-like shape with a dynamic size of 83.1 ± 6.6 nm. The final encapsulation efficiencies of ApoG2 and DOX in MLDC NCs were 94 ± 1.7% and 87 ± 5.8% with respect to drug-loading capacities of 13.3 ± 1.2% and 13.1 ± 3.7%, respectively. Almost no ApoG2 release was found within 80 h and less than 30% of DOX was released into the outer phase even after 72 h. In vivo fluorescence imaging revealed that MLDC NCs had highly efficient targeting and accumulation at the tumor in vivo and was maintained for 96 h after being injected intravenously in mice. Low LD₅₀ for the two drugs in MLDC NCs was found after acute toxicity test. One-fifth normal dosage of the two drugs in MLDC NCs exhibited significantly higher anti-tumor efficiency in reducing tumor size compared with free drugs combination or single drug-loaded nanoparticles individually, indicating that the mulberry-like dual-drug nanoplatform has a great potential in tumor therapy.     

Terminal modification of polymeric micelles with π-conjugated moieties for efficient anticancer drug delivery

High drug loading content is the critical factor to polymeric micelles for efficient chemotherapy. Small molecules of cinnamic acid, 7-carboxymethoxy coumarin and chrysin with different π-conjugated moieties were immobilized on the terminal hydroxyl groups of PCL segments in mPEG-PCL micelles to improve drug loading content via the evocation of π-π stacking interaction between doxorubicin (DOX) and polymeric micelles. The modification of π-conjugated moieties enhanced the capability of crystallization of mPEG-PCL block copolymers. The drug loading content increased dramatically from 12.9% to 25.5% after modification. All the three modified mPEG-PCL micelles were nontoxic to cells. Chrysin modified polymeric micelles exhibited the most efficient anticancer activity. The in vivo anticancer activity of 10 mg/kg DOX dose of chrysin modified micelle formulation for twice injections was comparable to that of 5 mg/kg dose of free DOX·HCl for four injections under the circumstance of same total DOX amount. The systemic toxicity of DOX loaded chrysin modified micelles was significantly reduced. This research provided a facile strategy to achieve polymeric micelles with high drug loading content and efficient anticancer activity both in vitro and in vivo.     

Drug delivery with upconversion nanoparticles for multi-functional targeted cancer cell imaging and therapy

Upconversion nanoparticles (UCNPs) with unique multi-photon excitation photoluminescence properties have recently been intensively explored as novel contrast agents for low-background biomedical imaging. In this work, we functionalize UCNPs with a polyethylene glycol (PEG) grafted amphiphilic polymer. The PEGylated UCNPs are loaded with a commonly used chemotherapy molecule, doxorubicin (DOX), by simple physical adsorption via a supramolecular chemistry approach for intracellular drug delivery. The loading and releasing of DOX from UCNPs are controlled by varying pH, with an increased drug dissociation rate in acidic environment, favorable for controlled drug release. Upconversion luminescence (UCL) imaging by a modified laser scanning confocal microscope reveals the time course of intracellular delivery of DOX by UCNPs. It is found that DOX is shuttled into cells by the UCNP nano carrier and released inside cells after endocytosis. By conjugating nanoparticles with folic acid, which targets folate receptors over expressed on various types of cancer cells, we further demonstrate targeted drug delivery and UCL cell imaging with UCNPs. Besides DOX, this non-covalent drug loading strategy can also be used for loading of photosensitizer molecules on UCNPs for potential near-infrared light induced photodynamic therapy. Our results suggest the promise of UCNPs as interesting nano carriers for multi-functional cancer therapy and imaging.     

Matrix metalloproteinase-sensitive size-shrinkable nanoparticles for deep tumor penetration and pH triggered doxorubicin release

Nanocarriers are widely used for delivering drugs to tumors and are progressing in a stable trend. The enhanced permeability and retention (EPR) effect has been a key rationale for the development of stimulus-responsive nanocarriers to solid tumor. In this study, we developed a kind of novel nanocarrier, G-AuNPs-DOX-PEG, which was constructed with shrinkable gelatin nanoparticles coated, doxorubicin (DOX) tethered gold nanoparticles and long chain polyethylene glycol (PEG). The particle size of G-AuNPs-DOX-PEG was 186.5 nm with a zeta potential of −4.21 mV and the DOX loading capacity was 9.22%. In vitro, the G-AuNPs-DOX-PEG could be degraded by MMP-2 proteins with a size shrink from 186.5 nm to 59.3 nm. The release of DOX from G-AuNPs-DOX-PEG was in a pH- and time-dependent manner. At pH 5.0, the release of DOX was much quicker than that at high pH value and the cumulative release rate of DOX from G-AuNPs-DOX-PEG was approach 90.9%. Cellular uptake demonstrated that G-AuNPs-DOX-PEG could be internalized via the endosome-mediated pathway. Tumor spheroid penetration and collagen gel diffusion showed G-AuNPs-DOX-PEG with pre-incubation with MMP-2 could significantly enhance its penetrating efficiency. In vivo and ex vivo imaging exhibit that G-AuNPs-DOX-PEG could distribute into 4T1 and B16F10 tumor at a highest intensity. Correspondingly, 4T1 and B16F10 tumor bearing mice treated with G-AuNPs-DOX-PEG displayed the lowest tumor growth rate. In summary, the tumor microenvironment sensitive size-shrinkable G-AuNPs-DOX-PEG could deliver into deep tumor region and then release DOX, resulting in a best anti-tumor effect.