Synergetic Chemo-photothermal Therapy Research Articles

Hemostatic nanofibers/chitosan composite aerogel for potential chemo-photothermal therapy

Incomplete resection of tumor tissue and bleeding during skin cancer surgery can easily lead to early tumor recurrence and metastasis. In this study, a three-dimensional doxorubicin (DOX) loaded poly (lactic-co-glycolic acid) (PLGA) nanofibers/chitosan (CS) aerogel composite with hemostasis and chemo-photothermal effect was successfully prepared by electrospinning and lyophilization. The highly porous PLGA/MXene/DOX nanofibers@CS aerogel (PMD@CS) demonstrated exceptional photothermal conversion and pH/temperature-responsive drug release properties, which inhibited the growth of tumor cells, showing a potential chemo-photothermal effect. Furthermore, the nanofibers/aerogel composite showed desired hemostatic efficacy and biocompatibility, with a blood coagulation index of 65.1 ± 1.9% and a blood coagulation time within 3 min, indicating its potential for rapid bleeding control. This nanofibers/aerogel composite with bifunction of chemo-photothermal synergetic therapy and hemostasis can be an antineoplastic biomedical material for the prevention of postoperative tumor recurrence and metastasis.

Cancer Cell Membrane-Biomimetic Nanoparticles Based on Gelatin and Mitoxantrone for Synergetic Chemo-Photothermal Therapy of Metastatic Breast Cancer.

The purpose of this paper is to develop a cancer cell membrane biomimetic nanodrug delivery system (NDDS) to achieve an enhanced chemo-photothermal synergistic antitumor effect. The biomimetic NDDSs are composed of mitoxantrone (MIT)-loaded gelatin nanoparticles and IR820-encapsulated 4T1 cancer cell membrane-derived vesicles. The biomimetic NDDS displayed excellent stability and photothermal conversion efficiency. Compared to naked nanoparticles, the cell membrane-coated nanoparticles improved 4T1 cell uptake through homologous targeting and effectively reduced internalization of macrophages. In vivo photothermal imaging results further showed that the NDDS could be enriched at the tumor site for 48 h and could raise the temperature of the tumor area to 60 °C within 5 min under 808 nm laser irradiation. Finally, NDDS successfully inhibited primary tumor growth (over 89% inhibition) and significantly inhibited lung metastasis. This study may provide a new strategy for personalized chemotherapy-photothermal combination therapy of metastatic breast cancer using tumor cell membranes from cancer patients as drug carriers.

GSH-Responsive Prodrug Nanoassembly as a Carrier-Free Nanoplatform for Tumor-Targeting Delivery and Chemo-Photothermal Therapy.

Photothermal therapy, combined with chemotherapy, holds promising prospects for the therapeutic outcome of malignant tumors. However, the synergistic therapeutic effect suffers from low coloading capacity and inefficient synchronous tumor-targeting delivery of chemodrug and photothermal photosensitizers. Herein, we designed a versatile carrier-free nanoplatform to seek improvement for chemo-photothermal therapy. An NIR photosensitizer IR-808 was used for noninvasive cancer imaging, diagnosis, and imaging-guided photothermal therapy. A reduction-sensitive paclitaxel prodrug (PTX-SS-PEG2k) was rationally synthesized by covalently linking paclitaxel with polyethylene glycol 2000 via a disulfide bond. Then, the carrier-free nanoassemblies were constructed with an inner core of IR-808 and an amphiphilic paclitaxel prodrug shell. PTX-SS-PEG2k served as a stabilizer and chemodrug and could facilitate the self-assembly of IR-808 nanoparticles with high coloading efficiency and reduction-sensitive drug release. The versatile nanoplatform exhibited multiple advantages, including high drug payload, reduction-sensitive drug release, tumor-targeting drug delivery, and potent synergistic antitumor effect. We provide a versatile theranostic nanoplatform, which improves the effectiveness of synergetic chemo-photothermal therapy and reduces the off-target toxicity.

A Targeted and pH-Responsive Nano-Graphene Oxide Nanoparticle Loaded with Doxorubicin for Synergetic Chemo-Photothermal Therapy of Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is a malignant disease with serious impacts on human health and quality of life worldwide. This disease is traditionally treated through a combination of surgery, radiotherapy, and chemotherapy. However, the efficacy of traditional treatments is hindered by systemic toxicity, limited therapeutic effects, and drug resistance. Fibroblast activation protein (FAP) is a membrane-bound protease. Although FAP has limited expression in normal adult tissues, it is highly expressed in the tumor microenvironment of many solid cancers - a characteristic that makes it an ideal target for anticancer therapy. In this study, we constructed a nano-drug delivery system (NPF@DOX) targeting FAP to increase the therapeutic efficiency of synergistic chemo-photothermal therapy against OSCC. We utilized PEGylated nano-graphene oxide (NGO) to link doxorubicin (DOX) and fluorescently-labeled, FAP-targeted peptide chains via hydrogen bonding and π-π bonding to enhance the targeting capability of NPF@DOX. The synthesis of NPF@DOX was analyzed using UV-Vis and FT-IR spectroscopy and its morphology using transmission electron microscopy (TEM). Additionally, the drug uptake efficiency in vitro, photo-thermal properties, release performance, and anti-tumor effects of NPF@DOX were evaluated and further demonstrated in vivo. Data derived from FT-IR, UV-Vis, and TEM implied successful construction of the NPF@DOX nano-drug delivery system. Confocal laser scanning microscopy images and in vivo experiments demonstrated the targeting effects of FAP on OSCC. Furthermore, NPF@DOX exhibited a high photothermal conversion efficiency (52.48%) under near-infrared radiation. The thermogenic effect of NPF@DOX simultaneously promoted local release of DOX and apoptosis based on a pH-stimulated effect. Importantly, FAP-targeted NPF@DOX in combination with PTT showed better tumor suppression performance in vivo and in vitro than did either therapy individually. NPF@DOX can precisely target OSCC, and combined treatment with chemical and photothermal therapy can improve the therapeutic outcomes of OSCC. This method serves as an efficient therapeutic strategy for the development of synergistic anti-tumor research.

Enhanced Nuclear Accumulation of Doxorubicin Delivered by pH-Triggered Polydopamine-Shelled Mesoporous Silica for Chemo-Photothermal Therapy.

Adequate delivery of therapeutic agents to their intended molecular targets is crucial in tumor therapy. Versatile drug carriers need to overcome the challenges coming from the systemic circulation, membrane barriers, and endo-lysosomal degradation. Herein, hyaluronic acid-conjugated polydopamine (HA-PDA)-shelled mesoporous silica nanoparticles encapsulated with doxorubicin (MSNs-DOX) were successfully fabricated for targeted tumor therapy. Compared with reported studies focusing on the pH-sensitive release in tumors, we especially revealed the significant role of lysosomal release in DOX nuclear accumulation. After active targeting and CD44-mediated endocytosis in tumor cells, the PDA layer of the nanoparticles would be peeled off to trigger drug release owing to MSNs gatekeeper in acidic lysosomes. Subsequently, DOX molecules passively diffused into nuclei. The intracellular DOX transportation was evidenced by DOX accumulation in nuclei, lysosomal location of nanoparticles, and lysosome acidification inhibition test. After discharging of the cargoes from nanoparticles, PDA shells from residual nanoparticles were able to produce localized hyperthermia under NIR irradiation entrapped in lysosomes, inducing synergistic chemo-photothermal effect. Under NIR treatment, HA-PDA@MSNs-DOX presented a prominent tumor inhibition rate without obvious side effects. This study indicated the potent nuclear delivery and synergetic chemo-photothermal therapy achieved by HA-PDA-shelled MSNs.

A novel MMP-responsive nanoplatform with transformable magnetic resonance property for quantitative tumor bioimaging and synergetic chemo-photothermal therapy

Quantifying bio-targeted markers in the tumor microenvironment through non-invasive approaches remains challenging. In this study, a novel matrix metalloproteinase-9 (MMP9) responsive nanoplatform (PMP@USPIO/DOX, PMPSD) with transformable magnetic resonance property is designed for quantitative tumor bioimaging and synergetic chemo-photothermal therapy. The nanoplatform acts as a T2 contrast agent in physiological conditions due to the ultrasmall superparamagnetic iron oxide (USPIO) aggregation state, whereas in the tumor microenvironment, the nanoclusters are dissociated by MMP9, thus transforming the nanoplatform into a T1 contrast agent. T1&T2 weighted image and T1&T2 maps are utilized to quantitatively study the correlation between MRI signal changes and MMP9 concentrations and to evaluate MMP9 activity. In addition, the PMP@USPIO/DOX nanoplatform possesses excellent photothermal properties. PMPSD combined with laser irradiation is more effective than single chemo-/photothermal therapy, and up-regulation of the MMP9 level in the tumor can further improve the therapeutic effect. The nanoplatform is of great significance in evaluating disease prognosis and non-invasive monitoring of drug release. The concept reported here provides a creative idea for the non-invasive quantitative study of the tumor microenvironment.

Stimulus-Responsive Nanoparticle-Integrated Dissolving Microneedles for Synergetic Chemo-Photothermal Therapy of Superficial Skin Tumors

Stimulus-Responsive Nanoparticle-Integrated Dissolving Microneedles for Synergetic Chemo-Photothermal Therapy of Superficial Skin Tumors

Multifunctional Human Serum Albumin Fusion Protein as a Docetaxel Nanocarrier for Chemo-photothermal Synergetic Therapy of Ovarian Cancer.

Modification of inorganic nanoparticles with human serum albumin (HSA) that load with chemotherapeutic agents has been reported to conduct chemo-photothermal synergistic therapy of tumors. However, loading some highly insoluble drugs would cause the conformation disorder of HSA, which is unable to give full play to tumor targeting and biological compatibility. Besides, inorganic nanoparticles with too large of a size would appear with unsatisfactory metabolism and lead to biological toxicity. Herein, the recombinant protein integrating histidine (His), HSA, enzyme responsive site, and arginine-glycine-aspartic acid (RGD) by genetic engineering technology was developed to co-load docetaxel (DTX) and gold nanoparticles (Au NPs) to construct RHMH18@AuD NPs. In which, DTX was encapsulated in the micelle part that self-assembled by histidine, while ultrasmall Au NPs were clustered in the HSA part through biomimetic mineralization. RHMH18@AuD NPs could maintain a consistent conformation with HSA and a uniform dispersion in saline. In vitro experiments verified that RHMH18@AuD NPs could target cancer cells followed by being structurally separated into RGD-HSA@Au and His@DTX under the restriction of MMP-2 enzymes. In vivo results verified the favorable biocompatibility and positive chemo-photothermal synergetic therapy efficiency of RHMH18@AuD NPs on a human ovarian tumor.

Supercritical Fluid-Assisted Fabrication of PDA-Coated Poly (l-lactic Acid)/Curcumin Microparticles for Chemo-Photothermal Therapy of Osteosarcoma

After traditional osteosarcoma resection, recurrence of tumor is still a major clinical challenge. The combination of chemotherapy and photothermal therapy (PTT) has great potential in improving therapeutic effect. However, the studies using polydopamine (PDA) as photothermal transducing agent to improve the anti-cancer activity of curcumin (CM)-loaded poly (l-lactic acid) (PLLA) microparticles (PLLA/CM) have seldom been investigated. In this study, we reported the synthesis of PDA-coated PLLA/CM microparticles (PDA-PLLA/CM) prepared by PDA coating on the surface of the PLLA/CM microparticles fabricated by solution-enhanced dispersion by supercritical CO2 (SEDS) for chemo-photothermal therapy of osteosarcoma. The average particle sizes of PLLA/CM and PDA-PLLA/CM microparticles with a spherical shape were (802.6 ± 8.0) nm and (942.5 ± 39.5) nm, respectively. PDA-PLLA/CM microparticles exhibited pH- and near-infrared (NIR)-responsive release behavior to promote CM release in the drug delivery system. Moreover, PDA-PLLA/CM microparticles displayed good photothermal conversion ability and photothermal stability attributed to PDA coating. Additionally, the results of in vitro anti-cancer experiment showed that 500 μg/mL PDA-PLLA/CM microparticles had good anti-cancer effect on MG-63 cells and no obvious toxicity to MC3T3-E1 cells. After incubation with PDA-PLLA/CM microparticles for 2 days, NIR irradiation treatment improved the anti-cancer activity of PDA-PLLA/CM microparticles obviously and reduced the cell viability of osteosarcoma from 47.4% to 20.6%. These results indicated that PDA-PLLA/CM microparticles possessed a synergetic chemo-photothermal therapy for osteosarcoma. Therefore, this study demonstrated that PDA-PLLA/CM microparticles may be an excellent drug delivery platform for chemo-photothermal therapy of tumors.

Glycosaminoglycans immobilized core-shell gold mesoporous silica nanoparticles for synergetic chemo-photothermal therapy of cancer cells

In this study, glycosaminoglycans hyaluronic acid (HA), heparin sulfate (HS) and heparin (HP) functionalized core-shell gold@mesoporous silica nanoparticles (Au@MSN) were fabricated. Their cellular behaviors were evaluated by culturing with GSH overexpressed tumor cells, which can cut off the disulfide bond between glycosaminoglycans (GAGs) and particles. Notably, Au@MSN@HS, Au@MSN@HP NPs could be swallowed by cells faster than Au@MSN@HA. Additionally, these GAGs functionalized nanoparticles possessed favorable photothermal effect under NIR laser irrradiation, contributing to a synergistic chemophotothermal treatment of cancer cells.

Preparation and synergistic chemo-photothermal therapy of redox-responsive carboxymethyl cellulose/chitosan complex nanoparticles

Chemo-photothermal combination therapy has great promise for enhanced tumor treatment. Hereby, we developed a complex nanoparticle using electrostatic absorption method, in which the inner chitosan (CS) NPs loaded polypyrrole (PPy) nanoparticles and 5-fluorouracil (5Fu), the outer shell was carboxymethyl cellulose (CMC) crosslinked with disulfide. The drug loaded polysaccharide complex nanoparticles displayed good photothermal effects, and the drug release would be triggered by multi-model response of NIR irradiation, high glutathione (GSH) and weak acidity in tumor environment. In vitro biological studies indicated the nanopartiles could be effectively internalized by HepG2 cancer cells. Moreover, the remarkable inhibition of the CMC complex PPy and 5Fu loaded CS nanoparticles (CMC/CS@PPy + 5Fu NPs) against tumor growth was achieved in HepG2-bearing mice model, suggesting its great potential for synergetic chemo-photothermal therapy.

Intelligent and spatiotemporal drug release based on multifunctional nanoparticle-integrated dissolving microneedle system for synergetic chemo-photothermal therapy to eradicate melanoma

Cutaneous melanoma is one of the most common malignant skin cancer with high lethality. Chemotherapy and photothermal therapy are important and extensively studied treatment modalities for melanoma. However, these therapies still face some challenges, which severely restrict their further applications, such as unsatisfactory efficacy of monotherapy, nonspecific uptake and release during drug delivery, and unexpected adverse effects from system administration. Recently, the strategies of collaboration, functional modification, stimuli-responsive design, and topical administration all show great prospect for solving above problems. In this research, a multifunctional nanoparticle-integrated dissolving microneedle drug delivery system was constructed, in which the nanoparticles were prepared based on the framework with the incorporation of photothermal agent (CuS) into Zeolitic imidazolate framework-8 and functionalized by hyaluronic acid. This system can co-load multi-modal drugs, improve specific uptake and distribution of targeted tumor, deliver drug locally, and release drug intelligently and spatiotemporally, thereby promising a low-dose administration with high efficiency. The high inhibiting tumor performance and excellent systematic safety were verified both in vitro and in vivo. Together, this smart design overcame the drawbacks of monotherapy and conventional system administration. We believe the nanoparticle-integrated dissolving microneedles will be in prospect of clinical application for more superficial tumors with further delicate optimization. Statement of significanceMelanoma is one of the most common skin cancers with high lethality. Extensively studied chemotherapy and photothermal therapy still face some challenges, such as the limited therapeutic efficacy and the severe system adverse effects. In order to overcome these drawbacks, the multifunctional nanoparticle-integrated dissolving microneedles (DMNs) were designed. Especially, the nanoparticles could co-load multi-modal drugs, improve specific uptake, and release drug intelligently and spatiotemporally. The microneedles could increase the drug accumulation in tumor, thus achieving excellent therapeutic efficacy and reducing side effects. This system paved the way to a less invasive, more focused and efficient therapeutic strategy for melanoma therapy.

Novel Multifunctional Stimuli-Responsive Nanoparticles for Synergetic Chemo–Photothermal Therapy of Tumors

In this study, a novel class of multifunctional responsive nanoparticles is designed and fabricated as drug nanocarriers for synergetic chemo-photothermal therapy of tumors. The proposed nanoparticles are composed of a thermo-/pH-responsive poly(N-isopropylacrylamide-co-acrylic acid) (PNA) nanogel core, a polydopamine (PDA) layer for photothermal conversion, and an outer folic acid (FA) layer as a targeting agent for the folate receptors on tumor cells. The fabricated nanoparticles show good biocompatibility and outstanding photothermal conversion efficiency. The proposed nanoparticles loaded with doxorubicin (DOX) drug molecules are stable under physiological conditions with low leakage of drugs, while rapidly release drugs in environments with low pH conditions and at high temperature. The experimental results show that the drug release process is mainly governed by Fickian diffusion. In vitro cell experimental results demonstrate that the PNA-DOX@PDA-FA nanoparticles can be phagocytized by 4T1 tumor cells and release drugs in tumor cell acidic environments, and confirm that the combined chemo and photothermal therapeutic efficacy of PNA-DOX@PDA-FA nanoparticles is higher than the photothermal therapeutic efficacy or the chemotherapeutic efficacy alone. The proposed multifunctional responsive nanoparticles in this study provide a novel class of drug nanocarriers as a promising tool for synergetic chemo-photothermal therapy of tumors.

Aptamer-functionalized molybdenum disulfide nanosheets for tumor cell targeting and lysosomal acidic environment/NIR laser responsive drug delivery to realize synergetic chemo-photothermal therapeutic effects.

Molybdenum disulfide (MoS2), one representative 2D nanomaterial, has recently emerged as a unique platform in the biomedical field. However, its application in drug delivery systems should be further exploited. Here, we report a novel tumor cell targeting and lysosomal acidic environment/NIR laser dual responsive drug delivery system for synergetic chemo-photothermal treatment of cancer cells. The MoS2 nanosheets were loaded with chemotherapy drug doxorubicin (DOX) and coated with polydopamine (PDA) layer. Then, thiolated aptamer AS1411 and polyethylene glycol (PEG) were modified onto MoS2 nanosheets through Michael addition reaction to construct DOX@Apt-PEG-PDA-MoS2 nanosheets. The aptamer modification endowed the nanoplatform with targeting ability to breast cancer MCF-7 cells. MoS2 and PDA converted 808nm NIR laser into heat and played the role of photothermal therapy (PTT). Tumor lysosomal acidic environment and NIR laser irradiation accelerated the release of DOX from the nanosheets. The nanocarrier Apt-PEG-PDA-MoS2 showed good biocompatibility, and DOX@Apt-PEG-PDA-MoS2 showed synergetic chemo-photothermal therapy effects with significantly enhanced anti-tumor efficacy, suggesting that this MoS2-based drug delivery platform is promising for targeted and synergetic treatment of cancer.

Phospholipid-Decorated Glycogen Nanoparticles for Stimuli-Responsive Drug Release and Synergetic Chemophotothermal Therapy of Hepatocellular Carcinoma.

Dendritic macromolecules are potential candidates for nanomedical application. Herein, glycogen, the natural hyperbranched polysaccharide with favorable biocompatibility, is explored as an effective drug vehicle for treating liver cancer. In this system, glycogen is oxidized and conjugated with cancer drugs through a disulfide link, followed by in situ loading of polypyrrole nanoparticles and then coated with functional phospholipids to form the desired system, Gly-ss-DOX@ppy@Lipid-RGD. The phospholipid layer has good cell affinity and can assist the system to penetrate into cells smoothly. Additionally, combined with the "fusion targeting" of glycogen and the active targeting effect of RGD toward liver cancer cells, Gly-ss-DOX@ppy@Lipid-RGD presents efficient specificity and enrichment of hepatocellular carcinoma. Owing to the glutathione-triggered cleavage of disulfide linkers, Gly-ss-DOX@ppy@Lipid-RGD can controllably release drugs to induce cell nucleus damage. Meanwhile, the polypyrrole nanoparticles can absorb near-infrared light and radiate heat energy within tumors. Besides enhancing drug release, the heat can also provide photothermal treatment for tumors. As proved by in vitro and in vivo experiments, Gly-ss-DOX@ppy@Lipid-RGD is a remarkable candidate for synergistic chemophotothermal therapy with high anticancer therapeutic activity and reduced systematic toxicity, efficiently suppressing tumor growth. All results demonstrate that glycogen nanoparticles are expected to be a new building block for accurate hepatocellular carcinoma treatment.

Polydopamine-doped virus-like mesoporous silica coated reduced graphene oxide nanosheets for chemo-photothermal synergetic therapy.

Multifunctional nanocarriers have been widely accepted and utilized for biomedical applications, because of their structural regularity, convenient post-modification and controllable structure and morphology. Herein, we reported polydopamine-doped virus-like mesoporous silica coated reduced graphene oxide nanosheets (rGO@PVMSNs) nanocomposites by a facile oil-water biphase stratification method. The synthesized rGO@PVMSNs nanocomposites performed excellent biocompatibility and photothermal performance. They could be employed as photoacoustic imaging contrast in vivo. Furthermore, the rGO@PVMSNs nanocarriers were used for loading the antitumor drug doxorubicin (DOX), the rGO@PVMSNs@DOX nanocomposites were also demonstrated to be with high inhibition of HepG2 cancer cells, especially with the help of near-infrared irradiation, which were more efficient than single chemotherapy or photothermal therapy. The rGO@PVMSNs@DOX nanocomposites of this work could be used as photoacoustic imaging and chemo-photothermal synergetic therapy agents, which show a new perspective for clinical tumor diagnosis and therapy.

Tumor environment responsive degradable CuS@mSiO2@MnO2/DOX for MRI guided synergistic chemo-photothermal therapy and chemodynamic therapy

Chemo-photothermal therapy and chemodynamic therapy have a great promise for enhanced tumor treatment effect for integration of Reactive Oxygen Species (ROS) and O2 generation. Hereby, a smart tumor environment (TME) responsive theranostic agent based on CuS@mSiO2@MnO2 nanocomposites was fabricated by a facile method. When the nanocomposites entered tumor, the drug release was triggered by multi-model response of NIR irradiation, weak acidity and high glutathione (GSH) in TME. The O2 and toxic •OH were generated from H2O2 in TME through catalyzing by MnO2, which relieved hypoxia and enhanced the effect of chemodynamic therapy (CDT). Meanwhile, the generated Mn2+ in TME was used to monitor the nanocomposites delivery by magnetic resonance imaging (MRI). Also, the excellent photothermal therapy effect could be triggered by NIR irradiation for CuS core. More importantly, the growth of tumors was greatly inhibited by the synergetic chemo-photothermal therapy and CDT. This work may open a wide route for tumor environment responsive theranostic, including relieving hypoxia, chemo-photothermal therapy, CDT and MR imaging.

Composite phospholipid-coated hollow mesoporous silica nanoplatform with multi-stimuli responsiveness for combined chemo-photothermal therapy

Chemo-photothermal therapy can improve the therapeutic effects of simple chemotherapy with the help of cytotoxic heat generated by photothermal therapy. In this paper, a novel nanoplatform based on hollow mesoporous silica (HMSN) was constructed, which could achieve multi-stimuli-responsive release through chemo-photothermal interaction. Cypate as a NIR photothermal agent was conjugated to the outer surface of HMSN by disulfide bonds. Due to the insoluble feature, Cypate imparted lipophilicity to the surface of HMSN, thereby promoting the strong encapsulation of complex phospholipid layer by hydrophobic interaction. The phospholipid layer hindered the premature release of the model drug doxorubicin (DOX), prolonged the circulation time in vivo, and improved the biocompatibility and stability in physiological environment. Under glutathione, acidic conditions and NIR irradiation, the release of DOX was significantly accelerated, indicating that DOX/HMSN-CyL exhibited redox/pH/NIR multi-stimuli in response to drug release. Cytotoxicity experiments have proved that combination therapy induced the maximum levels of cell killing. Furthermore, combination index of DOX/HMSN-CyL was 0.26, demonstrating the chemo-photothermal synergetic therapy. Multicellular tumor spheroid experiments were also performed, and the same trend was showed. In summary, this novel nanoplatform has broad application prospects as a drug delivery system for combination therapy.

Tumor microenvironment and NIR laser dual-responsive release of berberine 9-O-pyrazole alkyl derivative loaded in graphene oxide nanosheets for chemo-photothermal synergetic cancer therapy.

A berberine 9-O-pyrazole alkyl derivative, a chemical compound (called B3) previously synthesized by our group, shows anti-cancer activity. However, B3 lacks targeting cytotoxicity to cancer cells, leading to obvious toxic side effects on normal cells. To solve this problem, here, we prepared a drug delivery system, namely, AS1411-GO/B3 for tumor targeting, in which nano-graphene oxide (GO) sheets were employed as the drug carrier, and the aptamer AS1411 was conjugated onto GO for tumor targeting. GO also had a photothermal effect, which helped the release of B3 from GO as well as the thermal cytotoxicity to cells. We found that the release of B3 could respond to acid conditions, indicating that the tumor intracellular environment could promote the release of B3, thus allowing it to perform chemotherapy effects. This system could also release B3 in response to photothermal heating, moreover, combined photothermal therapy and chemotherapy to improve the anticancer activity was achieved. This AS1411-GO/B3 platform with chemo-photothermal synergetic therapy provides a very promising treatment for tumors.

PH-Controlled Intracellular in Situ Reversible Assembly of a Photothermal Agent for Smart Chemo-Photothermal Synergetic Therapy and ATP Imaging.

To advance anti-tumor efficiency and lessen the adverse effect caused by nanodrug residues in the body, a smart nanoagent system is developed and successfully used in intracellular ATP imaging and in vivo chemo-photothermal synergetic therapy. The nanoagent system is facilely prepared using a DNA complex to modify gold nanoparticles (AuNPs). The DNA complex is formed by three oligonucleotides (ATP aptamer, rC-DNA, and rG-DNA). The CG-rich structure in a ternary DNA complex could be exploited for payload of chemotherapeutic medicine doxorubicin (DOX), thus making efficient DOX transport into the tumor site possible. In tumor cells, especially in acidic organelles (e.g., endosome and lysosome), DOX could be rapidly released via the dual stimuli of overexpressed ATP and pH. What is more, the specific recognition of a fluorescently labeled aptamer strand to ATP can achieve the intracellular ATP imaging. pH-controlled reversible folding and unfolding of intermolecular i-motif formed by C-rich strands can lead to intracellular in situ assembly of AuNP aggregates with high photothermal conversion efficiency and promote relatively facile renal clearance of AuNPs through the disassociation of the aggregates in extracellular environments. Experiments in vivo and vitro present feasibility for a synergetic chemo-photothermal therapy. Such an in situ reversible assembly strategy of a chemo-photothermal agent also presents a new paradigm for a smart and highly efficient disease treatment with reduced side effects.