Thermosensitive Hydrogel Co-loaded with Gold Nanoparticles and Doxorubicin for Effective Chemoradiotherapy.
ABSTRACT: Chemoradiotherapy, as a well-established paradigm to treat various cancers, still calls for novel strategies. Recently, gold nanoparticles (AuNPs) have been shown to play an important role as a radiosensitizer in cancer radiotherapy. The aim of this study was to evaluate the combination of polyethylene glycol (PEG) modified AuNPs and doxorubicin (DOX) to improve cancer chemoradiotherapy, in which the AuNPs was the radiosensitizer and the DOX was the model chemotherapeutic. A Pluronic® F127-based thermosensitive hydrogel (Au-DOX-Gel) loading AuNPs and DOX was developed by "cold method" for intratumoral injection. The formulation was optimized at a F127 concentration of 22% for Au-DOX-Gel. The release profiles compared to a control group were assessed in vitro and in vivo. Au-DOX-Gel showed sustained release of AuNPs and DOX. The cell viability and surviving fraction of mouse melanoma (B16) and Human hepatocellular liver carcinoma (HepG2) cells were significantly inhibited by the combination treatment of DOX and AuNPs under radiation. Tumor sizes of mice were significantly decreased by Au-DOX-Gel compared to controls. Interestingly, 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and Ki-67 staining results showed that tumor cell growth and proliferation were inhibited by AuNPs combined with DOX under radiation, suggesting that the radiosensitization activity and combination effects might be caused by inhibition of tumor cell growth and proliferation. Furthermore, the results of skin safety tests, histological observation of organs, and the body weight changes indicated in vivo safety of Au-DOX-Gel. In conclusion, the Au-DOX-Gel developed in this study could represent a promising strategy for improved cancer chemoradiotherapy.
Project description:Radiotherapy performs an important function in the treatment of cancer, but resistance of tumor cells to radiation still remains a serious concern. More research on more effective radiosensitizers is urgently needed to overcome such resistance and thereby improve the treatment outcome. The goal of this study was to evaluate and compare the radiosensitizing efficacies of gold nanoparticles (AuNPs) and silver nanoparticles (AgNPs) on glioma at clinically relevant megavoltage energies. Both AuNPs and AgNPs potentiated the in vitro and in vivo antiglioma effects of radiation. AgNPs showed more powerful radiosensitizing ability than AuNPs at the same mass and molar concentrations, leading to a higher rate of apoptotic cell death. Furthermore, the combination of AgNPs with radiation significantly increased the levels of autophagy as compared with AuNPs plus radiation. These findings suggest the potential application of AgNPs as a highly effective nano-radiosensitizer for the treatment of glioma.
Project description:Gold nanoparticles (AuNPs) have generated interest as both imaging and therapeutic agents. AuNPs are attractive for imaging applications since they are nontoxic and provide nearly three times greater X-ray attenuation per unit weight than iodine. As therapeutic agents, AuNPs can sensitize tumor cells to ionizing radiation. To create a nanoplatform that could simultaneously exhibit long circulation times, achieve appreciable tumor accumulation, generate computed tomography (CT) image contrast, and serve as a radiosensitizer, gold-loaded polymeric micelles (GPMs) were prepared. Specifically, 1.9 nm AuNPs were encapsulated within the hydrophobic core of micelles formed with the amphiphilic diblock copolymer poly(ethylene glycol)-b-poly(?-capralactone). GPMs were produced with low polydispersity and mean hydrodynamic diameters ranging from 25 to 150 nm. Following intravenous injection, GPMs provided blood pool contrast for up to 24 h and improved the delineation of tumor margins via CT. Thus, GPM-enhanced CT imaging was used to guide radiation therapy delivered via a small animal radiation research platform. In combination with the radiosensitizing capabilities of gold, tumor-bearing mice exhibited a 1.7-fold improvement in the median survival time, compared with mice receiving radiation alone. It is envisioned that translation of these capabilities to human cancer patients could guide and enhance the efficacy of radiation therapy.
Project description:BACKGROUND This study aimed to prepare doxorubicin- and tetrahydrocurcumin-loaded and transferrin-modified PEG-PLGA nanoparticles (Tf-NPs-DOX-THC) for enhanced and synergistic chemoradiotherapy. MATERIAL AND METHODS Tf-NPs-DOX-THC were prepared via the double-emulsion method. The morphologies and particle sizes of the prepared nanoparticles were examined by TEM and DLS, respectively. The in vitro MTT, apoptosis, and clone formation assays were performed to detect the proliferation and radiosensitivity of cells with various treatments. Cellular uptake assay was also conducted. The tissue distribution of Tf-NPs was investigated by ex vivo DOX fluorescence imaging. The in vivo tumor growth inhibition efficiency of various treatments was evaluated in orthotopic C6 mouse models and C6 subcutaneously grafted mouse models. RESULTS Tf-NPs-DOX-THC exhibited high drug-loading efficiency (6.56±0.32%) and desirable particle size (under 250 nm). MTT, apoptosis, and clone formation assays revealed the enhanced anti-cancer activity and favorable radiosensitizing effect of Tf-NPs-DOX-THC. Strong fluorescence was observed in the brains of mice treated with Tf-NPs-DOX. The in vitro release of drug from nanoparticles was in a pH-sensitive manner. Tf-NPs-DOX-THC in combination with radiation also achieved favorable anti-tumor efficacy in vivo. CONCLUSIONS All results suggest that a combination of Tf-NPs-DOX-THC and radiation is a promising strategy for synergistic and sensitizing chemoradiotherapy of glioma.
Project description:Development of drug delivery system conjugated with doxorubicin (dox) on the surface of AuNPs with polyvinylpyrrolidone (Dox@PVP-AuNPs), we have demonstrated that human lung cancer cells can significantly overcome by the combination of highly effective cellular entry and responsive intracellular release of doxorubicin from Dox@PVP-AuNPs complex. Previously drug release from doxorubicin-conjugated AuNPs was confirmed by the recovered fluorescence of doxorubicin from quenching due to the nanosurface energy transfer between doxorubicinyl groups and AuNPs. Dox@PVP-AuNPs achieved enhanced inhibition of lung cancer cells growth than free Doxorubicin and PVP-AuNPs. The in vitro cytotoxic effect of PVP-AuNPs, free Dox and Dox@PVP-AuNPs inhibited the proliferation of human lung cancer cells with IC50 concentration. Compared with control cells, PVP-AuNPs and free Dox, Dox@PVP-AuNPs can increases ROS generation, sensitize mitochondrial membrane potential and induces both early and late apoptosis in lung cancer cells. Moreover, Dox@PVP-AuNPs highly upregulates the expression of tumor suppressor genes than free Dox and PVP-AuNPs and induces intrinsic apoptosis in lung cancer cells. From the results, Dox@PVP-AuNPs can be considered as an potential drug delivery system for effective treatment of human lung cancer.
Project description:The use of radiosensitizers in clinical radiotherapy is limited by systemic toxicity. The biopolymeric, biodegradable, injectable liposome-in-gel-paclitaxel (LG-PTX) system was developed for regional delivery of the radiosensitizer paclitaxel (PTX), and its efficacy was evaluated with concurrent fractionated radiation. LG-PTX is composed of nano-sized drug-loaded fluidizing liposomes, which are incorporated into a porous biodegradable gellan hydrogel. This allows enhanced drug permeation while maintaining a localization of the drug depot. LG-PTX had an IC50 of 325±117 nM in B16F10 melanoma cells, and cytotoxicity with concurrent doses of fractionated radiation showed significant increase in apoptotic cells (75%) compared to radiation (39%) or LG-PTX (43%) alone. Peri-tumoral injection in tumor-bearing mice showed PTX localization in the tumor 2 hours after administration, with no drug detected in plasma or other organs. LG-PTX administration with doses of focal radiation (5×3 Gy) significantly reduced tumor volumes compared to control (6.4 times) and radiation alone (1.6 times) and improved animal survival. LG-PTX thus efficiently localizes the drug at the tumor site and synergistically enhances the effect of concurrent radiotherapy. This novel liposome-in-gel system can potentially be used as a platform technology for the delivery of radiosensitizing drugs to enhance the efficacy of chemoradiotherapy.
Project description:In this study, a transferrin (Tf)-conjugated polymeric nanoparticle was developed for the targeted delivery of the chemotherapeutic agent doxorubicin (Dox) in order to overcome multi-drug resistance in cancer treatment. Our objective was to improve Dox delivery for producing significant antitumor efficacy in Dox-resistant (R) breast cancer cell lines with minimum toxicity to healthy cells. The results of our experiments revealed that Dox was successfully loaded inside a transferrin (Tf)-conjugated polymeric nanoparticle composed of poloxamer 407 (F127) and 123 (P123) (Dox/F127&P123-Tf), which produced nanosized particles (~90 nm) with a low polydispersity index (~0.23). The accelerated and controlled release profiles of Dox from the nanoparticles were characterized in acidic and physiological pH and Dox/F127&P123-Tf enhanced Dox cytotoxicity in OVCAR-3, MDA-MB-231, and MDA-MB-231(R) cell lines through induction of cellular apoptosis. Moreover, Dox/F127&P123-Tf inhibited cell migration and altered the cell cycle patterns of different cancer cells. In vivo study in MDA-MB-231(R) tumor-bearing mice demonstrated enhanced delivery of nanoparticles to the tumor site when coated in a targeting moiety. Therefore, Dox/F127&P123-Tf has been tailored, using the principles of nanotherapeutics, to overcome drug-resistant chemotherapy.
Project description:Functionalized gold nanoparticles (AuNPs) have been successfully used in many fields as a result of having low cytotoxicity, good biocompatibility, excellent optical properties, and their ability to target cancer cells. Here, we synthesized AuNP carriers that were modified by hyaluronic acid (HA), polyethylene glycol (PEG), and adipic dihydrazide (ADH). The antitumor drug doxorubicin (Dox) was loaded into AuNP carriers and attached chemically. The Au nanocomposite AuNPs@MPA-PEG-HA-ADH-Dox was able to disperse uniformly in aqueous solution, with a diameter of 15 nm. The results of a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay indicated that AuNP carriers displayed very little toxicity toward cells in high doses, although the antitumor properties of Au nanocomposites were significantly enhanced. Cellular uptake experiments demonstrated that AuNPs modified with hyaluronic acid were more readily ingested by HepG2 and HCT-116 cells, as they have a large number of CD44 receptors. A series of experiments measuring apoptosis such as Rh123 and annexin V-FITC staining, and analysis of mitochondrial membrane potential (MMP) analysis, indicated that apoptosis played a role in the inhibition of cell proliferation by AuNPs@MPA-PEG-HA-ADH-Dox. Excessive production of reactive oxygen species (ROS) was the principal mechanism by which the Au nanocomposites inhibited cell proliferation, leading to apoptosis. Thus, the Au nanocomposites, which allowed cell imaging in real-time and induced apoptosis in specific cell types, represent theragnostic agents with potential for future clinical applications in bowel cancer.
Project description:Treatment of malignant glioma is a challenge facing cancer therapy. In addition to surgery, and chemotherapy, radiotherapy (RT) is one of the most effective modalities of glioma treatment. However, there are two crucial challenges for RT facing malignant glioma therapy: first, gliomas are known to be resistant to radiation due to their intratumoral hypoxia; second, radiosensitizers may exhibit a lack of target specificity, which may cause a lower concentration of radiosensitizers in tumors and toxic side effects in normal tissues. Thus, novel angiopep-2-lipid-poly-(metronidazoles)n (ALP-(MIs)n) hypoxic radiosensitizer-polyprodrug nanoparticles (NPs) were designed to enhance the radiosensitizing effect on gliomas. Methods: In this study, different degrees and biodegradabilites of hypoxic radiosensitizer MIs-based polyprodrug (P-(MIs)n) were synthesized as a hydrophobic core. P-(MIs)n were mixed with DSPE-PEG2000, angiopep-2-DSPE-PEG2000 and lecithin to self-assemble ALP-(MIs)n through a single-step nanoprecipitation method. The ALP-(MIs)n encapsulate doxorubicin (DOX) (ALP-(MIs)n/DOX) and provoke the release of DOX under hypoxic conditions for glioma chemo- and radiotherapy. In vivo glioma targeting was tested in an orthotopic glioma using live animal fluorescence/bioluminescence imaging. The effect on sensitization to RT of ALP-(MIs)n and the combination of chemotherapy and RT of ALP-(MIs)n/DOX for glioma treatment were also investigated both in vitro and in vivo. Results: ALP-(MIs)n/DOX effectively accumulated in gliomas and could reach the hypoxic glioma site after systemic in vivo administration. These ALP-(MIs)n showed a significant radiosensitizing effect on gliomas and realized combination chemotherapy and RT for glioma treatment both in vitro and in vivo. Conclusions: In summary, we constructed a lipid-poly-(hypoxic radiosensitized polyprodrug) nanoparticles for enhancing the RT sensitivity of gliomas and achieving the combination of radiation and chemotherapy for gliomas.
Project description:The development of stereotactic body radiation therapy (SBRT) has revolutionized radiation therapy for lung cancers and is an emerging treatment option for pancreatic cancers. However, there are many questions on how to optimize its use in chemoradiotherapy. The most relevant addition to radiotherapy regimens are inhibitors of DNA repair and DNA damage response pathways. One such class of agents are inhibitors of poly (ADP-ribose) polymerase (PARP). In this study we examined the effects of the PARP inhibitor LT626 in combination with ionizing radiation in lung and pancreatic cancers. Our study demonstrated that combination treatment with LT626 and radiation effectively inhibited growth in lung and pancreatic cancer cell lines, better than individual treatment alone. Combination treatment also increased expression of ?H2AX and 53BP1 foci and upregulated expression of phosphorylated ATM, ATR and their respective kinases. Using in vivo lung cancer xenograft models we demonstrated that LT626 functioned as an effective radiosensitizer during fractionated radiation treatment, leading to significant decrease in tumor burden and doubling the median survival compared to control group. Overall our in vitro and in vivo studies showed that PARP inhibitor LT626 acted synergistically with radiation in lung and pancreatic cancers.
Project description:The current research demonstrates the feasible biomedical application of AuNPs coated with doxorubicin (Dox)-loaded fucoidan (Fu) for dual-chemotherapy and photothermal treatment (PTT) on eye tumors in vitro and in vivo. Marine-derived Fu was used as a capping agent to achieve high photostability for AuNPs, and Dox as a FDA-approved anti-cancer drug was added to induce chemotherapy. The synthesized Dox-Fu@AuNPs exhibited high cytotoxicity on the tumor cells and strong light absorption for temperature increase in vitro. After intratumoral injection of Dox-Fu@AuNPs in the rabbit eye tumors, PTT-assisted Dox-Fu@AuNPs entailed the complete removal of the eye tumors without recurrence for 14 days after the treatment. Photoacoustic image contrast from the tumor regions was enhanced due to selective light absorption by the administered Dox-Fu@AuNPs. Therefore, the proposed Dox-Fu@AuNPs can be a potential nano-theranostic material for treating and diagnosing the eye tumors.