-
Ultrasonics Aug 2023Phase-changing nanodroplets are nanometric sized constructs that can be vaporized via external stimuli, such as focused ultrasound, to generate gaseous bubbles that are...
Phase-changing nanodroplets are nanometric sized constructs that can be vaporized via external stimuli, such as focused ultrasound, to generate gaseous bubbles that are visible in ultrasound. Their activation can also be leveraged to release their payload, creating a method for ultrasound-modulated localized drug delivery. Here, we develop a perfluoropentane core nanodroplet that can simultaneously load paclitaxel and doxorubicin, and release them in response to an acoustic trigger. A double emulsion method is used to incorporate the two drugs with different physio-chemical properties, which allows for a combinatorial chemotherapy regimen to be used. Their loading, release, and biological effects on a triple negative breast cancer mouse model are investigated. We show that activation enhances the drug-delivery effect and delays the tumor growth rate in vivo. Overall, the phase-changing nanodroplets are a useful platform to allow on-demand delivery of combinations of drugs.
Topics: Animals; Mice; Pharmaceutical Preparations; Nanoparticles; Drug Delivery Systems; Doxorubicin; Drug Therapy, Combination; Fluorocarbons
PubMed: 37269682
DOI: 10.1016/j.ultras.2023.107056 -
Molecular Pharmaceutics Aug 2023Nanoparticles (NPs) show great advantages in cancer treatment by enabling controlled and targeted delivery of payloads to tumor sites through the enhanced permeability...
Nanoparticles (NPs) show great advantages in cancer treatment by enabling controlled and targeted delivery of payloads to tumor sites through the enhanced permeability and retention (EPR) effect. In this study, highly effective pH-responsive and biodegradable calcium orthophosphate@liposomes (CaP@Lip) NPs with a diameter of 110 ± 20 nm were designed and fabricated. CaP@Lip NPs loaded with hydrophobic paclitaxel and hydrophilic doxorubicin hydrochloride achieved excellent drug loading efficiencies of 70 and 90%, respectively. Under physiological conditions, the obtained NPs are negatively charged. However, they switched to positively charged when exposed to weak acidic environments by which internalization can be promoted. Furthermore, the CaP@Lip NPs exhibit an obvious structural collapse under acid conditions (pH 5.5), which confirms their excellent biodegradability. The "proton expansion" effect in endosomes and the pH-responsiveness of the NPs facilitate the release of encapsulated drugs from individual channels. The effectiveness and safety of the drug delivery systems were demonstrated through in vitro and in vivo experiments, with a 76% inhibition of tumor growth. These findings highlight the high targeting ability of the drug-loaded NPs to tumor sites through the EPR effect, effectively suppressing tumor growth and metastasis. By combining CaP NPs and liposomes, this study not only resolves the toxicity of CaP but also enhances the stability of liposomes. The CaP@Lip NPs developed in this study have significant implications for biomedical applications and inspire the development of intelligent and smart drug nanocarriers and release systems for clinical use.
Topics: Humans; Female; Doxorubicin; Breast Neoplasms; Liposomes; Paclitaxel; Calcium; Phosphates; Cell Line, Tumor; Drug Delivery Systems; Nanoparticles; Hydrogen-Ion Concentration
PubMed: 37384449
DOI: 10.1021/acs.molpharmaceut.3c00015 -
Cardiovascular Toxicology Aug 2023Doxorubicin is associated with cardiotoxicity, and physical exercise seeks to minimize the toxic effects of doxorubicin through physiological cardiac remodeling, as well...
Doxorubicin is associated with cardiotoxicity, and physical exercise seeks to minimize the toxic effects of doxorubicin through physiological cardiac remodeling, as well as the reduction of oxidative stress, evidenced by previous studies. This study aimed to analyze whether running training before treatment with doxorubicin influences tolerance to physical exertion and cardiotoxicity. Thirty-nine male Wistar rats, aged 90 days and weighing between 250 and 300 g, were divided into 4 groups: Control (C), Doxorubicin (D), Trained (T), and Trained + Doxorubicin (TD). Animals in groups T and DT were submitted to treadmill running for 3 weeks, 5 times a week at 18 m/min for 20-30 min before treatment with doxorubicin. Animals in groups D and DT received intraperitoneal injections of doxorubicin hydrochloride three times a week for two weeks, reaching a total cumulative dose of 7.50 mg/kg. Our results show an increase in total collagen fibers in the D group (p = 0.01), but no increase in the TD group, in addition to the attenuation of the number of cardiac mast cells in the animals in the TD group (p = 0.05). The animals in the TD group showed maintenance of tolerance to exertion compared to group D. Therefore, running training attenuated the cardiac damage caused by the treatment with doxorubicin, in addition to maintaining the tolerance to exertion in the rats.
Topics: Rats; Male; Animals; Cardiotoxicity; Antibiotics, Antineoplastic; Rats, Wistar; Physical Conditioning, Animal; Doxorubicin
PubMed: 37402033
DOI: 10.1007/s12012-023-09798-2 -
International Journal of Molecular... Jul 2023Treatment of highly malignant soft tissue sarcomas (STSs) requires multicomponent therapy including surgery, radiotherapy, and chemotherapy. Despite the advancements in...
Treatment of highly malignant soft tissue sarcomas (STSs) requires multicomponent therapy including surgery, radiotherapy, and chemotherapy. Despite the advancements in targeted cancer therapies, cytostatic drug combinations remain the gold standard for STS chemotherapy. The lack of algorithms for personalized selection of STS chemotherapy leads to unhelpful treatment of chemoresistant tumors, causing severe side effects in patients. The goal of our study is to assess the applicability of in vitro chemosensitivity/resistance assays (CSRAs) in predicting STS chemoresistance. Primary cell cultures were obtained from 148 surgery samples using enzymatic and mechanical disaggregation. CSRA was performed using resazurin-based metabolic activity measurement in cells cultured with doxorubicin, ifosfamide, their combination and docetaxel, gemcitabine, and also their combination for 7 days. Both the clinical data of patients and the CSRA results demonstrated a higher resistance of some cancer histotypes to specific drugs and their combinations. The correlation between the CSRA results for doxorubicin and ifosfamide and clinical responses to the combination chemotherapy with these drugs was demonstrated via Spearman rank order correlation. Statistically significant differences in recurrence-free survival were also shown for the groups of patients formed, according to the CSRA results. Thus, CSRAs may help both practicing physicians to avoid harmful and useless treatment, and researchers to study new resistance markers and to develop new STS drugs.
Topics: Humans; Ifosfamide; Antineoplastic Combined Chemotherapy Protocols; Sarcoma; Soft Tissue Neoplasms; Doxorubicin
PubMed: 37569668
DOI: 10.3390/ijms241512292 -
Advanced Healthcare Materials Dec 2023Blockage of blood supply while administering chemotherapy to tumors, using trans-arterial chemoembolization (TACE), is the most common treatment for intermediate and...
Blockage of blood supply while administering chemotherapy to tumors, using trans-arterial chemoembolization (TACE), is the most common treatment for intermediate and advanced-stage unresectable Hepatocellular carcinoma (HCC). However, HCC is characterized by a poor prognosis and high recurrence rates (≈30%), partly due to a hypoxic pro-angiogenic and pro-cancerous microenvironment. This study investigates how modifying tissue stress while improving drug exposure in target organs may maximize the therapeutic outcomes. Porous degradable polymeric microspheres (MS) are designed to obtain a gradual occlusion of the hepatic artery that nourishes the liver, while enabling efficient drug perfusion to the tumor site. The fabricated porous MS are introduced intrahepatically and designed to release a combination therapy of Doxorubicin (DOX) and Tirapazamine (TPZ), which is a hypoxia-activated prodrug. Liver cancer cell lines that are treated with the combination therapy under hypoxia reveal a synergic anti-proliferation effect. An orthotopic liver cancer model, based on N1-S1 hepatoma in rats, is used for the efficacy, biodistribution, and safety studies. Porous DOX-TPZ MS are very effective in suppressing tumor growth in rats, and induction tissue necrosis is associated with high intratumor drug concentrations. Porous particles without drugs show some advantages over nonporous particles, suggesting that morphology may affect the treatment outcomes.
Topics: Rats; Animals; Liver Neoplasms; Carcinoma, Hepatocellular; Microspheres; Tissue Distribution; Porosity; Chemoembolization, Therapeutic; Doxorubicin; Tirapazamine; Hypoxia; Tumor Microenvironment
PubMed: 37315950
DOI: 10.1002/adhm.202301548 -
Journal of Nanobiotechnology Oct 2023The combination of drug delivery with immune checkpoint targeting has been extensively studied in cancer therapy. However, the clinical benefit for patients from this...
BACKGROUND
The combination of drug delivery with immune checkpoint targeting has been extensively studied in cancer therapy. However, the clinical benefit for patients from this strategy is still limited. B7 homolog 3 protein (B7-H3), also known as CD276 (B7-H3/CD276), is a promising therapeutic target for anti-cancer treatment. It is widely overexpressed on the surface of malignant cells and tumor vasculature, and its overexpression is associated with poor prognosis. Herein, we report B7H3 targeting doxorubicin (Dox)-conjugated gold nanocages (B7H3/Dox@GNCs) with pH-responsive drug release as a selective, precise, and synergistic chemotherapy-photothermal therapy agent against non-small-cell lung cancer (NSCLC).
RESULTS
In vitro, B7H3/Dox@GNCs exhibited a responsive release of Dox in the tumor acidic microenvironment. We also demonstrated enhanced intracellular uptake, induced cell cycle arrest, and increased apoptosis in B7H3 overexpressing NSCLC cells. In xenograft tumor models, B7H3/Dox@GNCs exhibited tumor tissue targeting and sustained drug release in response to the acidic environment. Wherein they synchronously destroyed B7H3 positive tumor cells, tumor-associated vasculature, and stromal fibroblasts.
CONCLUSION
This study presents a dual-compartment targeted B7H3 multifunctional gold conjugate system that can precisely control Dox exposure in a spatio-temporal manner without evident toxicity and suggests a general strategy for synergistic therapy against NSCLC.
Topics: Humans; B7 Antigens; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Doxorubicin; Drug Liberation; Gold; Hydrogen-Ion Concentration; Hyperthermia, Induced; Lung Neoplasms; Nanoparticles; Phototherapy; Photothermal Therapy; Tumor Microenvironment; Antineoplastic Agents; Animals; Mice; Xenograft Model Antitumor Assays
PubMed: 37848956
DOI: 10.1186/s12951-023-02078-9 -
Small (Weinheim An Der Bergstrasse,... Dec 2023Bacterial therapy is an emerging hotspot in tumor immunotherapy, which can initiate antitumor immune activation through multiple mechanisms. Porphyromonas gingivalis...
Bacterial therapy is an emerging hotspot in tumor immunotherapy, which can initiate antitumor immune activation through multiple mechanisms. Porphyromonas gingivalis (Pg), a pathogenic bacterium inhabiting the oral cavity, contains a great deal of pathogen associated molecular patterns that can activate various innate immune cells to promote antitumor immunity. Owing to the presence of protoporphyrin IX (PpIX), Pg is also an excellent photosensitizer for photodynamic therapy (PDT) via the in situ generation of reactive oxygen species. This study reports a bacterial nanomedicine (nmPg) fabricated from Pg through lysozyme degradation, ammonium chloride lysis, and nanoextrusion, which has potent PDT and immune activation performances for oral squamous cell carcinoma (OSCC) treatment. To further promote the tumoricidal efficacy, a commonly used chemotherapeutic drug doxorubicin (DOX) is efficiently encapsulated into nmPg through a simple incubation method. nmPg/DOX thus prepared exhibits significant synergistic effects on inhibiting the growth and metastasis of OSCC both in vitro and in vivo via photodynamic-immunotherapy and chemotherapy. In summary, this work develops a promising bacterial nanomedicine for enhanced treatment of OSCC.
Topics: Humans; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Mouth Neoplasms; Photochemotherapy; Nanomedicine; Photosensitizing Agents; Doxorubicin; Head and Neck Neoplasms; Immunotherapy; Cell Line, Tumor
PubMed: 37653616
DOI: 10.1002/smll.202304014 -
Carbohydrate Polymers May 2024Lumpectomy plus radiation is a treatment option offering better survival than conventional mastectomy for patients with early-stage breast cancer. However, successive...
Lumpectomy plus radiation is a treatment option offering better survival than conventional mastectomy for patients with early-stage breast cancer. However, successive radioactive therapy remains tedious and unsafe with severe adverse reactions and secondary injury. Herein, a composite hydrogel with pH- and photothermal double-sensitive activity is developed via physical crosslinking. The composite hydrogel incorporated with tempo-oxidized cellulose nanofiber (TOCN), polyvinyl alcohol (PVA) and a polydopamine (PDA) coating for photothermal therapy (PTT) triggered in situ release of doxorubicin (DOX) drug was utilized to optimize postoperative strategies of malignant tumors inhibition. The incorporation of TOCN significantly affects the performance of composite hydrogels. The best-performing TOCN/PVA7 was selected for drug loading and polydopamine coating by rational design. In vitro studies have demonstrated that the composite hydrogel exhibited high NIR photothermal conversion efficiency, benign cytotoxicity to L929 cells, pH-dependent release profiles, and strong MCF-7 cell inhibitory effects. Then the TOCN/PVA7-PDA@DOX hydrogel is implanted into the tumor resection cavity for local in vivo chemo-photothermal synergistical therapy to ablate residue tumor tissues. Overall, this work suggests that such a chemo-photothermal hydrogel delivery system has great potential as a promising tool for the postsurgical management of breast cancer.
Topics: Humans; Female; Breast Neoplasms; Cellulose, Oxidized; Photothermal Therapy; Hydrogels; Phototherapy; Hyperthermia, Induced; Mastectomy; Doxorubicin; Hydrogen-Ion Concentration
PubMed: 38431421
DOI: 10.1016/j.carbpol.2024.121931 -
Circulation Research Mar 2024
Topics: Humans; Cardiotoxicity; Cardio-Oncology; Doxorubicin; Heart Diseases
PubMed: 38422182
DOI: 10.1161/CIRCRESAHA.124.324243 -
Nanoscale May 2024Nanotechnology has the potential to provide formulations of antitumor agents with increased selectivity towards cancer tissue thereby decreasing systemic toxicity. This...
Nanotechnology has the potential to provide formulations of antitumor agents with increased selectivity towards cancer tissue thereby decreasing systemic toxicity. This study evaluated the potential of novel nanoformulation based on poly(lactic--glycolic acid) (PLGA) to reduce the cardiotoxic potential of doxorubicin (DOX). toxicity of PLGADOX was compared with clinically approved non-PEGylated, liposomal nanoformulation of DOX (LipoDOX) and conventional DOX form (ConvDOX). The study was performed using Wistar Han rats of both sexes that were treated intravenously for 28 days with 5 doses of tested substances at intervals of 5 days. Histopathological analyses of heart tissues showed the presence of myofiber necrosis, degeneration processes, myocytolysis, and hemorrhage after treatment with ConvDOX, whereas only myofiber degeneration and hemorrhage were present after the treatment with nanoformulations. All DOX formulations caused an increase in the troponin T with the greatest increase caused by convDOX. qPCR analyses revealed an increase in the expression of inflammatory markers IL-6 and IL-8 after ConvDOX and an increase in IL-8 expression after lipoDOX treatments. The mass spectra imaging (MSI) of heart tissue indicates numerous metabolic and lipidomic changes caused by ConvDOX, while less severe cardiac damages were found after treatment with nanoformulations. In the case of LipoDOX, autophagy and apoptosis were still detectable, whereas PLGADOX induced only detectable mitochondrial toxicity. Cardiotoxic effects were frequently sex-related with the greater risk of cardiotoxicity observed mostly in male rats.
Topics: Doxorubicin; Animals; Polylactic Acid-Polyglycolic Acid Copolymer; Rats; Male; Cardiotoxicity; Female; Rats, Wistar; Apoptosis; Nanoparticles; Myocardium; Polyethylene Glycols; Antibiotics, Antineoplastic; Heart; Liposomes
PubMed: 38650478
DOI: 10.1039/d3nr06269d