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Scientific Reports Jun 2024Liver cancer ranks as the fifth leading cause of cancer-related death globally. Direct intratumoral injections of anti-cancer therapeutics may improve therapeutic...
Liver cancer ranks as the fifth leading cause of cancer-related death globally. Direct intratumoral injections of anti-cancer therapeutics may improve therapeutic efficacy and mitigate adverse effects compared to intravenous injections. Some challenges of intratumoral injections are that the liquid drug formulation may not remain localized and have unpredictable volumetric distribution. Thus, drug delivery varies widely, highly-dependent upon technique. An X-ray imageable poloxamer 407 (POL)-based drug delivery gel was developed and characterized, enabling real-time feedback. Utilizing three needle devices, POL or a control iodinated contrast solution were injected into an ex vivo bovine liver. The 3D distribution was assessed with cone beam computed tomography (CBCT). The 3D distribution of POL gels demonstrated localized spherical morphologies regardless of the injection rate. In addition, the gel 3D conformal distribution could be intentionally altered, depending on the injection technique. When doxorubicin (DOX) was loaded into the POL and injected, DOX distribution on optical imaging matched iodine distribution on CBCT suggesting spatial alignment of DOX and iodine localization in tissue. The controllability and localized deposition of this formulation may ultimately reduce the dependence on operator technique, reduce systemic side effects, and facilitate reproducibility across treatments, through more predictable standardized delivery.
Topics: Hydrogels; Animals; Doxorubicin; Drug Delivery Systems; Poloxamer; Cattle; Cone-Beam Computed Tomography; Needles; Liver
PubMed: 38858467
DOI: 10.1038/s41598-024-64189-z -
Carbohydrate Polymers Sep 2024Targeted and stimuli-responsive drug delivery enhances therapeutic efficacy and minimizes undesirable side effects of cancer treatment. Although cellulose nanocrystals...
Targeted and stimuli-responsive drug delivery enhances therapeutic efficacy and minimizes undesirable side effects of cancer treatment. Although cellulose nanocrystals (CNCs) are used as drug carriers because of their robustness, spindle shape, biocompatibility, renewability, and nontoxicity, the lack of programmability and functionality of CNCs-based platforms hampers their application. Thus, high adaptability and the capacity to form dynamic 3D nanostructures of DNA may be advantageous, as they can provide functionalities such as target-specific and stimuli-responsive drug release. Using DNA nanotechnology, the functional polymeric form of DNA nanostructures can be replicated using rolling circle amplification (RCA), and the biologically and physiologically stable DNA nanostructures may overcome the challenges of CNCs. In this study, multifunctional polymeric DNAs produced with RCA were strongly complexed with surface-modified CNCs via electrostatic interactions to form polymeric DNA-decorated CNCs (pDCs). Particle size, polydispersity, zeta potential, and biostability of the nanocomplexes were analyzed. As a proof of concept, the dynamic structural functionalities of DNA nanostructures were verified by observing cancer-targeted intracellular delivery and pH-responsive drug release. pDCs showed anticancer properties without side effects in vitro, owing to their aptamer and i-motif functionalities. In conclusion, pDCs exhibited multifunctional anticancer activities, demonstrating their potential as a promising hybrid nanocomplex platform for targeted cancer therapy.
Topics: Cellulose; Humans; Nanoparticles; DNA; Drug Liberation; Nanostructures; Drug Carriers; Drug Delivery Systems; Antineoplastic Agents; Polymers; Hydrogen-Ion Concentration; Doxorubicin; Cell Survival
PubMed: 38858000
DOI: 10.1016/j.carbpol.2024.122270 -
International Journal of Nanomedicine 2024Breast cancer is a prevalent malignancy among women worldwide, and malignancy is closely linked to the tumor microenvironment (TME). Here, we prepared mixed nano-sized...
PURPOSE
Breast cancer is a prevalent malignancy among women worldwide, and malignancy is closely linked to the tumor microenvironment (TME). Here, we prepared mixed nano-sized formulations composed of pH-sensitive liposomes (Ber/Ru486@CLPs) and small-sized nano-micelles (Dox@CLGs). These liposomes and nano-micelles were modified by chondroitin sulfate (CS) to selectively target breast cancer cells.
METHODS
Ber/Ru486@CLPs and Dox@CLGs were prepared by thin-film dispersion and ethanol injection, respectively. To mimic actual TME, the in vitro "condition medium of fibroblasts + MCF-7" cell model and in vivo "4T1/NIH-3T3" co-implantation mice model were established to evaluate the anti-tumor effect of drugs.
RESULTS
The physicochemical properties showed that Dox@CLGs and Ber/Ru486@CLPs were 28 nm and 100 nm in particle size, respectively. In vitro experiments showed that the mixed formulations significantly improved drug uptake and inhibited cell proliferation and migration. The in vivo anti-tumor studies further confirmed the enhanced anti-tumor capabilities of Dox@CLGs + Ber/Ru486@CLPs, including smaller tumor volumes, weak collagen deposition, and low expression levels of α-SMA and CD31 proteins, leading to a superior anti-tumor effect.
CONCLUSION
In brief, this combination therapy based on Dox@CLGs and Ber/Ru486@CLPs could effectively inhibit tumor development, which provides a promising approach for the treatment of breast cancer.
Topics: Tumor Microenvironment; Animals; Female; Breast Neoplasms; Humans; Mice; Liposomes; MCF-7 Cells; Doxorubicin; Cell Proliferation; Mice, Inbred BALB C; NIH 3T3 Cells; Chondroitin Sulfates; Particle Size; Nanoparticle Drug Delivery System; Drug Delivery Systems; Cell Movement; Nanoparticles
PubMed: 38855730
DOI: 10.2147/IJN.S460874 -
International Journal of Radiation... Jul 2024
Topics: Humans; Lymphoma, Large B-Cell, Diffuse; Neoplasm Recurrence, Local; Antineoplastic Combined Chemotherapy Protocols; Lymph Node Excision; Lymph Nodes; Doxorubicin
PubMed: 38851269
DOI: 10.1016/j.ijrobp.2024.01.228 -
Molecular Pharmaceutics Jul 2024Renal fibrosis plays a key role in the pathogenesis of chronic kidney disease (CKD), in which the persistent high expression of transforming growth factor β1 (TGF-β1)...
Renal fibrosis plays a key role in the pathogenesis of chronic kidney disease (CKD), in which the persistent high expression of transforming growth factor β1 (TGF-β1) and α-smooth muscle actin (α-SMA) contributes to the progression of CKD to renal failure. In order to improve the solubility, bioavailability, and targeting of tanshinone IIA (Tan IIA), a novel targeting material, aminoethyl anisamide-polyethylene glycol-1,2-distearoyl--glycero-3-phosphate ethanolamine (AEAA-PEG-DSPE, APD) modified Tan IIA liposomes (APD-Tan IIA-L) was constructed. An animal model of glomerulonephritis induced by doxorubicin in BALB/c mice was established. APD-Tan IIA-L significantly decreased blood urea nitrogen and serum creatinine (SCr), and the consequences of renal tissue oxidative stress indicators showed that APD-Tan IIA-L downregulated malondialdehyde, upregulated superoxide dismutase, catalase, and glutathione peroxidase. Masson's trichrome staining showed that the deposition of collagen in the APD-Tan IIA-L group decreased significantly. The pro-fibrotic factors (fibronectin, collagen I, TGF-β1, and α-SMA) and epithelial-mesenchymal transition marker (N-cadherin) were significantly inhibited by APD-Tan IIA-L. By improving the microenvironment of fibrotic kidneys, APD-Tan IIA-L attenuated TGF-β1-induced excessive proliferation of fibroblasts and alleviated oxidative stress damage to the kidney, providing a new strategy for the clinical treatment of renal fibrosis.
Topics: Animals; Doxorubicin; Mice; Liposomes; Abietanes; Fibrosis; Mice, Inbred BALB C; Kidney; Male; Glomerulonephritis; Transforming Growth Factor beta1; Oxidative Stress; Epithelial-Mesenchymal Transition; Disease Models, Animal; Renal Insufficiency, Chronic
PubMed: 38848439
DOI: 10.1021/acs.molpharmaceut.4c00042 -
Medicine Jun 2024Intestinal T-cell lymphomas are exceedingly rare diseases. Intestinal T-cell lymphoma NOS, as a "wastebasket" category, is difficult to diagnosis. Endoscopy can identify...
RATIONALE
Intestinal T-cell lymphomas are exceedingly rare diseases. Intestinal T-cell lymphoma NOS, as a "wastebasket" category, is difficult to diagnosis. Endoscopy can identify abnormal mucosa in most patients at a reasonably early stage. Therefore, it is crucial to increase the understanding of endoscopists in terms of the endoscopic characteristics of ITCL.
PATIENT CONCERNS
A 74-year-old male alone with wasting as the major complaint, had multiple polypoid lesions in the large intestine. The patient then had endoscopic care.
DIAGNOSES
Only 1 polypoid lesion on white-light endoscopy in the sigmoid colon was pathologically diagnosed as intestinal T-cell lymphomas, not otherwise specified (ITCL-NOS).
INTERVENTIONS
The patient underwent intensity-reduced CHOP therapy.
OUTCOMES
The patient is still with controlled disease but developed chemotherapy-related side effects.
LESSONS
In the individual with unexplained anemia and waste, endoscopy should not be delayed. For each of polypoid lesion on white-light endoscopy, the endoscopist need to remain cautious, because every lesion in the same patient can exhibit the independence of histopathological features. Meanwhile, we suggest that endoscopists should routinely observe the terminal ileum, even take biopsy samples if necessary.
Topics: Humans; Aged; Male; Antineoplastic Combined Chemotherapy Protocols; Lymphoma, T-Cell; Doxorubicin; Vincristine; Intestinal Neoplasms; Cyclophosphamide; Prednisone; Colonoscopy
PubMed: 38847694
DOI: 10.1097/MD.0000000000038465 -
Oncoimmunology 2024Rituximab (RTX) plus chemotherapy (R-CHOP) applied as a first-line therapy for lymphoma leads to a relapse in approximately 40% of the patients. Therefore, novel...
Rituximab (RTX) plus chemotherapy (R-CHOP) applied as a first-line therapy for lymphoma leads to a relapse in approximately 40% of the patients. Therefore, novel approaches to treat aggressive lymphomas are being intensively investigated. Several RTX-resistant (RR) cell lines have been established as surrogate models to study resistance to R-CHOP. Our study reveals that RR cells are characterized by a major downregulation of CD37, a molecule currently explored as a target for immunotherapy. Using CD20 knockout (KO) cell lines, we demonstrate that CD20 and CD37 form a complex, and hypothesize that the presence of CD20 stabilizes CD37 in the cell membrane. Consequently, we observe a diminished cytotoxicity of anti-CD37 monoclonal antibody (mAb) in complement-dependent cytotoxicity in both RR and CD20 KO cells that can be partially restored upon lysosome inhibition. On the other hand, the internalization rate of anti-CD37 mAb in CD20 KO cells is increased when compared to controls, suggesting unhampered efficacy of antibody drug conjugates (ADCs). Importantly, even a major downregulation in CD37 levels does not hamper the efficacy of CD37-directed chimeric antigen receptor (CAR) T cells. In summary, we present here a novel mechanism of CD37 regulation with further implications for the use of anti-CD37 immunotherapies.
Topics: Humans; Antigens, CD20; Rituximab; Tetraspanins; Cell Line, Tumor; Lymphoma, B-Cell; Immunotherapy; Antigens, Neoplasm; Drug Resistance, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Cyclophosphamide; Vincristine; Antibodies, Monoclonal; Receptors, Chimeric Antigen; Gene Expression Regulation, Neoplastic
PubMed: 38846084
DOI: 10.1080/2162402X.2024.2362454 -
Journal of Materials Chemistry. B Jun 2024Despite enormous advancements in its management, cancer is the world's primary cause of mortality. Therefore, tremendous strides were made to produce intelligent...
pH-Sensitive doxorubicin delivery using zinc oxide nanoparticles as a rectified theranostic platform: anti-proliferative, apoptotic, cell cycle arrest and radio-distribution studies.
Despite enormous advancements in its management, cancer is the world's primary cause of mortality. Therefore, tremendous strides were made to produce intelligent theranostics with mitigated side effects and improved specificity and efficiency. Thus, we developed a pH-sensitive theranostic platform composed of dextran immobilized zinc oxide nanoparticles, loaded with doxorubicin and radiolabeled with the technetium-99m radionuclide (Tc-labelled DOX-loaded ZnO@dextran). The platform measured 11.5 nm in diameter with -12 mV zeta potential, 88% DOX loading efficiency and 98.5% radiolabeling efficiency. It showed DOX release in a pH-responsive manner, releasing 93.1% cumulatively at pH 5 but just 7% at pH 7.4. It showed improved intracellular uptake, which resulted in a high growth suppressive effect against MCF-7 cancer cells as compared to the free DOX. It boasted a 4 times lower IC than DOX, indicating its significant anti-proliferative potential (0.14 and 0.55 μg ml, respectively). The biological evaluation revealed that its molecular mode of anti-proliferative action included downregulating Cdk-2, which provoked G1/S cell cycle arrest, and upregulating both the intracellular ROS level and caspase-3, which induced apoptosis and necrosis. The experiments in Ehrlich-ascites carcinoma bearing mice demonstrated that DOX-loaded ZnO@dextran showed a considerable 4-fold increase in anti-tumor efficacy compared to DOX. Moreover, by utilizing the diagnostic radionuclide (Tc), the radiolabeled platform (Tc-labelled DOX-loaded ZnO@dextran) was monitored in tumor-bearing mice, revealing high tumor accumulation (14% ID g at 1 h p.i.) and reduced uptake in non-target organs with a 17.5 T/NT ratio at 1 h p.i. Hence, Tc-labelled DOX-loaded ZnO@dextran could be recommended as a rectified tumor-targeted theranostic platform.
Topics: Doxorubicin; Zinc Oxide; Humans; Animals; Apoptosis; Mice; Hydrogen-Ion Concentration; Cell Proliferation; Theranostic Nanomedicine; Cell Cycle Checkpoints; MCF-7 Cells; Nanoparticles; Tissue Distribution; Antibiotics, Antineoplastic; Dextrans; Drug Carriers; Technetium; Particle Size
PubMed: 38845545
DOI: 10.1039/d4tb00615a -
Nature Communications Jun 2024Given the marginal penetration of most drugs across the blood-brain barrier, the efficacy of various agents remains limited for glioblastoma (GBM). Here we employ...
Given the marginal penetration of most drugs across the blood-brain barrier, the efficacy of various agents remains limited for glioblastoma (GBM). Here we employ low-intensity pulsed ultrasound (LIPU) and intravenously administered microbubbles (MB) to open the blood-brain barrier and increase the concentration of liposomal doxorubicin and PD-1 blocking antibodies (aPD-1). We report results on a cohort of 4 GBM patients and preclinical models treated with this approach. LIPU/MB increases the concentration of doxorubicin by 2-fold and 3.9-fold in the human and murine brains two days after sonication, respectively. Similarly, LIPU/MB-mediated blood-brain barrier disruption leads to a 6-fold and a 2-fold increase in aPD-1 concentrations in murine brains and peritumoral brain regions from GBM patients treated with pembrolizumab, respectively. Doxorubicin and aPD-1 delivered with LIPU/MB upregulate major histocompatibility complex (MHC) class I and II in tumor cells. Increased brain concentrations of doxorubicin achieved by LIPU/MB elicit IFN-γ and MHC class I expression in microglia and macrophages. Doxorubicin and aPD-1 delivered with LIPU/MB results in the long-term survival of most glioma-bearing mice, which rely on myeloid cells and lymphocytes for their efficacy. Overall, this translational study supports the utility of LIPU/MB to potentiate the antitumoral activities of doxorubicin and aPD-1 for GBM.
Topics: Doxorubicin; Animals; Humans; Programmed Cell Death 1 Receptor; Mice; Blood-Brain Barrier; Brain Neoplasms; Microbubbles; Cell Line, Tumor; Glioma; Brain; Female; Drug Delivery Systems; Ultrasonic Waves; Glioblastoma; Male; Microglia; Mice, Inbred C57BL; Antibodies, Monoclonal, Humanized; Immune Checkpoint Inhibitors; Polyethylene Glycols
PubMed: 38844770
DOI: 10.1038/s41467-024-48326-w -
ACS Applied Bio Materials Jun 2024Photosensitizing agents have received increased attention from the medical community, owing to their higher photothermal efficiency, induction of hyperthermia, and...
Photosensitizing agents have received increased attention from the medical community, owing to their higher photothermal efficiency, induction of hyperthermia, and sustained delivery of bioactive molecules to their targets. Micro/nanorobots can be used as ideal photosensitizing agents by utilizing various physical stimuli for the targeted killing of pathogens (e.g., bacteria) and cancer cells. Herein, we report sunflower-pollen-inspired spiky zinc oxide (s-ZnO)-based nanorobots that effectively kill bacteria and cancer cells under near-infrared (NIR) light irradiation. The as-fabricated s-ZnO was modified with a catechol-containing photothermal agent, polydopamine (PDA), to improve its NIR-responsive properties, followed by the addition of antimicrobial (e.g., tetracycline/TCN) and anticancer (e.g., doxorubicin/DOX) drugs. The fabricated s-ZnO/PDA@Drug nanobots exhibited unique locomotory behavior with an average speed ranging from 13 to 14 μm/s under 2.0 W/cm NIR light irradiation. Moreover, the s-ZnO/PDA@TCN nanobots exhibited superior antibacterial activity against and under NIR irradiation. The s-ZnO/PDA@DOX nanobots also displayed sufficient reactive oxygen species (ROS) amplification in B16F10 melanoma cells and induced apoptosis under NIR light, indicating their therapeutic efficacy. We hope the sunflower pollen-inspired s-ZnO nanorobots have tremendous potential in biomedical engineering from the phototherapy perspective, with the hope to reduce pathogen infections.
Topics: Photosensitizing Agents; Humans; Anti-Bacterial Agents; Helianthus; Antineoplastic Agents; Biocompatible Materials; Zinc Oxide; Particle Size; Drug Screening Assays, Antitumor; Materials Testing; Microbial Sensitivity Tests; Pollen; Escherichia coli; Staphylococcus epidermidis; Cell Survival; Cell Line, Tumor; Indoles; Animals; Mice; Doxorubicin; Infrared Rays
PubMed: 38842103
DOI: 10.1021/acsabm.4c00092