Drug Doxorubicin Research Articles

Preparing a Liposome-Aided Drug Delivery System: The Entrapment and Release Profiles of Doxorubicin and 9-(N-Piperazinyl)-5-methyl-12(H)-quino [3,4-b][1,4]benzothiazinium Chloride with Human Serum Albumin

Background/Objectives: The principal aim of this work was to prepare a liposomal drug delivery system based on the commercial drug doxorubicin (DOX) and a budding agent with promising anticancer activity, 9-(N-piperazinyl)-5-methyl-12(H)-quino [3,4-b][1,4]benzothiazinium chloride (9-PBThACl). Methods: A spectrophotometric methodology was used to meticulously investigate the drug entrapment and release characteristics of the new liposomal complexes (L) based on dipalmitoylphosphatidylcholine (DPPC) with human serum albumin (HSA) and its defeated analog (dHSA). Results: The impact of the operational parameters (temperature and pH) on the liposome/drug(s)/(d)HSA, namely [LDPPC/9-PBThACl/DOX ]:(d)HSA] systems, as well as the polarity of the phospholipid bilayer, was examined. In order to compare the experimental findings, mathematical models were employed to specify the analytical factors controlling the process of drug release/potential drug release from liposomes. The observed variations in the drug encapsulation and release profiles were due to the combination of liposomal conjugates with human plasma protein. Conclusions: It was proven that changes in the environmental pH directly affect the percentage of drug entrapment in liposomes and the medicine release efficiency. Moreover, the grouping tendency of the liposomal combinations was investigated using a principal component analysis (PCA) and a hierarchical clustering analysis (HCA). Finally, an analysis of variance (ANOVA) confirmed the statistical impact of pH buffering and changing temperature factors on the drug release characteristics of liposomal conjugates.

Evaluating the Drug Delivery Capacity of 3D Coordination Polymer for Anticancer Drugs.

We synthesized {[Cd2(dTMP)2(4,4'-azpy)2(H2O)2] ⋅ 3(O)}n a novel three-dimensional metal nucleotide coordination polymer (CP-1). An assessment of the CP-1 binding affinity for anticancer drugs was conducted using molecular dynamic simulations. The virtual screening results depict that CP-1 has a lot of potential for encapsulating the anthracycline anticancer drug doxorubicin (DOX). It hasn't yet been investigated how to accomplish high loading capacity, efficiency, and controlled release of DOX in dTMP-based 3D metal coordination polymers. Utilizing DOX as a drug model and our system as a drug-loading vehicle, we used UV-visible and circular dichroism titrations to examine the effects of its encapsulation and release. The mechanism of drug loading and release was investigated through pH-responsive behavior by adjusting the pH value to 8, 7, 6, and 5. The results indicate the CP-1 has a robust affinity for DOX at pH 7, which facilitates its loading on 3D porous coordination polymer. However, the maximum cumulative drug release of 87.11 % was observed at pH 5. The higher correlation coefficient (R2) was obtained at pH 5 with the Higuchi equation. It indicated that the drug released was primarily controlled with the diffusion mechanism. The CP-1 polymer's ability to encapsulate DOX while also permitting a possible controlled-release mechanism is confirmed by the combined insights from the experimental findings, energy graphs, RMSD analysis, and radius of gyration (Rg) data from MD simulations.

Development and characterization of hydrogel beads with carboxymethyl chitosan/graphene quantum dots@Pectin/MIL-88 for targeted doxorubicin delivery: An adaptable nanocomposite approach.

Hydrogels are adaptable substances with a 3D framework able to hold large quantities of water, which is why they are ideal for use in the field of biomedicine. This research project focused on creating a new hydrogel combining carboxymethyl chitosan (CMCS), graphene quantum dots (GQDs), pectin (Pe), and MIL-88 for precise and controlled release of the cancer drug doxorubicin (DOX). The creation of CMCS/GQDs@Pe/MIL-88 hydrogel beads was achieved through an eco-friendly one-step synthesis method. The hydrogel beads were then analyzed using various techniques including FE-SEM, EDX, FT-IR, XRD, BET surface area, DLS, and zeta potential measurements. The hydrogel beads showed great swelling ability and controlled breakdown in different pH environments, mimicking the conditions of the gastrointestinal tract and body. Research on drug loading and release showed that the hydrogel components can be adjusted to control the release of DOX. Cytotoxicity tests in a lab setting using K562 cells demonstrated successful delivery of DOX and the ability to target cancer cells specifically while reducing negative effects. Adding GQDs improved both the imaging abilities and the stability and mechanical characteristics of the hydrogel. This research indicates that the CMCS/GQDs@Pe/MIL-88 combination hydrogel beads show great potential for advanced drug delivery systems, especially in cancer treatment.

Thermosensitive Hydrogel Loaded with α-Mangostin for Enhanced Antitumor Effect of Doxorubicin.

The cancer-associated fibroblasts (CAFs) in tumor stroma present substantial barriers to drug penetration, resulting in tumor resistance and progression. One promising strategy is to reprogram CAFs into a quiescent state, which necessitates novel approaches. Our study introduces a sequential treatment strategy using chitosan thermosensitive hydrogels loaded with α-Mangostin (α-M), a small molecule drug with antifibrotic properties, aimed at reprogramming CAFs within the breast cancer tumor microenvironment (TME). We developed glutathione (GSH)-responsive nanoparticles (NPc) that carry the chemotherapeutic drug doxorubicin (DOX). Treatment with α-M results in the downregulation of CAF-specific biomarkers and a remodeled TME, which improves the penetration of NPc/DOX deep into the tumor tissue. This strategy holds great promise in enhancing cancer therapeutic outcomes in tumors rich in CAFs, particularly in the case of breast cancer.

Enhancing hepatocellular carcinoma therapy with DOX-loaded SiO2 nanoparticles via mTOR-TFEB pathway autophagic flux inhibition

Chemotherapeutic drugs often fail to provide long-term efficacy due to their lack of specificity and high toxicity. To enhance the biosafety and reduce the side effects of these drugs, various nanocarrier delivery systems have been developed. In this study, we loaded the anticancer drug doxorubicin (DOX) and an MRI contrast agent into silica nanoparticles, coating them with pH-responsive and tumor cell-targeting polymers. These polymers enable the carrier to achieve targeted delivery and controlled drug release in acidic environments. This integrated diagnostic and therapeutic strategy successfully achieved both the diagnosis and treatment of liver cancer. Additionally, we demonstrated that the nanocarrier inhibits autophagic flux in liver cancer cells by targeting the autophagy-lysosome pathway and regulating the nuclear translocation of TFEB, thereby promoting tumor cell death. This novel diagnostic-integrated nanocarrier is expected to be a promising tool for targeted liver cancer treatment.

Buthionine sulfoximine acts synergistically with doxorubicin as a sensitizer molecule on different tumor cell lines

ABSTRACT The chemotherapeutic drug doxorubicin (DOX) has been widely used for treating solid tumors attributed to its antiproliferative effectiveness; however, its clinical use is limited due to side effects, including cardiotoxicity, myelosuppression, and drug resistance. Combining DOX with buthionine sulfoximine (BSO), a glutathione (GSH) synthesis inhibitor, showed promising results in overcoming these adverse effects, potentially reducing the required DOX dose while maintaining efficacy. The aim of the present study was to examine the effects of different concentrations of BSO and DOX, both individually and in combination, utilizing B16/F10 (murine melanoma), SNB-19 (human glioblastoma), S180 (murine sarcoma), and SVEC4–10 (murine endothelial) cell lines. Cell viability, migration, and clonogenicity were assessed using the following assays MTT, scratch, and colony formation. Antioxidant levels of GSH, as well as activities catalase (CAT), and superoxide dismutase (SOD) were measured. BSO alone exhibited minimal cytotoxic effects, while DOX alone reduced cell viability significantly. The combination of BSO+DOX decreased IC50 values for most cell lines, demonstrating a synergistic effect, especially in B16/F10, S180, and SVEC4–10 cells. BSO+DOX combination significantly inhibited cell migration and clonogenicity compared to DOX alone. While GSH levels were decreased with BSO+DOX treatment activities of CAT and SOD increased following DOX administration but remained unchanged by BSO. These results suggest that BSO may be considered a valuable tool to improve DOX therapeutic efficacy, particularly in cases of chemotherapy-resistant tumors, as BSO enhances DOX activity while potentially reducing systemic chemotherapeutic drug toxicity.

MRI-Based Multifunctional Nanoliposomes for Enhanced HCC Therapy and Diagnosis.

The morbidity and mortality rates of hepatocellular carcinoma (HCC) are high and continue to increase. The antitumor effects of single therapies are limited because of tumor heterogeneity and drug resistance, and the lack of real-time monitoring of tumor progression during the treatment process leads to poor therapeutic outcomes. Therefore, novel nanodelivery platforms combining tumor therapy and diagnosis have garnered extensive attention. In this study, we developed a multifunctional nanodelivery vector, LPSD-DOX/siRNA, which was loaded with oleic acid-modified superparamagnetic iron oxide nanoparticles (OA-SPION) and the antitumor drug doxorubicin (DOX), further modified by DOTAP to carry small interfering RNA targeting phosphatidylinositol proteoglycan-3 (Glypican-3, GPC3) (siRNA-GPC3). These components were utilized for the combined treatment of HCC and tumor monitoring with magnetic resonance imaging. LPSD-DOX/siRNA exhibited high drug loading, high gene transfection efficiency, and low toxicity. Pharmacokinetic and in vivo distribution experiments showed that LPSD-DOX/siRNA significantly prolonged the circulation time of DOX and enhanced drug accumulation at the tumor site. Magnetic resonance imaging demonstrated that LPSD-DOX/siRNA can serve as a T2 imaging contrast agent to enhance the imaging contrast between the tumor site and other tissues and facilitate the imaging monitoring of tumor tissues. Antitumor experiments revealed that the effects of DOX were promoted by inhibiting the expression of GPC3 protein in HepG2 cell-transplanted tumors, with increased tumor apoptosis. In conclusion, LPSD-DOX/siRNA serves as a promising strategy for combination therapy and monitoring of HCC, with significant potential in antitumor therapy.

Drug carrier-assisted combined chemo- and radionuclide therapy for tumors of diverse origins: effects of therapeutic schemes on tumor responses.

Despite the promising results in cancer treatment, standard monotherapy remains insufficient for a wide range of oncological diseases. Combined therapy can significantly improve therapeutic outcomes compared to single-agent treatments. However, identifying the optimal treatment regimen for combined therapy can be a challenging task. In this work, we developed a therapeutic strategy for the treatment of three types of tumors - CT26 colorectal cancer, B16-F10 melanoma and 4T1 breast cancer using combined chemo- and radionuclide therapy. This was achieved by loading nanoparticles with radium-223 (223Ra-labeled NPs) and the chemotherapeutic drug doxorubicin (DOX). Each tumor model (CT26, B16-F10, 4T1) was treated using different therapeutic strategies: (i) intravenous or (ii) intratumoral administration of 223Ra-labeled NPs for single radionuclide therapy; (iii) intravenous injection of DOX for chemotherapy; and (iv) intratumoral injection of 223Ra-labeled NPs combined with intravenous administration of DOX for combined therapy. Our results demonstrated that each tumor model exhibited a distinct response to single and combined therapies. Notably, the combined chemo- and radionuclide therapy (DOX = 10 mg kg-1 and 223Ra-labeled NPs = 2.7 KBq kg-1) demonstrated a significantly higher therapeutic outcome than single therapies (DOX = 10 mg kg-1 or 223Ra-labeled NPs = 2.7 KBq kg-1). In particular, the average therapeutic response was >35% for monotherapy and >60%-80% for combined therapy. Importantly, the therapeutic effect across the three tumor types followed the order B16-F10 >4T1 >CT26. Thus, this work systematically investigated the response of three tumor types to the applicability of single chemo- or radionuclide therapy and their combination.

NIR Triggered Bionic Bilayer Membrane-Encapsulated Nanoparticles for Synergistic Photodynamic, Photothermal and Chemotherapy of Cervical Cancer.

A synergistic treatment strategy of phototherapy and chemotherapy has been shown to improve efficacy and offer unique advantages over monotherapy. The purpose of this study is to explore a new nanocarrier system with liposome as the inner membrane and erythrocyte membrane as the outer membrane, which aims to realize the leak-free load of phototherapy drug indocyanine green (ICG) and chemotherapy drug doxorubicin (DOX), prolong the circulation time in vivo and improve the therapeutic effect. In this study, bilayer membrane-loaded ICG and DOX nanoparticles (RBC@ICG-DOX NPs) were prepared and characterized. For in vitro analysis, the biocompatibility and tumor inhibition properties of the nanoparticles were evaluated. For in vivo analysis, the antitumor properties of the nanoparticles were explored in a mouse subcutaneous tumor model. RBC@ICG-DOX NPs were successfully prepared with strong safety and good blood compatibility, which can effectively reduce drug leakage and prolong drug circulation time in the body. In vitro performance evaluation showed that RBC@ICG-DOX NPs obtained excellent photothermal conversion ability and well reactive oxygen generation performance under near-infrared laser irradiation. Both in vitro and in vivo experiments showed well phototherapy-chemotherapy effect of RBC@ICG-DOX NPs with low toxic side effects. Drug delivery, imaging and tumor synergies were accomplished through combinatorial strategies as well as bilayer membrane encapsulation, opening up a new platform for the design of future tumor combination therapies.

Selective captivation of DOX via topotactic surface enrichment with hydrated sodium ions on engineered MXene nanosheets

Effective adsorption doxorubicin drug from aqueous system was achieved by utilizing a surface functionalized, two-dimensional transition metal carbide (MXene). Synthesis of impurity-free parent phase, subsequent etching and alkalization produced surface...

Immobilization and in vitro kinetic controlled release study of doxorubicin from temperature-sensitive mPEG-Ala-Asp polypeptide hydrogel

The loading of the doxorubicin drug into a new polyethylene glycol-polypeptide based temperature-sensitive hydrogel and the investigation of its properties have been carried out. It was determined that during the immobilization of the drug, equilibrium is reached, and saturation occurs within 3 hours in a solution with an initial antibiotic concentration of approximately 4.8 mg/mL. Currently, 84-87 % of the drug is adsorbed, meaning that 100 mg of gel drug capacity was 405.8 mg/gr. The samples were kept in different pH solutions (pH = 2, 7.4, and 8.6) at 37 °C, and the release of doxorubicin was kinetically studied over intervals ranging from 0-300 minutes. It was determined that changes in the ionic strength of the solution lead to a change in the polarity degree of the chemical bond between the hydrogel and doxorubicin. The results of doxorubicin release from the gel were tested against various kinetic models, including zero-order, first-order, Higuchi square root law, Korsmeyer-Peppas, and Hixson-Crowell square root models. When applying the kinetic results of doxorubicin release from the gel to the Korsmeyer-Peppas model, in acidic and neutral mediums, the value of n > 1, which is attributed to the breaking of protein segments in the terminal groups of the matrix. This makes the creation of thin-coated drug formulations from the matrix more advantageous. In an alkaline medium, however, n < 1, indicating that the release follows a non-Fickian mechanism, characterized by both diffusion and erosion. To ensure release in an alkaline medium, it is more appropriate to prepare cylindrical, spherical, or film-type drug forms from the PEG-Ala-Asp gel. Also, since the gel formation time can be adjusted, such systems can be recommended as analogues of injectable thermosetting insulation composites for the oil and gas industry. Keywords: temperature sensitive; polyethyenglycol; polypeptide gel; release kinetic; doxorubicine.

Deubiquitinase MYSM1 promotes doxorubicin-induced cardiotoxicity by mediating TRIM21-ferroptosis axis in cardiomyocytes

Anthracycline antitumor drug doxorubicin (DOX) induces severe cardiotoxicity. Deubiquitinating enzymes (DUBs) are crucial for protein stability and function and play a significant role in cardiac pathophysiology. By comparing RNA sequencing datasets and conducting functional screening, we determined that Myb-like, SWIRM, and MPN domains 1 (MYSM1) is a key regulator of DOX-induced cardiotoxicity. In this study, we aimed to explore the function and regulatory mechanisms of MYSM1 in DOX-induced cardiotoxicity. Genetic knockdown of MYSM1 significantly mitigated DOX-induced cardiomyopathy. Correspondingly, cardiomyocyte-specific knockdown of MYSM1 by AAV9 protected the heart from DOX-induced cardiotoxicity. Gain- and loss-of-function analysis verified that MYSM1 mediated DOX-induced cardiomyocyte injury in vitro. Through a Co-IP combined with LC-MS/MS analysis, we discovered that MYSM1 directly interacted with tripartite motif-containing protein 21 (TRIM21). Mechanistic investigations revealed that MYSM1 regulates the deubiquitination and the stability of TRIM21 via its MPN domain. Furthermore, MYSM1 exacerbated DOX-induced cardiotoxicity by enhancing ferroptosis. This study identified MYSM1 as a potential therapeutic target for DOX-induced cardiotoxicity and illustrated a MYSM1-TRIM21-ferroptosis axis in regulating DOX-induced cardiotoxicity.

Investigating the combinatory effect of Sclerocarya birrea with doxorubicin against selected colorectal cancer cell lines.

Colorectal cancer incidences continue to increase annually, worldwide. Herbal plants with antiproliferative properties received research interest as agents that can be adjuvant therapies with chemotherapy drugs to enhance their efficacy and reverse drug resistance. Sclerocarya birrea ethanolic (SBE) and aqueous (SBW) extracts combined with doxorubicin (DOX) against drug-sensitive and drug-resistant colorectal cancer cells were investigated for their potential adjuvant and drug resistance reversal. The extracts were assessed for their potential anticancer activities on HCT15 and HT29 cell lines as well as their doxorubicin potentiating and drug resistance reversal effects respectively. The extracts were assessed for their cytotoxicity on normal 3T3-L1 fibroblast cells. Both SBE and SBW extracts exhibited no toxicity against normal 3T3 cells and showed low activity on the HT29 cell line. Contrarily, resistant HCT15 cells showed moderate to low activity with significantly higher inhibitory concentration (IC)50 values. The combination of SBE with DOX and SBW with DOX resulted in antagonistic interactions, causing an increase in IC50 values for HT29 and HCT15 cells. In contrast, the combination of DOX and verapamil (VER) produced an additive effect, with no change in their IC50 values. Based on the findings from the combination treatment, the SBE and SBW extracts demonstrated higher efficacy and synergistic effects combined with DOX at IC75 compared to the combination of DOX and VER, suggesting their potential as anticancer agents. However, further research on both the SBE and SBW extracts' mechanisms of action and in vivo effects is warranted.

Avenanthramide-C ameliorate doxorubicin-induced hepatotoxicity via modulating Akt/GSK-3β and Wnt-4/β-Catenin pathways in male rats.

Doxorubicin (DOX) drugs used in cancer treatment can cause various adverse effects, including hepatotoxicity. Natural-derived constituents have shown promising effects in alleviating chemotherapy-induced toxicities. This study addressed the effect of Avenanthramides-C (AVN-C) treatment in rats with DOX-indued hepatotoxicity. AutoDock Vina was used for the molecular docking investigations. In silico toxicity prediction for AVN-C and DOX was performed using the Pro Tox-III server. Four groups of ten male Sprague-Dawley rats were created: Group 1 (Gp1) served as a negative control, Gp2 received an intraperitoneal (i.p.) injection of AVN-C (10 mg/kg), Gp3 received an i.p. dose of DOX (4 mg/kg) weekly for a month, and Gp4 received the same dose of DOX as G3 and AVN-C as G2. Histopathological, molecular, and biochemical analyses were conducted 1 month later. The study showed that treatment with AVN-C significantly ameliorated DOX-induced hepatotoxicity in rats by restoring biochemical alterations, boosting antioxidant activity, reducing inflammation, and modulating the Akt/GSK-3β and Wnt-4/β-Catenin signaling pathways in male rats. This study is the first to demonstrate the therapeutic effects of AVN-C therapy on DOX-induced liver damage in male rats. Therefore, AVN-C could have a pronounced palliative effect on the hepatotoxicity caused by DOX treatment. These findings suggest that AVN-C could potentially alleviate the hepatotoxicity associated with DOX-based chemotherapy.

Plant-derived extracellular vesicles release combined with systemic DOX exhibits synergistic effects in 3D bioprinted triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer, lacking targeted therapeutic options. Hydrogels, particularly gelatin methacrylate (GelMA), have emerged as promising materials for localized drug delivery due to their biocompatibility and tunable properties. This study investigates a dual-delivery system for enhancing the treatment efficacy of triple-negative breast cancer (TNBC) using a combination of extracellular vesicles (EVs) derived from Citrus limon L. and the chemotherapeutic drug doxorubicin (DOX). We fabricated 3D bioprinted GelMA scaffolds to achieve localized and controlled release of EVs and evaluated their synergistic effects with systemic DOX delivery on both primary and metastatic 3D TNBC models.The GelMA scaffolds, especially those with 95 % methacrylation, exhibited higher stiffness, which enhanced their sustained release. Following 48-h incubation, the combination of EVs and DOX significantly increased cytotoxicity in the primary 3D TNBC model, reducing cell viability to approximately 30 % compared to controls. This was notably more effective than treatments with DOX or EVs alone. During the extended 7-day incubation period, the combination treatment continued to show superior efficacy, with persistently high levels of ROS generation and further reduction in cell viability. In a metastatic 3D TNBC model, a significant sensitivity to the combined treatment was observed, which notably inhibited aggregate formation and migration. Importantly, EVs-embedded scaffolds promoted the proliferation of human fibroblasts, highlighting their non-toxic nature, while concurrently inhibiting TNBC cell growth. This approach provides a promising strategy to improve the treatment outcomes of TNBC by exploiting the synergistic effects of local EVs release and systemic chemotherapy.

Facile synthesis of CoFe2O4 and CoxNi1−xFe2O4 nanoparticles substituted in MoS2 nanosheets for photothermal/chemo therapy application

Cancer and its treatment have been one of the challenges of humans since the beginning, and much research has been conducted over many years on its treatment methods. In recent years, the use of new and low-complication methods, as well as combined methods, has become increasingly widespread. This study investigated the combined process of photothermal and chemotherapy for nanocomposite CoxNi1−xFe2O4∕MoS2. For this purpose, nanocomposite has been synthesized using a facile sol-gel and hydrothermal method. The structure and shape of nanostructures have been investigated using X-ray diffraction patterns, scanning electron microscopes, and transmission electron microscope images. The results confirmed the formation of CoxNi1−xFe2O4 nanoparticles with an approximate size of 55.44 nm, substituted in nanosheets MoS2. The results of UV–visible adsorption show that the synthesized nanocomposites have band gaps of 1.65 eV and 1.48 eV for nanostructures CoFe2O4∕MoS2 and Co0.5Ni0.5Fe2O4∕MoS2, respectively. Also, the photothermal efficiency of nanocomposites CoFe2O4∕MoS2 and Co0.5Ni0.5Fe2O4∕MoS2 irradiated with 808 nm diode laser and 1-watt power density are 31 % and 26 %, respectively. The loading rate of doxorubicin drug in nanocomposite is ∼ 60 %.

Transferrin-targeting pH-responsive and biodegradable mesoporous silica nanohybrid for nitric oxide-sensitized chemotherapy of cancer

Weakly acidic pH, low oxygen and high glutathione levels are the main characteristics of tumor cells. Taking advantage of the unique acidic microenvironment of tumor cells, acid-responsive mesoporous organosilica nanoparticles (AMON) were designed for nitric oxide (NO)-sensitized chemotherapy of tumors. AMON served as a nanocarrier co-loaded with a nitric oxide donor (NOD) and chemotherapeutic drug doxorubicin (DOX). Transferrin (Tf) was modified on the surface as a targeting ligand to form NOD&DOX@AMON. In vitro experiments showed that AMON could be completely degraded under acidic conditions (pH 5.0) after 48 h. NOD&DOX@AMON entered cells via transferrin receptor-mediated internalization and degraded in the acidic microenvironment to release its payloads. NOD released NO in presence of one-electron reducing substances like Glutathione (GSH) and ascorbic acid, inhibiting P-glycoprotein(P-gp) function and thereby increasing the intracellular concentration of DOX. In vivo distribution studies revealed that the nanohybrids accumulated maximally in tumor tissue 12 h after intravenous injection and exhibited significant inhibitory effects on HepG2 xenograft tumors. Western blot experiments demonstrated that NOD&DOX@AMON could inhibit the expression of drug resistance-associated proteins and was expected to be employed as a therapeutic approach for drug-resistant ttumors.

Antineoplastic effect of doxorubizen in vitro in continuous and primary human anaplastic thyroid cancer cells.

New drugs are needed for the therapy of anaplastic thyroid cancer (ATC). This study aims to investigate doxorubizen (a dual-action structural hybrid (chimera) of doxorubicin (Dox) and DNA methylating drug temozolomide), in comparison with Dox, and alone or in combination with lenvatinib in ATC 8305C cells, and in primary human ATC cell cultures (pATC). We have investigated doxorubizen, Dox, and lenvatinib on 5 different pATC and in continuous 8305C cell line in vitro, evaluating their effect on cells proliferation by WST-1, apoptosis (Hoechst ad Annexin V assays) and migration (Chemicon QCM™ 96-well Migration Assay). The results have demonstrated: (1) a significant antiproliferative and proapoptotic effect of doxorubizen in 8305C and in pATC; (2) a significant antiproliferative and proapoptotic effect of Dox in pATC, and in 8305C; (3) the antineoplastic effect of lenvatinib in 8305C and in pATC; (4) a stronger antiproliferative and proapoptotic effect of doxorubizen than that of Dox, or lenvatinib; (5) that doxorubizen induced an inhibition of migration in pATC stronger than that of Dox, or lenvatinib; (6) that doxorubizen is able to synergize in vitro with lenvatinib increasing the antiproliferative effect, while doxorubizen alone is the primary factor that promotes the proapoptotic impact. We have first shown that doxorubizen has a potent antineoplastic effect in vitro in 8305C and in 5 different pATC, and that can synergize with lenvatinib. These results open the way to a future evaluation of the antineoplastic effect of doxorubizen in ATC patients.

Enhancing localized chemotherapy with anti-angiogenesis and nanomedicine synergy for improved tumor penetration in well-vascularized tumors

Intratumoral delivery and localized chemotherapy have demonstrated promise in tumor treatment; however, the rapid drainage of therapeutic agents from well-vascularized tumors limits their ability to achieve maximum therapeutic efficacy. Therefore, innovative approaches are needed to enhance treatment efficacy in such tumors. This study utilizes a mathematical modeling platform to assess the efficacy of combination therapy using anti-angiogenic drugs and drug-loaded nanoparticles. Anti-angiogenic drugs are included to reduce blood microvascular density and facilitate drug retention in the extracellular space. In addition, incorporating negatively charged nanoparticles aims to enhance diffusion and distribution of therapeutic agents within well-vascularized tumors. The findings indicate that, in the case of direct injection of free drugs, using compounds with lower drainage rates and higher diffusion coefficients is beneficial for achieving broader diffusion. Otherwise, drugs tend to accumulate primarily around the injection site. For instance, the drug doxorubicin, known for its rapid drainage, requires the prior direct injection of an anti-angiogenic drug with a high diffusion rate to reduce microvascular density and facilitate broader distribution, enhancing penetration depth by 200%. Moreover, the results demonstrate that negatively charged nanoparticles effectively disperse throughout the tissue due to their high diffusion coefficient. In addition, a faster drug release rate from nanoparticles further enhance treatment efficacy, achieving the necessary concentration for complete eradication of tumor compared to slower drug release rates. This study demonstrates the potential of utilizing negatively charged nanoparticles loaded with chemotherapy drugs exhibiting high release rates for localized chemotherapy through intratumoral injection in well-vascularized tumors.

Development of Mg-Alginate Based Self Disassociative Bio-Ink for Magnetic Bio-Patterning of 3D Tumor Models.

Alginate forms a hydrogel via physical cross-linking with divalent cations. In literature, Ca2+ is mostly utilized due to strong interactions but additional procedures are required to disassociate Ca-alginate hydrogels. On the other hand, Mg-alginate hydrogels disassociate spontaneously, which might benefit certain applications. This study introduces Mg-alginate as the main component of a bio-ink for the first time to obtain 3D tumor models by magnetic bio-patterning technique. The bio-ink contains magnetic nanoparticles (MNPs) for magnetic manipulation, Mg-alginate hydrogel as a sacrificial material, and cells. The applicability of the methodology is tested for the formation of 3D tumor models using HeLa, SaOS-2, and SH-SY5Y cells. Long-term cultures are examined by Live/dead and MTT analysis and revealed high cell viability. Subsequently, Collagen and F-actin expressions are observed successfully in 3D tumor models. Finally, the anti-cancer drug Doxorubicin (DOX) effect is investigated on 3D tumor models, and IC50 values is calculated to assess the drug response. As a result, significantly higher drug resistance is observed for bio-patterned 3D tumor models up to tenfold compared to 2D control. Overall, Mg-alginate hydrogel is successfully used to form bio-patterned 3D tumor models, and the applicability of the model is shown effectively, especially as a drug screening platform.