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British Journal of Cancer Feb 2023In this perspective, the authors summarise some properties of the solid tumour micro-environment that have been explored during the last 55 years. It is well established... (Review)
Review
In this perspective, the authors summarise some properties of the solid tumour micro-environment that have been explored during the last 55 years. It is well established that the concentrations of nutrients, including oxygen, decrease with increasing distance from tumour blood vessels, and that low extracellular pH is found in nutrient-poor regions. Cell proliferation is dependent on nutrient metabolites and decreases in regions distal from patent blood vessels. Proliferating cells cause migration of neighbouring cells further from blood vessels where they may die, and their breakdown products pass into regions of necrosis. Anticancer drugs reach solid tumours via the vascular system and establish concentration gradients such that drug concentration within tumours may be quite variable. Treatment with chemotherapy such as doxorubicin or docetaxel can kill well-nourished proliferating cells close to blood vessels, thereby interrupting migration toward necrotic regions and lead to re-oxygenation and renewed proliferation of distal cells, as can occur with radiotherapy. This effect leads to the paradox that cancer treatment can rescue cells that were destined to die in the untreated tumour. Renewed and sometimes accelerated repopulation of surviving tumour cells can counter the effects of cell killing from repeated treatments, leading to tumour shrinkage and regrowth without changes in the intrinsic sensitivity of cells to the administered treatment. Strategies to prevent these effects include the combined use of chemotherapy with agents that selectively kill hypoxic tumour cells, including inhibitors of autophagy, since this is a process that may allow recycling of cellular macromolecules from dying cells and improve their survival.
Topics: Humans; Neoplasms; Antineoplastic Agents; Cell Proliferation; Doxorubicin; Docetaxel; Tumor Microenvironment
PubMed: 36564562
DOI: 10.1038/s41416-022-02109-6 -
International Journal of Molecular... Apr 2023Lesioned tissue requires synchronous control of disease and regeneration progression after surgery. It is necessary to develop therapeutic and regenerative scaffolds....
Lesioned tissue requires synchronous control of disease and regeneration progression after surgery. It is necessary to develop therapeutic and regenerative scaffolds. Here, hyaluronic acid (HA) was esterified with benzyl groups to prepare hyaluronic acid derivative (HA-Bn) nanofibers via electrospinning. Electrospun membranes with average fiber diameters of 407.64 ± 124.8 nm (H400), 642.3 ± 228.76 nm (H600), and 841.09 ± 236.86 nm (H800) were obtained by adjusting the spinning parameters. These fibrous membranes had good biocompatibility, among which the H400 group could promote the proliferation and spread of L929 cells. Using the postoperative treatment of malignant skin melanoma as an example, the anticancer drug doxorubicin (DOX) was encapsulated in nanofibers via hybrid electrospinning. The UV spectroscopy of DOX-loaded nanofibers (HA-DOX) revealed that DOX was successfully encapsulated, and there was a π-π interaction between aromatic DOX and HA-Bn. The drug release profile confirmed the sustained release of about 90%, achieved within 7 days. In vitro cell experiments proved that the HA-DOX nanofiber had a considerable inhibitory effect on B16F10 cells. Therefore, the HA-Bn electrospun membrane could facilitate the potential regeneration of injured skin tissues and be incorporated with drugs to achieve therapeutic effects, offering a powerful approach to developing therapeutic and regenerative biomaterial.
Topics: Biocompatible Materials; Hyaluronic Acid; Nanofibers; Doxorubicin; Antineoplastic Agents
PubMed: 37108186
DOI: 10.3390/ijms24087023 -
Molecules (Basel, Switzerland) Jul 2018A heterobifunctional reactive oxygen species (ROS)-responsive linker for directed drug assembly onto and delivery from a quantum dot (QD) nanoparticle carrier was...
A heterobifunctional reactive oxygen species (ROS)-responsive linker for directed drug assembly onto and delivery from a quantum dot (QD) nanoparticle carrier was synthesized and coupled to doxorubicin using -(3-dimethylaminopropyl)-'-ethylcarbodiimide hydrochloride (EDC)/sulfo⁻NHS coupling. The doxorubicin conjugate was characterized using ¹H NMR and LC-MS and subsequently reacted under conditions of ROS formation (Cu/H₂O₂) resulting in successful and rapid thioacetal oxidative cleavage, which was monitored using ¹H NMR.
Topics: Doxorubicin; Magnetic Resonance Spectroscopy; Molecular Structure; Nanoparticles; Oxidation-Reduction; Peptides; Quantum Dots; Reactive Oxygen Species
PubMed: 30037071
DOI: 10.3390/molecules23071809 -
International Journal of Nanomedicine 2023Drug delivery systems (DDSs) based on liposomes are potential tools to minimize the side effects and substantially enhance the therapeutic efficacy of chemotherapy....
INTRODUCTION
Drug delivery systems (DDSs) based on liposomes are potential tools to minimize the side effects and substantially enhance the therapeutic efficacy of chemotherapy. However, it is challenging to achieve biosafe, accurate, and efficient cancer therapy of liposomes with single function or single mechanism. To solve this problem, we designed a multifunctional and multimechanism nanoplatform based on polydopamine (PDA)-coated liposomes for accurate and efficient combinatorial cancer therapy of chemotherapy and laser-induced PDT/PTT.
METHODS
ICG and DOX were co-incorporated in polyethylene glycol modified liposomes, which were further coated with PDA by a facile two-step method to construct PDA-liposome nanoparticles (PDA@Lipo/DOX/ICG). The safety of nanocarriers was investigated on normal HEK-293 cells, and the cellular uptake, intracellular ROS production capacity, and combinatorial treatment effect of the nanoparticles were assessed on human breast cancer cells MDA-MB-231. In vivo biodistribution, thermal imaging, biosafety assessment, and combination therapy effects were estimated based on MDA-MB-231 subcutaneous tumor model.
RESULTS
Compared with DOX·HCl and Lipo/DOX/ICG, PDA@Lipo/DOX/ICG showed higher toxicity on MDA-MB-231 cells. After endocytosis by target cells, PDA@Lipo/DOX/ICG produced a large amount of ROS for PDT by 808 nm laser irradiation, and the cell inhibition rate of combination therapy reached up to 80.4%. After the tail vein injection (DOX equivalent of 2.5 mg/kg) in mice bearing MDA-MB-231 tumors, PDA@Lipo/DOX/ICG significantly accumulated at the tumor site at 24 h post injection. After 808 nm laser irradiation (1.0 W/cm, 2 min) at this timepoint, PDA@Lipo/DOX/ICG efficiently suppressed the proliferation of MDA-MB-231 cell and even thoroughly ablated tumors. Negligible cardiotoxicity and no treatment-induced side effects were observed.
CONCLUSION
PDA@Lipo/DOX/ICG is a multifunctional nanoplatform based on PDA-coated liposomes for accurate and efficient combinatorial cancer therapy of chemotherapy and laser-induced PDT/PTT.
Topics: Humans; Animals; Mice; Female; Liposomes; Phototherapy; Reactive Oxygen Species; Tissue Distribution; HEK293 Cells; Breast Neoplasms; Nanoparticles; Doxorubicin; Cell Line, Tumor
PubMed: 36844433
DOI: 10.2147/IJN.S382109 -
International Journal of Molecular... Sep 2022Despite its common side effects and varying degrees of therapeutic success, chemotherapy remains the gold standard method for treatment of cancer. Towards developing a...
Despite its common side effects and varying degrees of therapeutic success, chemotherapy remains the gold standard method for treatment of cancer. Towards developing a new therapeutic approach, we have engineered nanoparticles derived from erythrocytes that contain indocyanine green as a photo-activated agent that enables near infrared photothermal heating, and doxorubicin hydrochloride (DOX) as a chemotherapeutic drug. We hypothesize that milliseconds pulsed laser irradiation results in rapid heating and photo-triggered release of DOX, providing a dual photo-chemo therapeutic mechanism for tumor destruction. Additionally, the surface of the nanoparticles is functionalized with folate to target the folate receptor-α on tumor cells to further enhance the therapeutic efficacy. Using non-contract infrared radiometry and absorption spectroscopy, we have characterized the photothermal response and photostability of the nanoparticles to pulsed laser irradiation. Our in vitro studies show that these nanoparticles can mediate photo-chemo killing of SKOV3 ovarian cancer cells when activated by pulsed laser irradiation. We further demonstrate that this dual photo-chemo therapeutic approach is effective in reducing the volume of tumor implants in mice and elicits an apoptotic response. This treatment modality presents a promising approach in destruction of small tumor nodules.
Topics: Animals; Cell Line, Tumor; Doxorubicin; Erythrocytes; Folic Acid; Hyperthermia, Induced; Indocyanine Green; Lasers; Mice; Nanoparticles; Neoplasms; Phototherapy
PubMed: 36142205
DOI: 10.3390/ijms231810295 -
Biomedicine & Pharmacotherapy =... Sep 2023Doxorubicin (DOX) loaded liposomes have been used and studied in the last decades due to the significant decrease in DOX induced cardiac and systemic toxicity relative...
Doxorubicin (DOX) loaded liposomes have been used and studied in the last decades due to the significant decrease in DOX induced cardiac and systemic toxicity relative to administration of free drug. Therefore, new strategies are sought to improve DOX delivery and antitumor activity, while avoiding side effects. Recently, folate-coated pH-sensitive liposomes (SpHL-Fol) have been studied as a tool to enhance cellular uptake and antitumor activity of paclitaxel and DOX in breast cancer cells expressing folate receptor (FR+). However, the elucidation of folate functionalization relevance in DOX-loaded SpHL (SpHL-DOX-Fol) in different cell types (MDA-MB-231, MCF-7, and A549), as well as, the complete safety evaluation, is necessary. To achieve these objectives, SpHL-DOX-Fol was prepared and characterized as previously described. Antitumor activity and acute toxicity were evaluated in vivo through direct comparison of free DOX verses SpHL-DOX, a well-known formulation to reduce DOX cardiotoxicity. The obtained data are crucial to support future translational research. Liposomes showed long-term stability, suitable for biological use. Cellular uptake, cytotoxicity, and percentage of migration inhibition were significantly higher for MDA-MB-231 (FR+) treated with SpHL-DOX-Fol. In addition, SpHL-DOX-Fol demonstrated a decrease in the systemic toxic effects of DOX, mainly in renal and cardiac parameters evaluation, even using a higher dose (20 mg/kg). Collectively these data build the foundation of support demonstrating that SpHL-DOX-Fol could be considered a promising drug delivery strategy for the treatment of FR+ breast tumors.
Topics: Liposomes; Folic Acid; Doxorubicin; Drug Delivery Systems; Hydrogen-Ion Concentration; Cell Line, Tumor
PubMed: 37541172
DOI: 10.1016/j.biopha.2023.115280 -
Scientific Reports Dec 2023Tumor microenvironment (TME) targeted strategy could control the drug release in tumor cells more accurately and creates a new opportunity for enhanced site-specific...
Tumor microenvironment (TME) targeted strategy could control the drug release in tumor cells more accurately and creates a new opportunity for enhanced site-specific targeted delivery. In this study, (PAA-b-PCL-S-S-PCL-b-PAA) copolymeric nanoparticles (NPs) with size-switchable ability and dual pH/redox-triggered drug release behavior were designed to significantly promote cancer uptake (cell internalization of around 100% at 30 min) and site-specific targeted doxorubicin (DOX) delivery in MDA-MB-231 tumor cells. NPs surface charge was shifted from - 17.8 to - 2.4 and their size shrunk from 170.3 to 93 nm in TME. The cell cycle results showed that DOX-loaded NPs showed G2/M (68%) arrest, while free DOX showed sub-G1 arrest (22%). Apoptosis tests confirmed that the cells treated with DOX-loaded NPs showed a higher amount of apoptosis (71.6%) than the free DOX (49.8%). Western blot and RT-PCR assays revealed that the apoptotic genes and protein levels were significantly upregulated using the DOX-loaded NPs vs. the free DOX (P < 0.001). In conclusion, dual pH/redox-responsive and size-switchable DOX-loaded NPs developed here showed outstanding anti-tumoral features compared with free DOX that might present a prospective platform for tumor site-specific accumulation and drug release that suggest further in vivo research.
Topics: Humans; Tumor Microenvironment; Hydrogen-Ion Concentration; Doxorubicin; Neoplasms; Oxidation-Reduction; Nanoparticles; Drug Liberation; Cell Line, Tumor; Drug Carriers; Drug Delivery Systems
PubMed: 38110480
DOI: 10.1038/s41598-023-49446-x -
Molecular Therapy : the Journal of the... Jan 2010Drug delivery with microbubbles and ultrasound is gaining more and more attention in the drug delivery field due to its noninvasiveness, local applicability, and proven...
Drug delivery with microbubbles and ultrasound is gaining more and more attention in the drug delivery field due to its noninvasiveness, local applicability, and proven safety in ultrasonic imaging techniques. In this article, we tried to improve the cytotoxicity of doxorubicin (DOX)-containing liposomes by preparing DOX-liposome-containing microbubbles for drug delivery with therapeutic ultrasound. In this way, the DOX release and uptake can be restricted to ultrasound-treated areas. Compared to DOX-liposomes, DOX-loaded microbubbles killed at least two times more melanoma cells after exposure to ultrasound. After treatment of the melanoma cells with DOX-liposome-loaded microbubbles and ultrasound, DOX was mainly present in the nuclei of the cancer cells, whereas it was mainly detected in the cytoplasm of cells treated with DOX-liposomes. Exposure of cells to DOX-liposome-loaded microbubbles and ultrasound caused an almost instantaneous cellular entry of the DOX. At least two mechanisms were identified that explain the fast uptake of DOX and the superior cell killing of DOX-liposome-loaded microbubbles and ultrasound. First, exposure of DOX-liposome-loaded microbubbles to ultrasound results in the release of free DOX that is more cytotoxic than DOX-liposomes. Second, the cellular entry of the released DOX is facilitated due to sonoporation of the cell membranes. The in vitro results shown in this article indicate that DOX-liposome-loaded microbubbles could be a very interesting tool to obtain an efficient ultrasound-controlled DOX delivery in vivo.
Topics: Animals; Cell Line, Tumor; Cell Survival; Doxorubicin; Liposomes; Melanoma; Mice; Microbubbles; Microscopy, Confocal; Models, Theoretical
PubMed: 19623162
DOI: 10.1038/mt.2009.160 -
Theranostics 2023Chemoimmunotherapy is a promising approach in cancer immunotherapy. However, its therapeutic efficacy is restricted by high reactive oxygen species (ROS) levels, an...
Chemoimmunotherapy is a promising approach in cancer immunotherapy. However, its therapeutic efficacy is restricted by high reactive oxygen species (ROS) levels, an abundance of cancer-associated fibroblasts (CAFs) in tumor microenvironment (TME) as well as immune checkpoints for escaping immunosurveillance. Herein, a new type of TME and reduction dual-responsive polymersomal prodrug (TRPP) nanoplatform was constructed when the D-peptide antagonist (PPA-1) of programmed death ligand-1 was conjugated onto the surface, and talabostat mesylate (Tab, a fibroblast activation protein inhibitor) was encapsulated in the watery core (PPA-TRPP/Tab). Doxorubicin (DOX) conjugation in the chain served as an immunogenic cell death (ICD) inducer and hydrophobic part. PPA-TRPP/Tab reassembled into a micellar structure with TME modulation by Tab, ROS consumption by 2, 2'-diselanediylbis(ethan-1-ol), immune checkpoint blockade by PPA-1 and ICD generation by DOX. This resolved the dilemma between a hydrophilic Tab release in the TME for CAF inhibition and intracellular hydrophobic DOX release for ICD via re-assembly in weakly acidic TME with polymersome-micelle transformation. results indicated that PPA-TRPP/Tab could improve tumor accumulation, suppress CAF formation, downregulate regulatory T cells and promote T lymphocyte infiltration. In mice, it gave a 60% complete tumor regression ratio and a long-term immune memory response. The study offers potential in tumor eradication via exploiting an "all-in-one" smart polymeric nanoplatform.
Topics: Animals; Mice; Prodrugs; Immune Checkpoint Inhibitors; Tumor Microenvironment; Reactive Oxygen Species; Immunogenic Cell Death; Antineoplastic Agents; Immunotherapy; Doxorubicin; Neoplasms; Micelles; Cell Line, Tumor
PubMed: 37064869
DOI: 10.7150/thno.83912 -
Cancer Chemotherapy and Pharmacology Dec 2016Doxorubicin is a key component in many pediatric oncology treatment regimens; still pharmacology data on which current dosing regimens are based are very limited. (Clinical Trial)
Clinical Trial
PURPOSE
Doxorubicin is a key component in many pediatric oncology treatment regimens; still pharmacology data on which current dosing regimens are based are very limited.
METHODS
We conducted a multinational pharmacokinetic study investigating age dependency of doxorubicin metabolism and elimination in children with cancer. One hundred and one patients treated with doxorubicin according to a cancer-specific national or European therapeutic trial were recruited. Doses of doxorubicin ranged from 10.4 to 57.7 mg/m. Blood samples for measurement of doxorubicin and its metabolite doxorubicinol were collected after two administrations, with five samples collected in children <3 years and eight in children ≥3 years. A population pharmacokinetic approach was used for analysis, including pharmacogenetic covariates. Natriuretic peptides and cardiac troponins were measured to evaluate their role as early indicators of cardiotoxicity.
RESULTS
Age dependence of doxorubicin clearance was demonstrated, with children less than 3 years having a statistically significant lower clearance (21.1 ± 5.8 l/h/m) than older children (26.6 ± 6.7 l/h/m) (p = 0.0004) after correcting for body surface area. No effect of the investigated genetic polymorphisms on the pharmacokinetics could be observed. Although natriuretic peptides were transiently elevated after each doxorubicin administration and troponin levels increased with increasing doxorubicin exposure, only limited correlation could be observed between their blood levels and doxorubicin pharmacokinetics.
CONCLUSION
In the European framework of funding and regulatory support, an add-on study to existing therapeutic trials was developed. The pediatric need concerning missing PK data could be addressed with limited burden for the patients. Empirically used dose adaptations for infants were generally found to be justified based on our PK analyses.
Topics: Adolescent; Antibiotics, Antineoplastic; Child; Child, Preschool; Doxorubicin; Female; Heart; Humans; Infant; Male; Neoplasms; Polymorphism, Genetic; Troponin
PubMed: 27770238
DOI: 10.1007/s00280-016-3174-8