ABSTRACT
In this work, an injectable in situ depot-forming lipidic lyotropic liquid crystal (L3C) system is developed to codeliver a precisely synchronized combination of chemotherapeutics intratumorally. The developed L3C system is composed of amphiphilic lipids and surfactants, including monoolein, phosphatidylcholine, tocopherol acetate, and d-α-tocopherol polyethylene glycol 1000 succinate. Owing to its amphiphilic nature, the developed formulation can coaccommodate both hydrophobic and hydrophilic chemotherapeutic moieties simultaneously. The study presents a proof of concept by designing a combination chemotherapy regimen in vitro and demonstrating its in vivo translation using doxorubicin and paclitaxel as model hydrophilic and hydrophobic drug moieties, respectively. The synchronized combination of the two chemotherapeutics with maximum synergistic activity was identified, coloaded in the developed L3C system at predefined stoichiometric ratios, and evaluated for antitumor efficacy in the 4T1 breast tumor model in BALB/c mice. The drug-loaded L3C formulation is a low-viscosity injectable fluid with a lamellar phase that transforms into a hexagonal mesophase depot system upon intratumoral injection. The drug-loaded depot system locally provides sustained intratumoral delivery of the chemotherapeutics combination at their precisely synchronized ratio for over a period of one month. Results demonstrate that the exposure of the tumor to the precisely synchronized intratumoral chemotherapeutics combination via the developed L3C system resulted in significantly higher antitumor activity and reduced cardiotoxicity compared to the unsynchronized combination chemotherapy or the synchronized but uncoordinated drug delivery administered by a conventional intravenous route. These findings demonstrate the potential of the developed L3C system for achieving synchronized codelivery of the chemotherapeutics combination intratumorally and improving the efficacy of combination chemotherapy.
Subject(s)
Doxorubicin , Liquid Crystals , Mice, Inbred BALB C , Animals , Liquid Crystals/chemistry , Mice , Doxorubicin/chemistry , Doxorubicin/pharmacology , Female , Paclitaxel/chemistry , Paclitaxel/pharmacology , Paclitaxel/pharmacokinetics , Cell Line, Tumor , Humans , Glycerides/chemistry , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/chemistry , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Carriers/chemistryABSTRACT
Triple negative breast cancer (TNBC) represents the most aggressive and heterogenous disease, and combination therapy holds promising potential. Here, an enzyme-responsive polymeric prodrug with self-assembly properties was synthesized for targeted co-delivery of paclitaxel (PTX) and ursolic acid (UA). Hyaluronic acid (HA) was conjugated with UA, yielding an amphiphilic prodrug with 13.85 mol% UA and a CMC of 32.3 µg/mL. The HA-UA conjugate exhibited â¼14 % and 47 % hydrolysis at pH 7.4 and in tumor cell lysate. HA-UA/PTX NPs exhibited a spherical structure with 173 nm particle size, and 0.15 PDI. The nanoparticles showed high drug loading (11.58 %) and entrapment efficiency (76.87 %) of PTX. Release experiments revealed accelerated drug release (â¼78 %) in the presence of hyaluronidase enzyme. Cellular uptake in MDA-MB-231 cells showed enhanced uptake of HA-UA/PTX NPs through CD44 receptor-mediated endocytosis. In vitro, HA-UA/PTX NPs exhibited higher cytotoxicity, apoptosis, and mitochondrial depolarization compared to PTX alone. In vivo, HA-UA/PTX NPs demonstrated improved pharmacokinetic properties, with 2.18, 2.40, and 2.35-fold higher AUC, t1/2, and MRT compared to free PTX. Notably, HA-UA/PTX NPs exhibited superior antitumor efficacy with a 90 % tumor inhibition rate in 4T1 tumor model and low systemic toxicity, showcasing their significant potential as carriers for TNBC combination therapy.
Subject(s)
Hyaluronic Acid , Nanoparticles , Paclitaxel , Triple Negative Breast Neoplasms , Triterpenes , Ursolic Acid , Triterpenes/chemistry , Triterpenes/pharmacology , Hyaluronic Acid/chemistry , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Humans , Nanoparticles/chemistry , Animals , Female , Paclitaxel/pharmacology , Paclitaxel/chemistry , Paclitaxel/administration & dosage , Paclitaxel/therapeutic use , Cell Line, Tumor , Drug Liberation , Apoptosis/drug effects , Mice , Drug Carriers/chemistry , Prodrugs/chemistry , Prodrugs/pharmacology , Mice, Inbred BALB C , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/chemistryABSTRACT
Combination chemotherapy is considered an effective strategy to inhibit tumor growth. Here, beta-sheet-rich silk nanofibers are co-loaded with hydrophilic doxorubicin (DOX) and hydrophobic paclitaxel (PTX) through a sequential physical blending-centrifugation-blending process. The ratio and amount of DOX and PTX on the nanofibers are regulated independently to optimize cooperative interaction. Both PTX and DOX are immobilized on the same nanofibers to avoid burst release problems. Besides the water-insoluble PTX, more than half of the DOX remained fixed on the nanofibers for more than 28 days, which facilitated the co-internalization of both DOX and PTX by tumor cells in vitro. Changing the ratio of co-loaded DOX and PTX achieved optimal combination therapy in vitro. The DOX-PTX co-loaded nanofibers are assembled into injectable hydrogels to facilitate in situ injection around tumor tissues in vivo. Long-term inhibition is achieved for tumors treated with DOX-PTX co-loaded hydrogels, superior to those treated with free DOX and PTX, and hydrogels loaded with only DOX or PTX. Considering the mild and controllable physical loading process and superior loading capacity for both hydrophilic and hydrophobic ingredients, these injectable silk nanofiber hydrogels are promising carriers to deliver multiple drug types simultaneously in situ, enhancing combination chemotherapies towards clinical applications.
Subject(s)
Doxorubicin , Drug Carriers , Hydrophobic and Hydrophilic Interactions , Nanofibers , Paclitaxel , Silk , Nanofibers/chemistry , Doxorubicin/pharmacology , Doxorubicin/chemistry , Paclitaxel/pharmacology , Paclitaxel/chemistry , Animals , Humans , Silk/chemistry , Drug Carriers/chemistry , Mice , Hydrogels/chemistry , Hydrogels/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/chemistry , Cell Line, Tumor , Drug LiberationABSTRACT
Combination chemotherapy, which involves the simultaneous use of multiple anticancer drugs in adequate combinations to disrupt multiple mechanisms associated with tumor growth, has shown advantages in enhanced therapeutic efficacy and lower systemic toxicity relative to monotherapy. Herein, we employed coordination-driven self-assembly to construct discrete Pt(II) metallacycles as monodisperse, modular platforms for combining camptothecin and combretastatin A4, two chemotherapy agents with a disparate mechanism of action, in precise arrangements for combination chemotherapy. Formulation of the drug-loaded metallacycles with folic acidfunctionalized amphiphilic diblock copolymers furnished nanoparticles with good solubility and stability in physiological conditions. Folic acids on the surface of the nanoparticles promote their internalization into cancer cells. The intracellular reductive environment of cancer cells induces the release of the drug molecules at an exact 1:1 ratio, leading to a synergistic anticancer efficacy. In vivo studies on tumor-bearing mice demonstrated the favorable therapeutic outcome and minimal side effects of the combination chemotherapy approach based on a self-assembled metallacycle.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Camptothecin , Neoplasms , Platinum , Stilbenes , Animals , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/chemistry , Camptothecin/administration & dosage , Camptothecin/pharmacology , Drug Liberation , Drug Synergism , Folic Acid/chemistry , Humans , Mice , Nanoparticles , Neoplasms/drug therapy , Platinum/chemistry , Polymers/therapeutic use , Stilbenes/administration & dosage , Stilbenes/pharmacology , Tumor MicroenvironmentABSTRACT
The human gonadotropin releasing hormone (GnRH-I) and its sea lamprey analogue GnRH-III specifically bind to GnRH receptors on cancer cells and can be used as targeting moieties for targeted tumor therapy. Considering that the selective release of drugs in cancer cells is of high relevance, we were encouraged to develop cleavable, self-immolative GnRH-III-drug conjugates which consist of a p-aminobenzyloxycarbonlyl (PABC) spacer between a cathepsin B-cleavable dipeptide (Val-Ala, Val-Cit) and the classical anticancer drugs daunorubicin (Dau) and paclitaxel (PTX). Alongside these compounds, non-cleavable GnRH-III-drug conjugates were also synthesized, and all compounds were analyzed for their antiproliferative activity. The cleavable GnRH-III bioconjugates revealed a growth inhibitory effect on GnRH receptor-expressing A2780 ovarian cancer cells, while their activity was reduced on Panc-1 pancreatic cancer cells exhibiting a lower GnRH receptor level. Moreover, the antiproliferative activity of the non-cleavable counterparts was strongly reduced. Additionally, the efficient cleavage of the Val-Ala linker and the subsequent release of the drugs could be verified by lysosomal degradation studies, while radioligand binding studies ensured that the GnRH-III-drug conjugates bound to the GnRH receptor with high affinity. Our results underline the high value of GnRH-III-based homing devices and the application of cathepsin B-cleavable linker systems for the development of small molecule drug conjugates (SMDCs).
Subject(s)
Gonadotropin-Releasing Hormone , Molecular Targeted Therapy , Ovarian Neoplasms , Receptors, LHRH , Animals , Antineoplastic Combined Chemotherapy Protocols/chemistry , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cathepsin B/chemistry , Cathepsin B/therapeutic use , Cell Line, Tumor , Daunorubicin/chemistry , Daunorubicin/therapeutic use , Female , Gonadotropin-Releasing Hormone/therapeutic use , Humans , Molecular Targeted Therapy/methods , Paclitaxel/chemistry , Paclitaxel/therapeutic use , Petromyzon , Pyrrolidonecarboxylic Acid/analogs & derivatives , Pyrrolidonecarboxylic Acid/therapeutic use , Receptors, LHRH/therapeutic useABSTRACT
Nowadays, the usage of nanoparticles in various fields such as drug delivery, attracts the attention of many researchers in the treatment of cancers. Graphene oxide (GO) is one of the novel drug delivery systems which is used broadly owing to its unique features. In this survey, doxorubicin (DOX) was accompanied by natural medicine, curcumin (CUR), to diminish its side effects and enhance its efficiency. Cytotoxicity assay in human gastric cancer (AGS), prostate cancer (PC3), and ovarian cancer (A2780), was evaluated. Also, the uptake of DOX and CUR into cells, was assessed using a fluorescence microscope. Moreover, real-time PCR was applied for the evaluation of the expression of RB1 and CDK2 genes, which were involved in the cell cycle. In both separate and simultaneous forms, DOX and CUR were loaded with high efficiency and the release behavior of both drugs was pH-sensitive. The higher release rate was attained at pH 5.5 and 42 °C for DOX (80.23%) and CUR (13.06), respectively. The intensity of fluorescence in the free form of the drugs, was higher than the loaded form. In the same concentration, the free form of CUR and DOX were more toxic than the loaded form in all cell lines. Also, free drugs showed more impact on the expression of RB1 and CDK2 genes. Co-delivery of CUR and DOX into the mentioned cell lines, was more effective than the free form of CUR and DOX due to its lower toxicity to normal cells.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Curcumin/administration & dosage , Doxorubicin/administration & dosage , Drug Carriers , Graphite/chemistry , Neoplasms/drug therapy , Stimuli Responsive Polymers , Antineoplastic Combined Chemotherapy Protocols/chemistry , Antineoplastic Combined Chemotherapy Protocols/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Curcumin/chemistry , Curcumin/metabolism , Cyclin-Dependent Kinase 2/genetics , Cyclin-Dependent Kinase 2/metabolism , Doxorubicin/chemistry , Doxorubicin/metabolism , Drug Compounding , Drug Liberation , Female , Humans , Hydrogen-Ion Concentration , Kinetics , Male , Neoplasms/genetics , Neoplasms/metabolism , Neoplasms/pathology , Retinoblastoma Binding Proteins/genetics , Retinoblastoma Binding Proteins/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolismABSTRACT
Roburic acid (ROB) is a naturally occurred tetracyclic triterpenoid, and the anticancer activity of this compound has not been reported. Docetaxel (DOC) is the first-line chemotherapeutic agent for advanced stage prostate cancer but toxic side effects and drug resistance limit its clinical success. In this study, the potential synergistic anticancer effect and the underlying mechanisms of ROB in combination with DOC on prostate cancer were investigated. The results showed that ROB and DOC in combination synergistically inhibited the growth of prostate cancer cells. The combination also strongly induced apoptosis, and suppressed cell migration, invasion and sphere formation. Mechanistic study showed that the combined effects of ROB and DOC on prostate cancer cells were associated with inhibition of NF-κB activation, down regulation of Bcl-2 and up regulation of Bax. Knockdown of NF-κB by small interfering RNA (siRNA) significantly decreased the combined effect of ROB and DOC. Moreover, we found that esomeprazole (ESOM), a proton pump inhibitor (PPI), strongly enhanced the effectiveness of ROB and DOC on prostate cancer cells in acidic culture medium. Since acidic micro environment is known to impair the efficacy of current anticancer therapies, ESOM combined with ROB and DOC may be an effective approach for improving the treatment of prostate cancer patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Docetaxel , Prostatic Neoplasms , Humans , Male , Antineoplastic Combined Chemotherapy Protocols/chemical synthesis , Antineoplastic Combined Chemotherapy Protocols/chemistry , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cell Proliferation/drug effects , Cell Survival/drug effects , Docetaxel/chemistry , Docetaxel/pharmacology , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Esomeprazole/chemistry , Esomeprazole/pharmacology , Molecular Structure , NF-kappa B/antagonists & inhibitors , NF-kappa B/metabolism , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Proto-Oncogene Proteins c-bcl-2/metabolism , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Queen bee acid or 10-hydroxy-2-decenoic acid (10-HDA) is one of the main and unique lipid components (fatty acids) in royal jelly. Previous studies have demonstrated that 10-HDA has various pharmacological and biological activities. The present study aims to evaluate the anti-tumor effects of 10-HDA alone and combined with cyclophosphamide (CP), as an alkylating agent which widely used for the treatment of neoplastic cancers, against the Ehrlich solid tumors (EST) in mice. Methods: A total of 72 female Swiss albino mice were divided into eight groups. EST mice were treated with 10-HDA (2.5 and 5 mg/kg) alone and combined with CP (25 mg/kg) orally once a day for 2 weeks. Tumor growth inhibition, body weight, the serum level of alpha-fetoprotein (AFP) and carcinoembryonic antigen tumor (CAE), liver and kidney enzymes, tumor lipid peroxidation (LPO) and nitric oxide (NO), antioxidant enzymes (e.g. glutathione reductase (GR), glutathione peroxidase (GPx), catalase enzyme (CAT)), tumor necrosis factor alpha level (TNF-α), and the apoptosis-regulatory genes expression were assessed in tested mice. Results: the findings exhibited that treatment of EST-suffering mice with 10-HDA at the doses of 2.5 and 5 mg/kg especially in combination with CP significantly (p < 0.001) decreased the tumor volume and inhibition rate, tumor markers (AFP and CEA), serum level of liver and kidney, LPO and NO, TNF-α level, as well as the expression level of Bcl-2 in comparison with the mice in the C2 group; while 10-HDA at the doses of 2.5 and 5 mg/kg especially in combination with CP significantly (p < 0.001) improved the level of antioxidant enzymes of GPx, CAT, and SOD and the expression level of caspase-3 and Bax genes. Conclusions: According to the results of the present investigations, 10-HDA at the doses of 2.5 and 5 mg/kg especially in combination with CP showed promising antitumor effects against EST in mice and can be recommended as a new or alternative anticancer agent against tumor; nevertheless, further investigations, particularly in clinical setting, are required to confirm these results.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carcinoma, Ehrlich Tumor , Fatty Acids, Monounsaturated/pharmacology , Neoplasm Proteins/metabolism , Animals , Antineoplastic Combined Chemotherapy Protocols/chemistry , Carcinoma, Ehrlich Tumor/drug therapy , Carcinoma, Ehrlich Tumor/metabolism , Carcinoma, Ehrlich Tumor/pathology , Cyclophosphamide/chemistry , Cyclophosphamide/pharmacology , Dose-Response Relationship, Drug , Fatty Acids/chemistry , Fatty Acids, Monounsaturated/chemistry , Female , MiceABSTRACT
Acute lymphoblastic leukemia (ALL) is one of the most common type of leukemia in children. It is caused by abnormal cell division of the lymphoid progenitor cells in the bone marrow. In the past decade, metformin has gained increased attention for its anti-leukemic potential. Moreover, other chemotherapeutic agents were investigated for the possible superior efficacy over the existing treatments in treating ALL. Several studies examined the effect of cisplatin as a potential candidate for therapy. Here, we investigate the anti-leukemic effect of metformin and cisplatin on 697 cells. Both compounds revealed significant cytotoxic effects. Specifically designed lipid-based cubosomal nanoformulations were used as drug carriers to facilitate compound entry in low doses. Our results indicate that the use of the carrier did not affect cytotoxicity significantly. In addition, combining the drugs in different carriers demonstrated an antagonistic effect through damping the efficacy of both drugs. This was evident from experiments investigating cellular viability, annexin V/PI staining, mitochondrial membrane potential and caspase-3 activity. Taken together, it appears that metformin does not represent a suitable option for sensitizing leukemia cells to cisplatin.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cisplatin/pharmacology , Metformin/pharmacology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Cisplatin/chemistry , Dose-Response Relationship, Drug , Drug Carriers , Drug Compounding , Drug Interactions , Humans , Lipids/chemistry , Membrane Potential, Mitochondrial/drug effects , Metformin/chemistry , Nanoparticles , Nanotechnology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathologyABSTRACT
BACKGROUND: Survival rate of patients affected with anaplastic thyroid carcinoma (ATC) is less than 5% with current treatment. In ATC, BRAFV600E mutation is the major mutation that results in the transformation of normal cells in to an undifferentiated cancer cells via aberrant molecular signaling mechanisms. Although vemurufenib is a selective oral drug for the BRAFV600E mutant kinase with a response rate of nearly 50% in metastatic melanoma, our study has showed resistance to this drug in ATC. Hence the rationale of the study is to explore combinational therapeutic effect to improve the efficacy of vemurafenib along with metformin. Metformin, a diabetic drug is an AMPK activator and has recently proved to be involved in preventing or treating several types of cancer. METHODS AND RESULTS: Using iGEMDock software, a protein-ligand interaction was successful between Metformin and TSHR (receptor present in the thyroid follicular cells). Our study demonstrates that combination of vemurufenib with metformin has synergistic anti-cancer effects which was evaluated through MTT assay (cytotoxicity), colony formation assay (antiproliferation evaluation) and suppressed the progression of ATC cells growth by inducing significant apoptosis, proven by Annexin V-FITC assay (Early Apoptosis Detection). Downregulation of ERK signaling, upregulation of AMPK pathway and precision in epithelial-mesenchymal transition (EMT) pathway which were assessed by RT-PCR and Western blot provide the evidence that the combination of drugs involved in the precision of altered molecular signaling Further our results suggest that Metformin act as a demethylating agent in anaplastic thyroid cancer cells by inducing the expression of NIS and TSHR. Our study for the first time explored cAMP signaling in ATC wherein cAMP signaling is downregulated due to decrease in intracellular cAMP level upon metformin treatment. CONCLUSION: To conclude, our findings demonstrate novel therapeutic targets and treatment strategies for undifferentiated ATC.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Neoplasm Proteins , Receptors, Thyrotropin , Thyroid Carcinoma, Anaplastic , Thyroid Neoplasms , Antineoplastic Combined Chemotherapy Protocols/chemistry , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cell Line, Tumor , Drug Synergism , Humans , Metformin/chemistry , Metformin/pharmacology , Neoplasm Proteins/chemistry , Neoplasm Proteins/metabolism , Receptors, Thyrotropin/chemistry , Receptors, Thyrotropin/metabolism , Thyroid Carcinoma, Anaplastic/chemistry , Thyroid Carcinoma, Anaplastic/drug therapy , Thyroid Carcinoma, Anaplastic/metabolism , Thyroid Neoplasms/chemistry , Thyroid Neoplasms/drug therapy , Thyroid Neoplasms/metabolism , Vemurafenib/chemistry , Vemurafenib/pharmacologyABSTRACT
Combination therapy between paclitaxel (PTX) and doxorubicin (DXR) is applied as the first-line treatment of breast cancer. Co-administration of drugs at synergistic ratio for treatment is facilitated with the use of nanocarriers, such as liposomes. However, despite the high response rate of solid tumors to this combination, a synergism of cardiotoxicity may limit the use. Thus, the objective of this work was to investigate the toxicity of long-circulating and fusogenic liposomes co-encapsulating PTX and DXR at the synergistic molar ratio (1:10) (LCFL-PTX/DXR). For this, clinical chemistry, histopathological analysis and electrocardiographic exams were performed on female Balb/c mice that received a single intravenous dose of LCFL-PTX/DXR. The results of the study indicated that the LD50 dose range (lethal dose for 50% of animals) of the LCFL-PTX/DXR treatment (28.9-34.7 mg/kg) is much higher than that found for free PTX/DXR treatment (20.8-23.1 mg/kg). In addition, liposomes promoted cardiac protection by not raising CK-MB levels in animals, keeping cardiomyocytes without injury or electrocardiographic changes. After 14 days of treatment, free PTX/DXR caused prolongation of the QRS interval when compared to LCFL-PTX/DXR treatment at the same dose (37.0 ± 5.01 ms and 30.83 ± 2.62 ms, respectively, with p = 0.017). The survival rate of animals treated with LCFL-PTX/DXR was three times higher than that of those treated with free drugs. Thus, it was established that the toxicity of LCFL-PTX/DXR is reduced compared to the combination of free PTX/DXR and this platform has advantages for the clinical treatment of breast cancer.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/toxicity , Doxorubicin/toxicity , Heart Diseases/chemically induced , Lipids/chemistry , Myocytes, Cardiac/drug effects , Paclitaxel/toxicity , Action Potentials/drug effects , Administration, Intravenous , Animals , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/chemistry , Cardiotoxicity , Doxorubicin/administration & dosage , Doxorubicin/chemistry , Drug Compounding , Drug Synergism , Electrocardiography , Female , Heart Diseases/metabolism , Heart Diseases/pathology , Lethal Dose 50 , Liposomes , Mice, Inbred BALB C , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Paclitaxel/administration & dosage , Paclitaxel/chemistryABSTRACT
Currently, the therapeutic performance of traditional mono-chemotherapy on cancers remains unsatisfactory because of the tumor heterogeneity and multidrug resistance. In light of intricate tumor structures and distinct tumor microenvironments (TMEs), combinational therapeutic strategies with multiple anticancer drugs from different mechanisms can synergistically optimize the outcomes and concomitantly minimize the adverse effects during the therapy process. Extensive research on polymeric micelles (PMs) for biomedical applications has revealed the growing importance of nanomedicines for cancer therapy in the recent decade. Starting from traditional simple delivery systems, PMs have been extended to multi-faceted therapeutic strategies. Here we review and summarize the most recent advances in combinational therapy based on multifunctional PMs including a combination of multiple anticancer drugs, chemo-gene therapy, chemo-phototherapy and chemo-immunotherapy. The design approaches, action mechanisms and therapeutic applications of these nanodrugs are summarized. In addition, we highlight the opportunities and potential challenges associated with this promising field, which will provide new guidelines for advanced combinational cancer chemotherapy.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Immunotherapy , Neoplasms/therapy , Polymers/chemistry , Antineoplastic Combined Chemotherapy Protocols/chemistry , Cell Proliferation/drug effects , Combined Modality Therapy , Humans , Micelles , Neoplasms/pathology , Tumor Microenvironment/drug effectsABSTRACT
This review presents data on dual conjugates of therapeutic and diagnostic action for targeted delivery to prostate cancer cells. The works of the last ten years on this topic were analyzed. The mail attention focuses on low-molecular-weight conjugates directed to the prostate-specific membrane antigen (PSMA); the comparison of high and low molecular weight PSMA-targeted conjugates was made. The considered conjugates were divided in the review into two main classes: diagnostic bimodal conjugates (which are containing two fragments for different types of diagnostics), theranostic conjugates (containing both therapeutic and diagnostic agents); also bimodal high molecular weight therapeutic conjugates containing two therapeutic agents are briefly discussed. The data of in vitro and in vivo studies for PSMA-targeted double conjugates available by the beginning of 2021 have been analyzed.
Subject(s)
Antigens, Surface/chemistry , Antineoplastic Combined Chemotherapy Protocols/chemistry , Cytostatic Agents/chemistry , Glutamate Carboxypeptidase II/chemistry , Prostatic Neoplasms/diagnosis , Antigens, Surface/metabolism , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cytostatic Agents/pharmacology , Glutamate Carboxypeptidase II/antagonists & inhibitors , Glutamate Carboxypeptidase II/metabolism , Humans , Male , Molecular Structure , Molecular Weight , Prostatic Neoplasms/drug therapyABSTRACT
Chlorin e6 (Ce6) is a promising photosensitizer for tumor photodynamic therapy (PDT). However, the efficacy of Ce6 PDT is limited by Ce6's poor water solubility, rapid blood clearance, and inadequate accumulation in the tumor tissue. This problem is tackled in this work, wherein functionalized superparamagnetic iron oxide nanoparticles (IO-NPs) were used as carriers to deliver Ce6 to melanoma. The IO-NPs were coated with polyglycerol (PG) to afford good aqueous solubility. The chemotherapeutic agent doxorubicin (DOX) was attached to the PG coating via the hydrazone bond to afford affinity to the cell membrane and thereby promote the cell uptake. The hydrophobic nature of DOX also induced the aggregation of IO-NPs to form nanoclusters. Ce6 was then loaded onto the IO nanoclusters through physical adsorption and coordination with surface iron atoms, yielding the final composites IO-PG-DOX-Ce6. In vitro experiments showed that IO-PG-DOX-Ce6 markedly increased Ce6 uptake in mouse melanoma cells, leading to much-enhanced photocytotoxicity characterized by intensified reactive oxygen species production, loss of viability, DNA damage, and stimulation of tumor cell immunogenicity. In vivo experiments corroborated the in vitro findings and demonstrated prolonged blood clearance of IO-PG-DOX-Ce6. Importantly, IO-PG-DOX-Ce6 markedly increased the Ce6 distribution and retention in mouse subcutaneous melanoma grafts and significantly improved the efficacy of Ce6-mediated PDT. No apparent vital organ damage was observed at the same time. In conclusion, the IO-PG-DOX NPs provide a simple and safe delivery platform for efficient tumor enrichment of Ce6, thereby enhancing antimelanoma PDT.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Chlorophyllides/administration & dosage , Melanoma/drug therapy , Nanoparticle Drug Delivery System/chemistry , Skin Neoplasms/drug therapy , Animals , Antineoplastic Combined Chemotherapy Protocols/chemistry , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Cell Line, Tumor , Chlorophyllides/chemistry , Chlorophyllides/pharmacokinetics , Disease Models, Animal , Doxorubicin/administration & dosage , Female , Humans , Magnetic Iron Oxide Nanoparticles/chemistry , Melanoma/pathology , Mice , Photochemotherapy , Skin Neoplasms/pathology , Solubility , Tissue DistributionABSTRACT
The acquired drug resistance of the platinum-based drug is a main obstacle in cancer therapy. Herein, an aminopyrrolic receptor 1 was synthesized to sensitize satraplatin for overcoming the drug resistance as well as improving tumor targeted ability. Thus, Pluronic F127-based polyaniline nanoparticles were designed to co-deliver satraplatin and aminopyrrolic receptor 1, which could control the drug release with the Near Infrared laser irradiation (808 nm) due to the polyaniline mediated photothermal conversion. Biological evaluation shows prepared nanoparticles (Pt-ARNPs) exhibited more effective cytotoxicity (IC50 = 2.7µM) against the tested cancer cell lines under laser irradiation, compared with free satraplatin or treatment without Near-infrared radiation. Moreover, Pt-ARNPs showed comparable cytotoxicity against A549 and A549/cis cells, implying that the combination of satraplatin and aminopyrrolic receptor 1 with nano carrier might be a promising strategy to reduce platinum resistance and improve therapeutic effect in cancer therapy.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Nanoparticles , Neoplasms/drug therapy , A549 Cells , Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Antineoplastic Combined Chemotherapy Protocols/chemistry , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Delayed-Action Preparations/chemistry , Delayed-Action Preparations/pharmacology , HeLa Cells , Humans , Infrared Rays , Nanoparticles/chemistry , Nanoparticles/therapeutic use , Neoplasms/metabolism , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/pharmacology , Poloxamer/chemistry , Poloxamer/pharmacologyABSTRACT
To achieve the co-delivery of chemotherapeutic drugs, genes, and immune agents in a single nanoparticulate system, p-mercaptobenzoic acid-grafted N, N, N-trimethyl chitosan nanoparticles (MT NPs) were successfully synthesized. Paclitaxel (PTX) was encapsulated into the hydrophobic core of the MT NPs, and meanwhile, survivin shRNA-expressing plasmid (iSur-pDNA) and recombinant human interleukin-2 (rhIL-2) were loaded onto the hydrophilic shell of the MT NPs. Owing to the redox-sensitiveness of MT NPs, a rapid release of PTX was triggered by the high concentration of glutathione. The synergistic effects of PTX (1.5 mg/kg), iSur-pDNA (1.875 mg/kg), and rhIL-2 (6 × 105 IU/kg) at a low dose endowed the MT/PTX/pDNA/rhIL-2 NPs with enhanced antitumor efficacies and improved tumor-induced immunosuppression. These results demonstrated that the co-delivery of PTX, iSur-pDNA, and rhIL-2 by the amphiphilic chitosan based NPs with redox-sensitiveness could be a promising strategy in the treatment of tumors.
Subject(s)
Antineoplastic Agents/pharmacology , Chitosan/chemistry , Drug Delivery Systems/methods , Nanoparticles/chemistry , Neoplasms/drug therapy , Paclitaxel/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Combined Chemotherapy Protocols/chemistry , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cell Line, Tumor , Female , Glutathione/metabolism , Humans , Interleukin-2/metabolism , Mice , Neoplasms/metabolism , Paclitaxel/chemistry , RNA, Small Interfering/metabolism , Survivin/metabolismABSTRACT
In the present study, a magnetic niosomal nanocarrier for co-delivery of curcumin and letrozole into breast cancer cells has been designed. The magnetic NiCoFe2O4 core was coated by a thin layer of silica, followed by a niosomal structure, allowing us to load letrozole and curcumin into the silica layer and niosomal layer, respectively, and investigate their synergic effects on breast cancer cells. Furthermore, the nanocarriers demonstrated a pH-dependent release due to the niosomal structure at their outer layer, which is a promising behavior for cancer treatment. Additionally, cellular assays revealed that the nanocarriers had low cellular uptake in the case of non-tumorigenic cells (i.e., MCF-10A) and related high viability but high cellular uptake in cancer cell lines (i.e., MDA-MB-231 and SK-BR-3) and related low viability, which is evidenced in their high cytotoxicity against different breast cancer cell lines. The cytotoxicity of the letrozole/curcumin co-loaded nanocarrier is higher than that of the aqueous solutions of both drugs, indicating their enhanced cellular uptake in their encapsulated states. In particular, NiCoFe2O4@L-Silica-L@C-Niosome showed the highest cytotoxicity effects on MDA-MB-231 and SK-BR-3 breast cancer cells. The observed cytotoxicity was due to regulation of the expression levels of the studied genes in breast cancer cells, where downregulation was observed for the Bcl-2, MMP 2, MMP 9, cyclin D, and cyclin E genes while upregulation of the expression of the Bax, caspase-3, and caspase-9 genes was observed. The flow cytometry results also revealed that NiCoFe2O4@L-Silica-L@C-Niosome enhanced the apoptosis rate in both MDA-MB-231 and SK-BR-3 cells compared to the control samples. The findings of our research show the potential of designing magnetic niosomal formulations for simultaneous targeted delivery of both hydrophobic and hydrophilic drugs into cancer cells in order to enhance their synergic chemotherapeutic effects. These results could open new avenues into the future of nanomedicine and the development of theranostic agents.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Breast Neoplasms/drug therapy , Magnetic Fields , Antineoplastic Combined Chemotherapy Protocols/chemistry , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Curcumin/chemistry , Curcumin/pharmacokinetics , Curcumin/pharmacology , Female , Humans , Letrozole/chemistry , Letrozole/pharmacokinetics , Letrozole/pharmacology , Liposomes , Magnetite Nanoparticles/chemistry , Magnetite Nanoparticles/therapeutic use , Neoplasm Proteins/metabolismABSTRACT
The study aims to clarify the current controversy related to conflicting reports on whether presence of Cr(VI) in rice is possible or not. For this purpose, a method was employed for the single run speciation analysis of Cr(III) and Cr(VI) in rice samples using species-specific isotope dilution (SS-ID) and high performance liquid chromatography coupled to inductively coupled mass-spectrometry (HPLC-ICP-MS) and selective single run species complexation/derivatisation. The quantification limits (LOQs) were 0.014 µg kg-1 for Cr(III) and 0.047 µg kg-1 for Cr(VI), while the detection limits (LODs) were 0.004 and 0.014 µg kg-1 for Cr(III) and Cr(VI), respectively. A total of 10 rice samples of different origin and colour (depending on the type of industrial processing) were analysed in this study. The content of Cr(VI) was below the limit of quantification in all of the rice samples analysed, while the Cr(III) levels ranged between 0.59 (whole grain rice) up to 104 µg kg-1 (brown rice). All samples were also analysed for their total Cr (Crtotal) content by ICP-MS solely and the results were in all cases comparable with the Cr(III) levels determined in the same samples. To assess the stability of Cr(III) and Cr(VI) in rice, one sample was spiked with Cr(III) and Cr(VI) (individually) at different levels (5.0, 10, 15 and 20 µg kg-1), held for 2 h, and then analysed by SS-ID HPLC-ICP-MS. The results showed a complete reduction of Cr(VI) to Cr(III), while Cr(III) remained stable at all spiking levels. These findings support the general statement from the European Food Safety Authority related to the complete absence of Cr(VI) in foods and confirms that Cr in rice is found solely as Cr(III) species.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/chemistry , Chromatography, High Pressure Liquid/methods , Food Contamination , Oryza/chemistry , Chlorambucil/chemistry , Limit of Detection , Mass Spectrometry , Prednisolone/chemistry , Procarbazine/chemistry , Vinblastine/chemistryABSTRACT
Pancreatic cancer is a lethal malignancy with a dismal prognosis. Gemcitabine is currently used to treat pancreatic cancer, but it is limited by significant toxicity. Clinical trials on the combination of gemcitabine and erlotinib reported unsatisfactory outcomes along with concerns of toxicity. The encapsulation of chemotherapy drugs in polylactic-co-glycolic acid (PLGA) nanoparticles (NPs) can alleviate toxicity through targeted delivery and sustained release. In addition, camouflaging the NPs with a macrophage membrane can evade the immune system and further improve tumor homing. We designed gemcitabine-loaded PLGA NPs with a macrophage membrane coating (MPGNPs) to reduce drug toxicity and increase the accumulation in the tumor. The combination of MPGNPs and erlotinib synergistically inhibited pancreatic cancer cell proliferation in vitro and in vivo by targeting the PI3K/AKT/mTOR and Ras/Raf/MEK/ERK signaling pathways. The MPGNPs were also able to evade phagocytosis and achieve passive targeting to the pancreatic tumors. The combination of MPGNPs and erlotinib showed synergistic anti-tumor efficacy in vitro and in vivo. This study provides a proof-of-concept for treating pancreatic cancer with a combination of MPGNPs and erlotinib.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Drug Carriers/chemistry , Drug Liberation , Macrophages/chemistry , Nanoparticles/administration & dosage , Pancreatic Neoplasms/drug therapy , Animals , Antineoplastic Combined Chemotherapy Protocols/chemistry , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Apoptosis , Cell Proliferation , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Erlotinib Hydrochloride/administration & dosage , Female , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Nanoparticles/chemistry , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Polyesters , Tissue Distribution , Tumor Cells, Cultured , Xenograft Model Antitumor Assays , GemcitabineABSTRACT
Cancer-targeted co-delivery of therapeutic agents has been recognized as an effective strategy for increasing efficacy and reducing side effects of therapeutic agents. In this study, we used methotrexate (MTX) alone as a targeting moiety and chemotherapeutic agent and in combination with docetaxel (DTX) and doxorubicin (DOX) as chemotherapeutic agents to stop cancer cell proliferation with the aid of newly designed nanostructured lipid carriers (NLCs). The physicochemical properties of our designed nanocomplexes were evaluated by DLS, FT-IR spectroscopy, SEM, and TEM. Moreover, the targeting efficiency of the designed and synthesized nanoplatforms was evaluated on the folate receptor (FR) positive human breast cancer cell line (MCF-7) and FR negative human alveolar basal epithelial cells (A549). The NLCs/DTX/DOX/CS and NLCs/DTX/DOX/CS-MTX complexes significantly increased the cell cytotoxicity and the cell apoptosis rate. However, the complexes significantly reduced the capability of colony formation and cell migration. Our results revealed that NLCs/DTX/DOX/CS-MTX had synergistic cytotoxicity, reactive oxygen spaces, autophagy, and the apoptosis induction ability with an enhanced cellular internalization rate in FR-positive cancer cells, thorough MTX recognition capability. We conclude that the NLCs/DTX/DOX/CS-MTX complex is a new promising paradigm for breast cancer-targeted co-delivery.