-
Biomedicine & Pharmacotherapy =... Jan 2019To associate paclitaxel (PTX) with doxorubicin (DXR) is one of the main chemotherapy strategies for breast cancer (BC) management. Despite the high response rates for...
Investigation of the antitumor activity and toxicity of long-circulating and fusogenic liposomes co-encapsulating paclitaxel and doxorubicin in a murine breast cancer animal model.
To associate paclitaxel (PTX) with doxorubicin (DXR) is one of the main chemotherapy strategies for breast cancer (BC) management. Despite the high response rates for this combination, it presents a cardiotoxic synergism, attributed to pharmacokinetic interactions between PTX and both DXR and its metabolite, doxorubicinol. One of the main strategies to minimize the cardiotoxicity of the combination is to extend the interval of time between DXR and PTX administration. However, it has been previously suggested that their co-administration leads to better efficacy compared to their sequential administration. In the present study, we investigated different molar ratio combinations of PTX:DXR (10:1; 1:1, and 1:10) against the 4T1 murine breast cancer cell line and concluded that there is no benefit of enhancing PTX concentration above that of DXR on the combination. Therefore, we obtained a long-circulating and fusogenic liposomal formulation co-encapsulating PTX and DXR (LCFL-PTX/DXR) at a molar ratio of 1:10, respectively, which maintained the in vitro biological activity of the combination. This formulation was investigated for its antitumor activity and toxicity in Balb/c mice bearing 4T1 breast tumor, and compared to treatments with free PTX, free DXR, and the mixture of free PTX:DXR at 1:10 molar ratio. The higher tumor inhibition ratios were observed for the treatments with free and co-encapsulated PTX:DXR in liposomes (66.87 and 66.52%, respectively, P>0.05) as compared to the control. The great advantage of the treatment with LCFL-PTX/DXR was its improved cardiac toxicity profile. While degeneration was observed in the hearts of all animals treated with the free PTX:DXR combination, no signs of cardiac toxicity were observed for animals treated with the LCFL-PTX/DXR. Thus, LCFL-PTX/DXR enables the co-administration of PTX and DXR, and might be considered valuable for breast cancer management.
Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cardiotoxicity; Dose-Response Relationship, Drug; Doxorubicin; Drug Carriers; Female; Humans; Liposomes; MCF-7 Cells; Mice; Mice, Inbred BALB C; Paclitaxel; Random Allocation; Tumor Burden
PubMed: 30551427
DOI: 10.1016/j.biopha.2018.11.011 -
Journal of Nanobiotechnology Mar 2018The systemic administration of cytotoxic chemotherapeutic agents for cancer treatment often has toxic side effects, limiting the usage dose. To increase chemotherapeutic...
BACKGROUND
The systemic administration of cytotoxic chemotherapeutic agents for cancer treatment often has toxic side effects, limiting the usage dose. To increase chemotherapeutic efficacy while reducing toxic effects, a rational design for synergy-based drug regimens is essential. This study investigated the augmentation of therapeutic effectiveness with the co-administration of paclitaxel (PTX; an effective chemotherapeutic drug for breast cancer) and curcumin (CUR; a chemosensitizer) in an MCF-7 cell line.
RESULTS
We optimized niosome formulations in terms of surfactant and cholesterol content. Afterward, the novel cationic PEGylated niosomal formulations containing Tween-60: cholesterol:DOTAP:DSPE-mPEG (at 59.5:25.5:10:5) were designed and developed to serve as a model for better transfection efficiency and improved stability. The optimum formulations represented potential advantages, including extremely high entrapment efficiency (~ 100% for both therapeutic drug), spherical shape, smooth-surface morphology, suitable positive charge (zeta potential ~ + 15 mV for both CUR and PTX), sustained release, small diameter (~ 90 nm for both agents), desired stability, and augmented cellular uptake. Furthermore, the CUR and PTX kinetic release could be adequately fitted to the Higuchi model. A threefold and 3.6-fold reduction in CUR and PTX concentration was measured, respectively, when the CUR and PTX was administered in nano-niosome compared to free CUR and free PTX solutions in MCF-7 cells. When administered in nano-niosome formulations, the combination treatment of CUR and PTX was particularly effective in enhancing the cytotoxicity activity against MCF-7 cells.
CONCLUSIONS
Most importantly, CUR and PTX, in both free form and niosomal forms, were determined to be less toxic on MCF-10A human normal cells in comparison to MCF-7 cells. The findings indicate that the combination therapy of PTX with CUR using the novel cationic PEGylated niosome delivery is a promising strategy for more effective breast cancer treatment.
Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line; Cell Line, Tumor; Cell Survival; Cholesterol; Curcumin; Drug Combinations; Drug Compounding; Drug Liberation; Drug Synergism; Female; Humans; Kinetics; Liposomes; MCF-7 Cells; Nanoparticles; Paclitaxel; Polyethylene Glycols; Polysorbates
PubMed: 29571289
DOI: 10.1186/s12951-018-0351-4 -
Biological & Pharmaceutical Bulletin 2023Niosomes are non-ionic surfactant (NIS)-based bilayer vesicles and, like liposomes, have great potential as drug-delivery systems. Our previous study revealed that...
Niosomes are non-ionic surfactant (NIS)-based bilayer vesicles and, like liposomes, have great potential as drug-delivery systems. Our previous study revealed that polyethylene glycol (PEG) niosomes using different sorbitan ester (Span) surfactants (sorbitan monoester, Span 20, 40, 60, 80; sorbitan triester, Span 65) distributed within tumors similarly to PEG liposomes. The aim of this study was to encapsulate efficiently an anti-cancer drug, paclitaxel (PTX) into Span PEG niosomes, and evaluate PTX release profiles and anti-tumor efficacy of PTX-loaded Span PEG niosomes. Niosome sizes ranged between 100-150 nm, and the PTX encapsulation efficiency was more than 50%. All niosomes examined, in the presence of serum, yielded sustained PTX-release profiles. PTX release at 24 and 48 h from Span 80 PEG niosomes was significantly the highest among the other Span PEG niosomes examined. In C26 tumor-bearing mice, PTX-loaded Span 40 PEG niosomes (the lowest PTX release in vitro) suppressed tumor growth while PTX-loaded Span 80 PEG niosomes (the highest PTX release in vitro) did not. Thus, we succeeded in the control of PTX release from Span PEG niosomes by modifying the component of niosomes, and it influenced the effects of drugs loaded into niosomes. This demonstrates that the excellent NIS physicochemical properties of Spans make them an ideal candidate for anti-cancer drug-carrier niosomes.
Topics: Mice; Animals; Liposomes; Paclitaxel; Polyethylene Glycols; Antineoplastic Agents; Drug Carriers; Surface-Active Agents
PubMed: 37779050
DOI: 10.1248/bpb.b23-00188 -
Pharmaceuticals (Basel, Switzerland) Jul 2022In this research, KLA-modified liposomes co-loaded with 5-fluorouracil and paclitaxel (KLA-5-FU/PTX Lps) were developed, and their antitumor activity against...
In this research, KLA-modified liposomes co-loaded with 5-fluorouracil and paclitaxel (KLA-5-FU/PTX Lps) were developed, and their antitumor activity against triple-negative breast cancer (TNBC) was evaluated. KLA-5-FU/PTX Lps were prepared using the thin-film dispersion method, and their in vitro anticancer efficacy was assessed in human breast cancer cells (MDA-MB-231). An MDA-MB-231 tumor-bearing mouse model was also established to evaluate their antitumor efficacy in vivo. KLA-5-FU/PTX Lps showed enhanced cytotoxicity against MDA-MB-231 cells, improved drug delivery to mitochondria, and induced mitochondria-mediated apoptosis. The modified liposomes also showed favorable antitumor activity in vivo due to their strong ability to target tumors and mitochondria. The liposomes showed no obvious systemic toxicity. Our results suggest that KLA-5-FU/PTX Lps are a promising system with which to target the delivery of antitumor drugs to mitochondria as a treatment for TNBC.
PubMed: 35890181
DOI: 10.3390/ph15070881 -
International Journal of Nanomedicine 2021Glioma is the most common primary malignant brain tumor with a dreadful overall survival and high mortality. One of the most difficult challenges in clinical treatment...
BACKGROUND
Glioma is the most common primary malignant brain tumor with a dreadful overall survival and high mortality. One of the most difficult challenges in clinical treatment is that most drugs hardly pass through the blood-brain barrier (BBB) and achieve efficient accumulation at tumor sites. Thus, to circumvent this hurdle, developing an effectively traversing BBB drug delivery nanovehicle is of significant clinical importance. Rabies virus glycoprotein (RVG) is a derivative peptide that can specifically bind to nicotinic acetylcholine receptor (nAChR) widely overexpressed on BBB and glioma cells for the invasion of rabies virus into the brain. Inspired by this, RVG has been demonstrated to potentiate drugs across the BBB, promote the permeability, and further enhance drug tumor-specific selectivity and penetration.
METHODS
Here, we used the RVG15, rescreened from the well-known RVG29, to develop a brain-targeted liposome (RVG15-Lipo) for enhanced BBB permeability and tumor-specific delivery of paclitaxel (PTX). The paclitaxel-cholesterol complex (PTX-CHO) was prepared and then actively loaded into liposomes to acquire high entrapment efficiency (EE) and fine stability. Meanwhile, physicochemical properties, in vitro and in vivo delivery efficiency and therapeutic effect were investigated thoroughly.
RESULTS
The particle size and zeta potential of PTX-CHO-RVG15-Lipo were 128.15 ± 1.63 nm and -15.55 ± 0.78 mV, respectively. Compared with free PTX, PTX-CHO-RVG15-Lipo exhibited excellent targeting efficiency and safety in HBMEC and C6 cells, and better transport efficiency across the BBB in vitro model. Furthermore, PTX-CHO-RVG15-Lipo could noticeably improve the accumulation of PTX in the brain, and then promote the chemotherapeutic drugs penetration in C6 orthotopic glioma based on in vivo imaging assays. The in vivo antitumor results indicated that PTX-CHO-RVG15-Lipo significantly inhibited glioma growth and metabasis, therefore improved survival rate of tumor-bearing mice with little adverse effect.
CONCLUSION
Our study demonstrated that the RVG15 was a promising brain-targeted specific ligands owing to the superior BBB penetration and tumor targeting ability. Based on the outstanding therapeutic effect both in vitro and in vivo, PTX-CHO-RVG15-Lipo was proved to be a potential delivery system for PTX to treat glioma in clinic.
Topics: Animals; Blood-Brain Barrier; Brain; Brain Neoplasms; Cell Line, Tumor; Cholesterol; Drug Delivery Systems; Glioma; Liposomes; Mice; Paclitaxel
PubMed: 34471351
DOI: 10.2147/IJN.S318266 -
Bioengineering & Translational Medicine May 2019The treatment of metastatic cancer is a great challenging issue throughout the world. Conventional chemotherapy can kill the cancer cells and, whereas, would exacerbate...
The treatment of metastatic cancer is a great challenging issue throughout the world. Conventional chemotherapy can kill the cancer cells and, whereas, would exacerbate the metastasis and induce drug resistance. Here, a new combinatorial treatment strategy of metastatic cancer was probed via subsequentially dosing dual nanomedicines, marimastat-loaded thermosensitive liposomes (MATT-LTSLs) and paclitaxel nanocrystals (PTX-Ns), via intravenous and intratumoral injection. First, the metastasis was blocked and cancer cells were locked in the tumor microenvironment (TME) by delivering the matrix metalloproteinase (MMP) inhibitor, MATT, to the tumor with LTSLs, downregulating the MMPs by threefold and reducing the degradation of the extracellular matrix. And then, the "locked" cancer cells were efficiently killed via intratumoral injection of the other cytotoxic nanomedicine, PTX-Ns, along with no metastasis and 100% inhibition of tumor growth. This work highlights the importance of the TME's integrity in the chemotherapy duration. We believe this is a generalized strategy for cancer treatment and has potential guidance for the clinical administration.
PubMed: 31249880
DOI: 10.1002/btm2.10130 -
Journal of Clinical Oncology : Official... Jan 2023Treatments for endocrine-refractory or triple-negative metastatic breast cancer (mBC) are modestly effective at prolonging life and improving quality of life but can be...
PURPOSE
Treatments for endocrine-refractory or triple-negative metastatic breast cancer (mBC) are modestly effective at prolonging life and improving quality of life but can be extremely expensive. Given these tradeoffs in quality of life and cost, the optimal choice of treatment sequencing is unclear. Cost-effectiveness analysis can explicitly quantify such tradeoffs, enabling more informed decision making. Our objective was to estimate the societal cost-effectiveness of different therapeutic alternatives in the first- to third-line sequences of single-agent chemotherapy regimens among patients with endocrine-refractory or triple-negative mBC.
METHODS
Using three dynamic microsimulation models of 10,000 patients each, three cohorts were simulated, based upon prior chemotherapy exposure: (1) unexposed to either taxane or anthracycline, (2) taxane- and anthracycline-exposed, and (3) taxane-exposed/anthracycline-naive. We focused on the following single-agent chemotherapy regimens as reasonable and commonly used options in the first three lines of therapy for each cohort, based upon feedback from oncologists treating endocrine-refractory or triple-negative mBC: (1) for taxane- and anthracycline-unexposed patients, paclitaxel, capecitabine (CAPE), or pegylated liposomal doxorubicin; (2) for taxane- and anthracycline-exposed patients, Eribulin, CAPE, or carboplatin; and (3) for taxane-exposed/anthracycline-naive patients, pegylated liposomal doxorubicin, CAPE, or Eribulin.
RESULTS
In each cohort, accumulated quality-adjusted life-years were similar between regimens, but total societal costs varied considerably. Sequences beginning first-line treatment with paclitaxel, carboplatin, and CAPE, respectively, for cohorts 1, 2, and 3, had lower costs and similar or slightly better outcomes compared with alternative options.
CONCLUSION
In this setting where multiple single-agent chemotherapy options are recommended by clinical guidelines and share similar survival and adverse event trajectories, treatment sequencing approaches that minimize costs early may improve the value of care.
Topics: Humans; Female; Cost-Benefit Analysis; Carboplatin; Quality of Life; Breast Neoplasms; Paclitaxel; Taxoids; Doxorubicin; Capecitabine; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36054865
DOI: 10.1200/JCO.21.02473 -
Theranostics 2020The development of improved or targeted drugs that discriminate between normal and tumor tissues is the key therapeutic issue in cancer research. However, the...
The development of improved or targeted drugs that discriminate between normal and tumor tissues is the key therapeutic issue in cancer research. However, the development of an analytical method with a high accuracy and sensitivity to achieve quantitative assessment of the tumor targeting of anticancer drugs and even intratumor heterogeneous distribution of these drugs at the early stages of drug research and development is a major challenge. Mass spectrometry imaging is a label-free molecular imaging technique that provides spatial-temporal information on the distribution of drugs and metabolites in organisms, and its application in the field of pharmaceutical development is rapidly increasing. : The study presented here accurately quantified the distribution of paclitaxel (PTX) and its prodrug (PTX-R) in whole-body animal sections based on the virtual calibration quantitative mass spectrometry imaging (VC-QMSI) method, which is label-free and does not require internal standards, and then applied this technique to evaluate the tumor targeting efficiency in three treatment groups-the PTX-injection treatment group, PTX-liposome treatment group and PTX-R treatment group-in nude mice bearing subcutaneous A549 xenograft tumors. : These results indicated that PTX was widely distributed in multiple organs throughout the dosed body in the PTX-injection group and the PTX-liposome group. Notably, in the PTX-R group, both the prodrug and metabolized PTX were mainly distributed in the tumor tissue, and this group showed a significant difference compared with the PTX-liposome group, the relative targeting efficiency of PTX-R group was increased approximately 50-fold, leading to substantially decreased systemic toxicities. In addition, PTX-R showed a significant and specific accumulation in the poorly differentiated intratumor area and necrotic area. : This method was demonstrated to be a reliable, feasible and easy-to-implement strategy to quantitatively map the absorption, distribution, metabolism and excretion (ADME) of a drug in the whole-body and tissue microregions and could therefore evaluate the tumor-targeting efficiency of anticancer drugs to predict drug efficacy and safety and provide key insights into drug disposition and mechanisms of action and resistance. Thus, this strategy could significantly facilitate the design and optimization of drugs at the early stage of drug research and development.
Topics: A549 Cells; Animals; Antineoplastic Agents; Drug Evaluation, Preclinical; Humans; Male; Mass Spectrometry; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Paclitaxel; Prodrugs
PubMed: 32194824
DOI: 10.7150/thno.41763 -
Journal of B.U.ON. : Official Journal... 2019To investigate the expression of miR-335 in triple-negative breast cancer (TNBC) and its effect on chemosensitivity.
PURPOSE
To investigate the expression of miR-335 in triple-negative breast cancer (TNBC) and its effect on chemosensitivity.
METHODS
The expression of miR-335 in cancer tissues and adjacent tissues of 42 patients with TNBC who underwent mastectomy in our hospital was detected by qRT-PCR. Liposome was used to transfect miR-335 mimics (miR-335-mimic) and empty vectors (miR-NC) into cells of TNBC cell line MDA-MB-231, and untransfected cells were used as blank control cells (NC). Three groups of cells were cultured in culture Levbeit's medium supplemented with 2 μmol/L paclitaxel, 5 μmol/L cisplatin and 4 μmol/L doxorubicin. Proliferation rate and apoptosis rate of tumor cells were measured by MTT assay and TUNEL assay 48 h after transfection.
RESULTS
The relative expression level of miR-335 in cancer tissues was significantly lower than that in adjacent tissues of TNBC patients (p<0.05). After paclitaxel, cisplatin and doxorubicin treatment, the proliferation and apoptosis rates of the three groups were statistically different (p<0.05). There was no significant difference in cell proliferation rate and apoptosis rate between NC group and miR-NC group (p>0.05), but the proliferation rate of cells was higher and apoptosis rate was lower in the NC group and miR-NC group than that in miR-335-mimic group (p<0.05).
CONCLUSION
The expression level of miR-335 in cancer tissues of TNBC patients is lower than that in adjacent tissues. Overexpression of miR-335 can increase the sensitivity of tumor cells to paclitaxel, cisplatin and doxorubicin, and improve the effect of chemotherapy.
Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Cisplatin; Doxorubicin; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Mastectomy; MicroRNAs; Middle Aged; Paclitaxel; Triple Negative Breast Neoplasms
PubMed: 31646803
DOI: No ID Found -
Cancers Jul 2021Triple-negative breast cancers (TNBCs) are highly aggressive and recurrent. Standard cytotoxic chemotherapies are currently the main treatment options, but their...
Triple-negative breast cancers (TNBCs) are highly aggressive and recurrent. Standard cytotoxic chemotherapies are currently the main treatment options, but their clinical efficacies are limited and patients usually suffer from severe side effects. The goal of this study was to develop and evaluate targeted liposomes-delivered combined chemotherapies to treat TNBCs. Specifically, the IC values of the microtubule polymerization inhibitor mertansine (DM1), mitotic spindle assembly defecting taxane (paclitaxel, PTX), DNA synthesis inhibitor gemcitabine (GC), and DNA damage inducer doxorubicin (AC) were tested in both TNBC MDA-MB-231 and MDA-MB-468 cells. Then we constructed the anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) tagged liposomes and confirmed its TNBC cell surface binding using flow cytometry, internalization with confocal laser scanning microscopy, and TNBC xenograft targeting in NSG female mice using In Vivo Imaging System. The safe dosage of anti-EGFR liposomal chemotherapies, i.e., <20% body weight change, was identified. Finally, the in vivo anti-tumor efficacy studies in TNBC cell line-derived xenograft and patient-derived xenograft models revealed that the targeted delivery of chemotherapies (mertansine and gemcitabine) can effectively inhibit tumor growth. This study demonstrated that the targeted liposomes enable the new formulations of combined therapies that improve anti-TNBC efficacy.
PubMed: 34359650
DOI: 10.3390/cancers13153749