“…Starting with the approval of Doxil ® , several attempts have been made to optimize the active loading of DOX into liposomes [33][34][35], but, when co-encapsulating two active substances, the quality profile of the formulation can be significantly influenced by several variables. To our knowledge, there is only one study that investigated and optimized the passive loading of a statin along with the active loading of DOX into liposomes [36]. The major disadvantage of this study was that the research group focused on optimizing only the encapsulation efficiency of the active substances, without considering the other quality attributes of liposomes, i.e., size, polydispersity index, and drug to drug ratio, which are also critical for an enhanced anticancer effect [36]; therefore, through this study, we aimed to achieve a more in-depth evaluation of the quality profile.…”
An increasing number of studies published so far have evidenced the benefits of Simvastatin (SIM) and Doxorubicin (DOX) co-treatment in colorectal cancer. In view of this, the current study aimed to investigate the pharmaceutical development of liposomes co-encapsulating SIM and DOX, by implementing the Quality by Design (QbD) concept, as a means to enhance the antiproliferative effect of the co-formulation on C26 murine colon cancer cells co-cultured with macrophages. It is known that the quality profile of liposomes is dependent on the critical quality attributes (CQAs) of liposomes (drug entrapped concentration, encapsulation efficiency, size, zeta potential, and drug release profile), which are, in turn, directly influenced by various formulation factors and processing parameters. By using the design of experiments, it was possible to outline the increased variability of CQAs in relation to formulation factors and identify by means of statistical analysis the material attributes that are critical (phospholipids, DOX and SIM concentration) for the quality of the co-formulation. The in vitro studies performed on a murine colon cancer cell line highlighted the importance of delivering the optimal drug ratio at the target site, since the balance antiproliferative vs. pro-proliferative effects can easily be shifted when the molar ratio between DOX and SIM changes.
“…Starting with the approval of Doxil ® , several attempts have been made to optimize the active loading of DOX into liposomes [33][34][35], but, when co-encapsulating two active substances, the quality profile of the formulation can be significantly influenced by several variables. To our knowledge, there is only one study that investigated and optimized the passive loading of a statin along with the active loading of DOX into liposomes [36]. The major disadvantage of this study was that the research group focused on optimizing only the encapsulation efficiency of the active substances, without considering the other quality attributes of liposomes, i.e., size, polydispersity index, and drug to drug ratio, which are also critical for an enhanced anticancer effect [36]; therefore, through this study, we aimed to achieve a more in-depth evaluation of the quality profile.…”
An increasing number of studies published so far have evidenced the benefits of Simvastatin (SIM) and Doxorubicin (DOX) co-treatment in colorectal cancer. In view of this, the current study aimed to investigate the pharmaceutical development of liposomes co-encapsulating SIM and DOX, by implementing the Quality by Design (QbD) concept, as a means to enhance the antiproliferative effect of the co-formulation on C26 murine colon cancer cells co-cultured with macrophages. It is known that the quality profile of liposomes is dependent on the critical quality attributes (CQAs) of liposomes (drug entrapped concentration, encapsulation efficiency, size, zeta potential, and drug release profile), which are, in turn, directly influenced by various formulation factors and processing parameters. By using the design of experiments, it was possible to outline the increased variability of CQAs in relation to formulation factors and identify by means of statistical analysis the material attributes that are critical (phospholipids, DOX and SIM concentration) for the quality of the co-formulation. The in vitro studies performed on a murine colon cancer cell line highlighted the importance of delivering the optimal drug ratio at the target site, since the balance antiproliferative vs. pro-proliferative effects can easily be shifted when the molar ratio between DOX and SIM changes.
“…10–30% and 13–18%, respectively, depending on the solution pH and the composition of the nanocarrier. This initial leakage from the particles is rather lower than that observed from different polymeric nanoparticles and micelles [62–64], nanogels [65] or solid lipid nanoparticles [66], and similar to that of many other anticancer drug-liposome [67, 68] and polymeric micelles and particles-based [14, 69, 70] formulations. However, it is worth recognising that nowadays some few different nanocarriers have designed that completely block the uncontrolled premature leakage of the cargo and allowing its complete release in the targeted site on-demand under controlled internal or external stimuli [24, 35, 71, 72].…”
Section: Resultsmentioning
confidence: 61%
“…65–70%). This larger toxic effect has been attributed to the targeting delivery of the nanocarrier to the cancerous cells and the synergistic effect provided by the released of the co-encapsulated drugs, as observed for some other formulations simultaneously encapsulating several chemodrugs as liposomes [68, 74], polymeric micelles and nanoparticles [8, 9, 14, 16], nanogels and hydrogels [75, 76], inorganic nanoparticles [18, 19], etc.Fig. 7Cellular viability of drug-loaded GNRs@HSA/CS hybrid NPs (closed symbols), and free drugs (open symbols) expressed as survival rates for free DTX (filled black square, open black square) and free DTX + DOXO (filled red circle, open red circle), respectively, in breast MDA-MB-231 cancerous cells for a 24 h and b 48 h of incubation as a function of DTX concentration.…”
Background
Improving the water solubility of hydrophobic drugs, increasing their accumulation in tumor tissue and allowing their simultaneous action by different pathways are essential issues for a successful chemotherapeutic activity in cancer treatment. Considering potential clinical application in the future, it will be promising to achieve such purposes by developing new biocompatible hybrid nanocarriers with multimodal therapeutic activity.
Results
We designed and characterised a hybrid nanocarrier based on human serum albumin/chitosan nanoparticles (HSA/chitosan NPs) able to encapsulate free docetaxel (DTX) and doxorubicin-modified gold nanorods (DOXO-GNRs) to simultaneously exploit the complementary chemotherapeutic activities of both antineoplasic compounds together with the plasmonic optical properties of the embedded GNRs for plasmonic-based photothermal therapy (PPTT). DOXO was assembled onto GNR surfaces following a layer-by-layer (LbL) coating strategy, which allowed to partially control its release quasi-independently release regarding DTX under the use of near infrared (NIR)-light laser stimulation of GNRs. In vitro cytotoxicity experiments using triple negative breast MDA-MB-231 cancer cells showed that the developed dual drug encapsulation approach produces a strong synergistic toxic effect to tumoral cells compared to the administration of the combined free drugs; additionally, PPTT enhances the cytostatic efficacy allowing cell toxicities close to 90% after a single low irradiation dose and keeping apoptosis as the main cell death mechanism.
Conclusions
This work demonstrates that by means of a rational design, a single hybrid nanoconstruct can simultaneously supply complementary therapeutic strategies to treat tumors and, in particular, metastatic breast cancers with good results making use of its stimuli-responsiveness as well as its inherent physico-chemical properties.
“…So far, two studies have evaluated the benefits of DOX and statins co-encapsulation in liposomes. In both cases, an inhibition of tumor growth due to synergistic effects between the two drugs was observed [15,16]. Regarding the characterization of liposomes, particularly entrapped drug concentration and drug release profile, it is worth mentioning that none of the studies managed to develop an analytical method for the simultaneous quantification of both drugs.…”
Section: Introductionmentioning
confidence: 99%
“…Regarding the characterization of liposomes, particularly entrapped drug concentration and drug release profile, it is worth mentioning that none of the studies managed to develop an analytical method for the simultaneous quantification of both drugs. In case of DOX, a spectrophotometric or fluorescent method was used, while for SMV or lovastatin, HPLC was the selected analytic strategy [15,16]. Additionally, neither of the studies provided a determination of the drug release profile on the co-formulation, excluding a possible influence of active substances on drug release processes, since there is a difference in their physicochemical properties.…”
The aim of this study was to develop a disposable, simple, fast, and sensitive sensor for the simultaneous electrochemical detection of doxorubicin (DOX) and simvastatin (SMV), which could be used in preclinical studies for the development of new pharmaceutical formulations for drug delivery. Firstly, the electrochemical behavior of each molecule was analyzed regarding the influence of electrode material, electrolyte solution, and scan rate. After this, the proper electrode material, electrolyte solution, and scan rate for both active substances were chosen, and a linear sweep voltammetry procedure was optimized for simultaneous detection. Two chronoamperometry procedures were tested, one for the detection of DOX in the presence of SMV, and the other one for the detection of DOX and SMV together. Finally, calibration curves for DOX and SMV in the presence of each other were obtained using both electrochemical methods and the results were compared. The use of amperometry allowed for a better limit of detection (DOX: 0.1 μg/mL; SMV: 0.7 μg/mL) than the one obtained in voltammetry (1.5 μg/mL for both drugs). The limits of quantification using amperometry were 0.5 μg/mL for DOX (dynamic range: 0.5–65 μg/mL) and 2 μg/mL for SMV (dynamic range: 2–65 μg/mL), while using voltammetry 1 μg/mL was obtained for DOX (dynamic range: 1–100 μg/mL) and 5 μg/mL for SMV (dynamic range: 5–100 μg/mL). This detection strategy represents a promising tool for the analysis of new pharmaceutical formulations for targeted drug delivery containing both drugs, whose association was proven to bring benefits in the treatment of cancer.
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