Nanoparticles For Delivery Of Doxorubicin Research Articles

Pluronic-Based Nanoparticles for Delivery of Doxorubicin to the Tumor Microenvironment by Binding to Macrophages.

The active targeting drug delivery system based on special types of endogenous cells such as macrophages has emerged as a promising strategy for tumor therapy, owing to its tumor homing property and biocompatibility. In this work, the active tumor-targeting drug delivery system carrying doxorubicin-loaded nanoparticles (DOX@MPF127-MCP-1, DMPM) on macrophage (RAW264.7) surfaces via the mediation of interaction with the CCR2/MCP-1 axis was exploited. Initially, the amphiphilic block copolymer Pluronic F127 (PF127) was carboxylated to MPF127 at the hydroxyl terminus. Subsequently, MPF127 was modified with MCP-1 peptide to prepare MPF127-MCP-1 (MPM). The DOX was wrapped in MPM to form DMPM nanomicelles (approximately 100 nm) during the self-assembly process of MPM. The DMPM spontaneously bound to macrophages (RAW264.7), which resulted in the construction of an actively targeting delivery system (macrophage-DMPM, MA-DMPM) in vitro and in vivo. The DOX in MA-DMPM was released in the acidic tumor microenvironment (TME) in a pH-responsive manner to increase DOX accumulation and enhance the tumor treatment effect. The ratio of MA-DMPM homing reached 220% in vitro compared with the control group, indicating that the MA-DMPM was excellently capable of tumor-targeting delivery. In in vivo experiments, nonsmall cell lung cancer cell (NCI-H1299) tumor models were established. The results of the fluorescence imaging system (IVIS) showed that MA-DMPM demonstrated tremendous tumor-targeting ability in vivo. The antitumor effects of MA-DMPM in vivo indicated that the proportion of tumor cell apoptosis in the DMPM-treated group was 63.33%. The findings of the tumor-bearing mouse experiment proved that MA-DMPM significantly suppressed tumor cell growth, which confirmed its immense potential and promising applications in tumor therapy.

Targeted Hyperbranched Nanoparticles for Delivery of Doxorubicin in Breast Cancer Brain Metastasis.

Breast cancer brain metastases (BM) are associated with a dismal prognosis and very limited treatment options. Standard chemotherapy is challenging in BM patients because the high dosage required for an effective outcome causes unacceptable systemic toxicities, a consequence of poor brain penetration, and a short physiological half-life. Nanomedicines have the potential to circumvent off-target toxicities and factors limiting the efficacy of conventional chemotherapy. The HER3 receptor is commonly expressed in breast cancer BM. Here, we investigate the use of hyperbranched polymers (HBP) functionalized with a HER3 bispecific-antibody fragment for cancer cell-specific targeting and pH-responsive release of doxorubicin (DOX) to selectively deliver and treat BM. We demonstrated that DOX-release from the HBP carrier was controlled, gradual, and greater in endosomal acidic conditions (pH 5.5) relative to physiologic pH (pH 7.4). We showed that the HER3-targeted HBP with DOX payload was HER3-specific and induced cytotoxicity in BT474 breast cancer cells (IC50: 17.6 μg/mL). Therapeutic testing in a BM mouse model showed that HER3-targeted HBP with DOX payload impacted tumor proliferation, reduced tumor size, and prolonged overall survival. HER3-targeted HBP level detected in ex vivo brain samples was 14-fold more than untargeted-HBP. The HBP treatments were well tolerated, with less cardiac and oocyte toxicity compared to free DOX. Taken together, our HER3-targeted HBP nanomedicine has the potential to deliver chemotherapy to BM while reducing chemotherapy-associated toxicities.

A pH-responsive chiral mesoporous silica nanoparticles for delivery of doxorubicin in tumor-targeted therapy

The purpose of this study was to develop a nano-drug delivery system with intelligent stimuli-responsive drug delivery in tumor microenvironment (TME). Based on chiral mesoporous silica nanoparticles (CMSN) with a chiral recognition function in our previous research, a pH-responsive CMSN (CS-CMSN) was successfully prepared by chemical modification of chitosan (CS), and the related physicochemical properties, drug release performance, potential anti-tumor effect, and biological safety were studied. The results showed that the CS-CMSN were successfully modified by CS. Moreover, CS-CMSN displayed superior encapsulation ability for doxorubicin (DOX) and exhibited controllable pH-responsive drug release properties. In particular, in a physiological environment (pH 7.4/6.5), CS shielded the nanopores, prevented DOX release, and minimized side effects on normal cells. Once the CS-CMSN was exposed to the TME (pH 5.0), the pH-sensitive moiety of CS was cleaved in an acidic environment, along with the rapid release of DOX. In vitro cell experiments further proved that DOX@CS-CMSN was more strongly taken up by 4T1 cells and could enhance the toxicity to 4T1 tumor cells as well as promote cell apoptosis. More importantly, CS-CMSN were shown to have good biosafety in vitro and in vivo. Overall, the delivery of DOX by CS-CMSN nanocarriers is a promising strategy for tumor-targeted therapy.

Anti-CD44 and EGFR Dual-Targeted Solid Lipid Nanoparticles for Delivery of Doxorubicin to Triple-Negative Breast Cancer Cell Line: Preparation, Statistical Optimization, and In Vitro Characterization.

Background Despite being more aggressive than other types of breast cancer, there is no suitable treatment for triple-negative breast cancer (TNBC). Here, we designed doxorubicin-containing solid lipid nanoparticles (SLNs) decorated with anti-EGFR/CD44 dual-RNA aptamers, which are overexpressed in TNBC. For more efficiency in the nuclear delivery of doxorubicin, dexamethasone (Dexa) was chemically attached to the surface of nanoparticles. Methods To prepare the cationic SLNs, 6-lauroxyhexyl BOC-ornithine (LHON) was synthesized and was chemically attached to dexamethasone to form Dexa-LHON complexes. The doxorubicin-containing SLNs were prepared via double emulsification (w/o/w) and the solvent evaporation technique. The preparation of SLNs was statistically optimized using the central composite response surface methodology. Independent factors were the GMS/lecithin concentration ratio and the amount of Tween 80, while responses considered were particle size, polydispersity index, and entrapment efficiency of the nanoparticles. The optimized nanoparticles were studied morphologically using transmission electron microscopy, and in vitro release of doxorubicin from nanoparticles was studied in phosphate-buffered saline. Then, the designated aptamers were attached to the surface of nanoparticles using electrostatic interactions, and their cytotoxicity was assessed in vitro. Results The size, PDI, zeta potential, EE%, and LE% of the prepared nanoparticles were 101 ± 12.6 nm, 0.341 ± 0.005, +13.6 ± 1.83 mV, 69.98 ± 7.54%, and 10.2 ± 1.06%, respectively. TEM images revealed spherical nanoparticles with no sign of aggregation. In vitro release study exhibited that 96.1 ± 1.97% of doxorubicin was released within 48 h of incubation. The electrostatic attachment of the designated aptamers to the nanoparticles' surface was confirmed by reducing the zeta potential to −15.6 ± 2.07 mV. The in vitro experiments revealed that the SLNs/DOX/Dexa/CD44 or EGFR aptamers were substantially more successful than SLNs/DOX/Dexa at inhibiting cell proliferation. Using the MDA-MB-468 cell line, we discovered that SLN/DOX/Dexa/CD44/EGFR aptamers were more effective than other constructs in inhibiting cell proliferation (p < 0.001). The reduction of cell viability using this construct suggests that targeting numerous proliferation pathways is effective. Conclusion Overall, the finding of this investigation suggested that SLNs/DOX/Dexa/CD44/EGFR could be a promising new enhanced anticancer delivery system and deserved further preclinical consideration.

Targeted biomimetic hollow mesoporous organosilica nanoparticles for delivery of doxorubicin to colon adenocarcinoma: In vitro and in vivo evaluation

Hollow mesoporous organosilica nanoparticles (HMOSNPs) have provided unique opportunities to improve therapeutic efficacy of the encapsulated drugs due to versatile hybrid frameworks and tunable pore sizes, biodegradable nature and intelligent performance. In the current study, we have designed HMOSNPs capped with red blood cell (RBC) membrane to provide biomimetic RBC-coated HMOS platform with controlled glutathione (GSH)-responsive doxorubicin (DOX)-releasing performance. DNA aptamer against MUC-1 receptor was used to prepare the targeted system (Apt-RBC-HMOS@DOX) for the guided delivery of DOX to colorectal tumor cells. Experimental data indicated that MUC1 aptamer could particularly facilitate drug uptake the designed biomimetic nanoparticles into HT29 and C26 cells. Moreover, targeted Apt-RBC-HMOS@DOX system remarkably enhanced tumor targeting capability in C26 tumor bearing mice compared to non-targeted RBC-HMOS@DOX and free drug. GSH-responsive Apt-RBC-HMOS@DOX system also reduced DOX-induced toxicity in terms of tumor growth suppression and survival rate, proposing its potential to translate in cancer therapy. • The efficacy of GSH-responsive Apt-RBC-HMOS@DOX system was studied for first time. • RBC membrane was used to provide desirable biomimetic intelligent platform. • MUC1 aptamer was administered to provide guided selective DOX delivery. • Cell internalization of targeted organosilica was higher than non-targeted one. • Targeted GSH-responsive HMOS displayed the effective tumor growth suppression.

Development of red-light cleavable PEG-PLA nanoparticles as delivery systems for cancer therapy

The development of targeted delivery systems can improve the selectivity of cancer drugs. Additionally, a system that promotes the controlled delivery of the drug triggered by an external stimulus in the exact target tissue is highly desirable. Regarding the light stimulus, the NIR window (650–950 nm) is the most suitable due to its higher capacity of penetration in human tissues and less harmful effects on normal cells. In this work, new red-light-responsive nanoparticles for doxorubicin delivery were developed. The nanoparticles were based on cleavable di-block copolymers of poly(ethylene glycol) (PEG) and poly(lactic acid) (PLA) linked by a red-light sensitive segment (1,2-bis(2-hydroxyethylthio)ethylene, BHETE). The PEG-BHETE-PLA copolymers were synthesized under mild conditions and exhibited a narrow polydispersity. The nanoparticles presented a size between 53 and 133 nm, with a doxorubicin loading capacity between 1.2 and 4.4 wt%. Release study of the encapsulated doxorubicin confirms the light-triggered nanoparticle disassembly process. In vitro cytotoxicity tests in MCF7 cell line, for the light-triggered nanoparticles, showed a decrease in cancer cells’ viability higher than 25% compared to non-irradiated cells. Due to the promising results obtained with the light-sensitive PEG-BHETE-PLA nanoparticles, these materials have great potential to be used in drug delivery systems for cancer therapy.

Liver-Targeted Combination Therapy Basing on Glycyrrhizic Acid-Modified DSPE-PEG-PEI Nanoparticles for Co-delivery of Doxorubicin and Bcl-2 siRNA.

Combination therapy based on nano-sized drug delivery system has been developed as a promising strategy by combining two or more anti-tumor mechanisms. Here, we prepared liver-targeted nanoparticles (GH-DPP) composed of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol-polyetherimide (DSPE-PEG-PEI) with Glycyrrhetinic acid-modified hyaluronic acid (GA-HA) for co-delivery of doxorubicin (DOX) and Bcl-2 siRNA. Particles size, zeta potential and morphology were determined for the drug-loaded GH-DPP nanoparticles (siRNA/DOX/GH-DPP). Cellular uptake and in vitro cytotoxicity were analyzed against HepG2 cells. In vivo bio-distribution and anti-tumor therapeutic effects of siRNA/DOX/GH-DPP were evaluated in H22-bearing mice. The results showed that siRNA/DOX/GH-DPP nanoparticles were nearly spherical and showed dose-dependent cytotoxicity against HepG2 cells. Compared to Glycyrrhetinic acid-free co-delivery system (siRNA/DOX/DPP) and GH-DPP nanoparticles for delivery of DOX or Bcl-2 siRNA alone, siRNA/DOX/GH-DPP nanoparticles could induce more cellular apoptosis, and showed higher anti-tumor effect. Herein GH-DPP nanoparticles could simultaneously deliver both chemotherapy drugs and siRNA into the tumor region, exhibiting great potential in anti-tumor therapy.

Preparation and characterization of β-casein stabilized lipopeptide lyotropic liquid crystal nanoparticles for delivery of doxorubicin.

A kind of lyotropic liquid crystal nanoparticle (LLC NPs) has been designed and prepared. LLC NPs are dSMO/OA/β-casein/water quaternary systems, and their cubic or hexagonal microstructures have been characterized by cryogenic transmission electron microscopy (cryo-TEM) and small angle X-ray scattering (SAXS). The phase transition of LLC NPs takes place with ratio and pH adjustments. The properties, such as cytotoxicity, stability, drug encapsulation and release ability, have been investigated with MTT assay, cryo-TEM and UV-Vis spectroscopy. The results showed that LLC NPs were nontoxic to cells and stable to enzymatic degradation. Hydrophilic drug doxorubicin hydrochloride (DOX·HCl) could be effectively encapsulated in LLC NPs and its release rate could be regulated by pH. It was concluded that LLC NPs are potential nanocarriers in nanomedicine technologies. We hope that this work provides new guidelines for the rational design of LLC NP systems with lipopeptides for biomedical applications.

Hydroxylethyl starch-g-polylactide nanoparticles for delivery of doxorubicin via a RES blockade strategy

Hydroxylethyl starch-g-polylactide nanoparticles for delivery of doxorubicin via a RES blockade strategy

Engineering of pectin-capped gold nanoparticles for delivery of doxorubicin to hepatocarcinoma cells: an insight into mechanism of cellular uptake

In this study, we have reported the fabrication and evaluation of pectin-capped gold nanoparticles (PEC-AuNPs) for delivery of anticancer drug, doxorubicin (DOX) to cells overexpressing asialoglycoprotein receptor (ASGPR). Pectin was used as a reducing, stabilizing and targeting agent. The pectin-capped gold nanoparticles demonstrated surface plasmon resonance band at 519 nm. The PEC-AuNPs were spherical in shape with a particle size of 14 nm and zeta potential value of −33 mV and were biocompatible and non-cytotoxic. The PEC-AuNPs exhibited a high drug loading efficiency of 78%. The DOX-loaded gold nanoparticles (DOX-PEC-AuNPs) showed excellent stability under varying pH and electrolytic conditions. The cytotoxicity study of the DOX-PEC-AuNPs in human Caucasian hepatocyte cells demonstrated their greater potency in killing these cells as compared to free DOX. The uptake and targeting potential of DOX-PEC-AuNPs was thoroughly investigated. Further, it was found that the PEC-AuNPs were taken up by HepG2 cells via a clathrin-dependent receptor-mediated endocytosis by asialoglycoprotein receptor present of the surface of these cells. Thus, the PEC-capped AuNPs can prove a promising carrier for anticancer drug in the treatment of hepatocellular carcinoma.

Synthesis of polydopamine as a new and biocompatible coating of magnetic nanoparticles for delivery of doxorubicin in mouse breast adenocarcinoma.

Carrier-mediated drug delivery systems can be used to increase the intracellular concentration of drugs in cancerous cells, thereby improving drug biodistribution and minimizing unwanted side effects. This study aimed to investigate the effect of synthesized magnetic molecularly imprinted polydopamine for controlled doxorubicin (DOX) delivery in a breast adenocarcinoma model of BALB/c mice with an external magnetic field. The synthesized DOX-imprinted polydopamine (DOX-IP) was characterized using Fourier transform infrared spectroscopy and scanning electron microscopy. The efficacy of DOX-IP in tumor growth suppression was assessed in terms of tumor growth delay, tumor doubling time, inhibition ratio, and histopathology. High-performance liquid chromatography and flame atomic absorption spectrometry were performed to investigate the drug distribution among tissues. The findings showed higher efficacy of DOX-IP with magnetic field in suppressing tumor growth than free DOX and DOX-IP without magnetic field. Significantly high DOX concentration in tumor tissue was found in the DOX-IP group with magnetic field. Magnetic DOX-IP demonstrates effective tumor-targeted drug delivery in a mouse model of breast cancer.

Luteinizing hormone-releasing hormone targeted poly(methyl vinyl ether maleic acid) nanoparticles for doxorubicin delivery to MCF-7 breast cancer cells.

The purpose of this study was to design a targeted anti-cancer drug delivery system for breast cancer. Therefore, doxorubicin (DOX) loaded poly(methyl vinyl ether maleic acid) nanoparticles (NPs) were prepared by ionic cross-linking method using Zn(2+) ions. To optimise the effect of DOX/polymer ratio, Zn/polymer ratio, and stirrer rate a full factorial design was used and their effects on particle size, zeta potential, loading efficiency (LE, %), and release efficiency in 72 h (RE72, %) were studied. Targeted NPs were prepared by chemical coating of tiptorelin/polyallylamin conjugate on the surface of NPs by using 1-ethyl-3-(3-dimethylaminopropyl) carboiimid HCl as cross-linking agent. Conjugation efficiency was measured by Bradford assay. Conjugated triptorelin and targeted NPs were studied by Fourier-transform infrared spectroscopy (FTIR). The cytotoxicity of DOX loaded in targeted NPs and non-targeted ones were studied on MCF-7 cells which overexpress luteinizing hormone-releasing hormone (LHRH) receptors and SKOV3 cells as negative LHRH receptors using Thiazolyl blue tetrazolium bromide assay. The best results obtained from NPs prepared by DOX/polymer ratio of 5%, Zn/polymer ratio of 50%, and stirrer rate of 960 rpm. FTIR spectrum confirmed successful conjugation of triptorelin to NPs. The conjugation efficiency was about 70%. The targeted NPs showed significantly less IC50 for MCF-7 cells compared to free DOX and non-targeted NPs.

Using doxorubicin and siRNA-loaded heptapeptide-conjugated nanoparticles to enhance chemosensitization in epidermal growth factor receptor high-expressed breast cancer cells

The aim of this study was to develop the heptapeptide-conjugated active targeting nanoparticles for delivery of doxorubicin and siRNA to epidermal growth factor receptor (EGFR) high-expressed breast cancer cells. The active targeting nanoparticles were prepared by using a synthesized poly(D,L-lactide-co-glycolide)-poly(ethylene glycol) (PLGA-PEG) copolymer conjugated with a heptapeptide. The particle size of peptide-conjugated nanoparticles was less than 200 nm with narrow size distribution and the surface charge was negative. The uptake of peptide-conjugated nanoparticles was more efficient in EGFR high-expressed MDA-MB-468 cells than in EGFR low-expressed HepG2 cells by 3.9 folds due to peptide specific binding to EGF receptor followed by EGF receptor-mediated endocytosis. The nanoparticles were used to deliver doxorubicin and siRNA, and their in vitro release was faster in pH 4.0 (500 U lipase) than in pH 7.4. The IC50 of doxorubicin-loaded peptide-conjugated nanoparticles was lower than that of peptide-free nanoparticles by 2.3 folds in MDA-MB-468 cells. Similarly, the cellular growth inhibition of siRNA/DOTAP-loaded peptide-conjugated nanoparticles was 2.1 folds higher than that of peptide-free nanoparticles. In conclusion, the heptapeptide-conjugated PLGA-PEG nanoparticles provided active targeting potential to EGFR high-expressed MDA-MB-468 breast cancer cells, and a synergistic cytotoxicity effect was achieved by co-delivery of doxorubicin and siRNA/DOTAP-loaded peptide-conjugated nanoparticles.

Preparation and evaluation of SiO2-deposited stearic acid-g-chitosan nanoparticles for doxorubicin delivery

Purpose:Both polymer micelles and mesoporous silica nanoparticles have been widely researched as vectors for small molecular insoluble drugs. To combine the advantages of copolymers and silica, studies on the preparation of copolymer-silica composites and cellular evaluation were carried out.Methods:First, a stearic acid-g-chitosan (CS-SA) copolymer was synthesized through a coupling reaction, and then silicone oxide (SiO2)-deposited doxorubicin (DOX)-loaded stearic acid-g-chitosan (CS-SA/SiO2/DOX) nanoparticles were prepared through the sol-gel reaction. Physical and chemical properties such as particle size, zeta potential, and morphologies were examined, and small-angle X-ray scattering (SAXS) analysis was employed to identify the mesoporous structures of the generated nanoparticles. Cellular uptake and cytotoxicity studies were also conducted.Results:CS-SA/SiO2/DOX nanoparticles with different amounts of SiO2 deposited were obtained, and SAXS studies showed that mesoporous structures existed in the CS-SA/SiO2/DOX nanoparticles. The mesoporous size of middle-ratio and high-ratio deposited CS-SA/SiO2/DOX nanoparticles were 4–5 nm and 8–10 nm, respectively. Based on transmission electron microscopy images of CS-SA/SiO2/DOX nanoparticles, dark rings around the nanoparticles could be observed in contrast with CS-SA/DOX micelles. Furthermore, CS-SA/SiO2/DOX nanoparticles exhibited faster release behavior in vitro than CS-SA/DOX micelles; cellular uptake research in A549 indicated that the CS-SA/SiO2/DOX nanoparticles were taken up by A549 cells more rapidly, and that CS-SA/SiO2/DOX nanoparticles entered the cell more easily when the amount of SiO2 was higher. IC50 values of CS-SA/DOX micelles, CS-SA/SiO2/DOX-4, CS-SA/SiO2/DOX-8, and CS-SA/SiO2/DOX-16 nanoparticles against A549 cells measured using the MTT assay were 1.69, 0.93, 0.32, and 0.12 μg/mL, respectively.Conclusion:SiO2-deposited stearic acid-g-chitosan organic–inorganic composites show promise as nanocarriers for hydrophobic drugs such as DOX.

Preparation and characterization of HA–PEG–PCL intelligent core–corona nanoparticles for delivery of doxorubicin

The objective of the present study was to synthesize core–corona nanoparticles of doxorubicin (DOX) using hyaluronic acid–polyethyleneglycol–polycaprolactone (HA–PEG–PCL) copolymer for tumor targeting. Targeting efficiency of HA–PEG–PCL nanoparticles was compared with non-HA-containing nanoparticles (methoxy poly ethylene glycol (MPEG)–PCL). The copolymers were chemically synthesized and characterized by IR and NMR spectroscopies. The nanoparticles were characterized for shape and morphology by transmission electron microscopy, particle size, percentage of drug entrapment, and in vitro drug release profile. Differential scanning calorimetry and X-ray diffraction studies were also performed to appraise the crystalline or amorphous nature of DOX inside the polymer matrix. Formulations were prepared using different DOX:polymer ratios (1:1–1:3 w/w) and the optimum formulation with the drug:polymer ratio of 1:1 showed the mean particle size of 95 ± 5 nm and entrapment efficiency of 95.56% in the case of HA–PEG–PCL nanoparticles, while the values were 115 nm and 95.50%, respectively, in the case of MPEG–PCL nanoparticles. The HA–PEG–PCL nanoparticles could release DOX for up to 17 days, whereas the MPEG–PCL nanoparticles could release it for up to 14 days. The hemolytic toxicity and hematological studies confirmed that both DOX-loaded HA–PEG–PCL and MPEG–PCL nanoparticles were safe and suitable for sustained and targeted drug delivery. The tissue distribution study and tumor growth inhibition were performed after intravenous injection of nanoparticles in Ehrlich ascites tumor (EAT)-bearing mice. The nanoparticles of HA–PEG–PCL copolymer accomplishes efficient delivery of DOX in EAT tumor when compared with the MPEG–PCL nanoparticles by the process of receptor-mediated endocytosis, as well as enhanced permeability and retention effect.