Transferrin-Conjugated Polymeric Nanoparticle for Receptor-Mediated Delivery of Doxorubicin in Doxorubicin-Resistant Breast Cancer Cells (original) (raw)
Related papers
Biomaterials, 2010
The purpose of this study was to develop polymeric nano-carriers of doxorubicin (DOX) that can increase the therapeutic efficacy of DOX for sensitive and resistant cancers. Towards this goal, two polymeric DOX nano-conjugates were developed, for which the design was based on the use of multi-functionalized poly(ethylene oxide)-block-poly(3-caprolactone) (PEO-b-PCL) micelles decorated with avb3 integrintargeting ligand (i.e. RGD4C) on the micellar surface. In the first formulation, DOX was conjugated to the degradable PEO-b-PCL core using the pH-sensitive hydrazone bonds, namely RGD4C-PEO-b-P(CL-Hyd-DOX). In the second formulation, DOX was conjugated to the core using the more stable amide bonds, namely RGD4C-PEO-b-P(CL-Ami-DOX). The pH-triggered drug release, cellular uptake, intracellular distribution, and cytotoxicity against MDA-435/LCC6 WT (a DOX-sensitive cancer cell line) and MDA-435/ LCC6 MDR (a DOX-resistant clone expressing a high level of P-glycoprotein) were evaluated. Following earlier in vitro results, SCID mice bearing MDA-435/LCC6 WT and MDA-435/LCC6 MDR tumors were treated with RGD4C-PEO-b-P(CL-Hyd-DOX) and RGD4C-PEO-b-P(CL-Ami-DOX), respectively. In both formulations, surface decoration with RGD4C significantly increased the cellular uptake of DOX in MDA-435/ LCC6 WT and MDA-435/LCC6 MDR cells. In MDA-435/LCC6 WT , the best cytotoxic response was achieved using RGD4C-PEO-b-P(CL-Hyd-DOX), that correlated with the highest cellular uptake and preferential nuclear accumulation of DOX. In MDA-435/LCC6 MDR , RGD4C-PEO-b-P(CL-Ami-DOX) was the most cytotoxic, and this effect correlated with the accumulation of DOX in the mitochondria. Studies using a xenograft mouse model yielded results parallel to those of the in vitro studies. Our study showed that RGD4C-decorated PEO-b-P(CL-Hyd-DOX) and PEO-b-P(CL-Ami-DOX) can effectively improve the therapeutic efficacy of DOX in human MDA-435/LCC6 sensitive and resistant cancer, respectively, pointing to the potential of these polymeric micelles as the custom-designed drug carriers for clinical cancer therapy.
Pharmaceutical Research, 2006
Purpose. This work is intended to develop and evaluate a new polymerYlipid hybrid nanoparticle system that can efficiently load and release water-soluble anticancer drug doxorubicin hydrochloride (Dox) and enhance Dox toxicity against multidrug-resistant (MDR) cancer cells. Methods. Cationic Dox was complexed with a new soybean-oil-based anionic polymer and dispersed together with a lipid in water to form Dox-loaded solid lipid nanoparticles (DoxYSLNs). Drug loading and release properties were measured spectrophotometrically. The in vitro cytotoxicity of DoxYSLN and the excipients in an MDR human breast cancer cell line (MDA435/LCC6/MDR1) and its wild-type line were evaluated by trypan blue exclusion and clonogenic assays. Cellular uptake and retention of Dox were determined with a microplate fluorometer. Results. DoxYSLNs were prepared with a drug encapsulation efficiency of 60Y80% and a particle size range of 80Y350 nm. About 50% of the loaded drug was released in the first few hours and an additional 10Y20% in 2 weeks. Treatment of the MDR cells with DoxYSLN resulted in over 8-fold increase in cell kill when compared to Dox solution treatment at equivalent doses. The blank SLN and the excipients exhibited little cytotoxicity. The biological activity of the released Dox remained unchanged from fresh, free Dox. Cellular Dox uptake and retention by the MDR cells were both significantly enhanced (p < 0.05) when Dox was delivered in DoxYSLN form. Conclusions. The new polymerYlipid hybrid nanoparticle system is effective for delivery of Dox and enhances its efficacy against MDR breast cancer cells.
Journal of Nanoparticle Research, 2020
Doxorubicin (DOX) is an efficient chemotherapeutic agent widely used to treat different types of cancer; however, there is an inherent risk of adverse effects due to its unspecific action in healthy cells. In order to enhance the DOX arrival and accumulation inside the cancerous cells, we have developed DOXloaded nanoparticles (NPs) using the biocompatible polymer poly(lactic-co-glycolic acid) (PLGA). pH sensitivity was achieved by incorporation of the surfactant, 77KS, while poloxamer was explored as stabilizer and chemosensitizer. The protein transferrin (Tf) was conjugated to the NPs with the role to actively targeting them to the cancerous cells. The nanoprecipitation method yielded NPs with size about 100 nm, with polydispersity index around 0.20 and a negative zeta potential. Transmission electron microscopy and infrared spectroscopy confirmed the shape and the functional groups presence. DOX release from the NPs followed a control and pH-sensitive pattern, allowing accelerated DOX release in acidic conditions. Through the hemolysis assay, using the erythrocyte as a model for the endosomal membrane, it was evidenced the pHsensitive membranolytic behavior of the NPs. Furthermore, the NPs were safe and compatible with blood. Finally, the formulations were applied to tumor and nontumor cell lines, HeLa and HaCaT, respectively. Over 72 h of incubation, the Tf-conjugated NPs induced a notable reduction in HeLa cell growth and were able to protect the HaCaT cells from the DOX unspecific cytotoxicity. The results suggest that the dual-active targeting promoted by 77KS and Tf is a promising platform to overcome the side effects of conventional chemotherapeutic drugs and nontargeted nanosystems.
Bio-Responsive Carriers for Controlled Delivery of Doxorubicin to Cancer Cells
Pharmaceutics
The cellular internalization of drug carriers occurs via different endocytic pathways that ultimately involve the endosomes and the lysosomes, organelles where the pH value drops to 6.0 and 5.0, respectively. We aimed to design and characterize pH/temperature-responsive carriers for the effective delivery of the anti-tumoral drug doxorubicin. To this purpose, poly(N-isopropylacrylamide-co-vinylimidazole) was synthesized as an attractive pH/temperature-sensitive copolymer. Microspheres made of this copolymer, loaded with doxorubicin (MS-DXR), disintegrate in monodisperse nanospheres (NS-DXR) under conditions similar to that found in the bloodstream (pH = 7.4, temperature of 36 °C) releasing a small amount of payload. However, in environments that simulate the endosomal and lysosomal conditions, nanospheres solubilize, releasing the entire amount of drug. We followed the NS-DXR internalization using two cancer cell lines, hepatic carcinoma HepG2 cells and lung adenocarcinoma A549 cell...
Journal of Polymer Research, 2020
Novel Pentaerythritol (PTL)-and dipentaerythritol (DPTL)-cored dendrimer-like star polymers with AB 2 miktoarms [A = poly(L-Lactide); poly(ethylene glycol)-folate] (1g and 2g) were synthesized and characterized by proton magnetic resonance spectroscopy, fourier transform infrared, gel permeation chromatography and differential scanning calorimetric techniques. Anticancer drug doxorubicin was encapsulated into the star polymer nanoparticles using nanoprecipitation technique. The doxorubicin-loaded nanoparticles of the star polymer with PTL core (1g-NPs-DOX) and DPTL core (2g-NPs-DOX) were spherical and had average diameters of 185.88 ± 27.53 nm and 203.66 ± 20.69 nm, and zeta potential of −19.54 ± 0.57 mV and − 14.77 ± 1.16 mV, respectively. 2g-NPs-DOX had higher doxorubicin loading and encapsulation efficiency (14.59% ± 0.001; 87.54% ± 0.003) than those of 1g-NPs-DOX (12.88% ± 0.006; 77.29% ± 0.039). In vitro release studies showed that an initial burst release of doxorubicin was followed by a sustained release over 7 days, which were significantly higher at pH 5.3 than at pH 7.4. Both drug-free nanoparticles 1g-NPs and 2g-NPs exhibited low cytotoxic effect against MCF-7 and MCF-10a with over 80% cell viability at maximum concentration (100 μM) after 72 h of incubation. Due to sustained release, the IC 50 values (72 h) of 1g-NPs-DOX and 2g-NPs-DOX against MCF-7 cells were 22.5 μM and 19.5 μM respectively, as compared to 41.0 μM and 32.0 μM against MCF-10a cells, which suggested that 1g-NPs-DOX and 2g-NPs-DOX are more effective in inhibiting the breast cancer cell viability. Hence, the dendrimer-like star polymers, 1g and 2g, showed good potential as nanocarriers for preferential delivery of doxorubicin to the breast cancer cells.
International Journal of Nanomedicine, 2019
Background: Lipid polymer hybrid nanoparticles (LPHNPs) for the controlled delivery of hydrophilic doxorubicin hydrochloride (DOX.HCl) and lipophilic DOX base have been fabricated by the single step modified nanoprecipitation method. Materials and methods: Poly (D, L-lactide-co-glicolide) (PLGA), lecithin, and 1,2-distearoyl-Sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)-2000 (DSPE-PEG 2000) were selected as structural components. Results: The mean particle size was 173-208 nm, with an encapsulation efficiency of 17.8 ±1.9 to 43.8±4.4% and 40.3±0.6 to 59. 8±1.4% for DOX.HCl and DOX base, respectively. The drug release profile was in the range 33-57% in 24 hours and followed the Higuchi model (R 2 =0.9867-0.9450) and Fickian diffusion (n<0.5). However, the release of DOX base was slower than DOX.HCl. The in vitro cytotoxicity studies and confocal imaging showed safety, good biocompatibility, and a higher degree of particle internalization. The higher internalization of DOX base was attributed to higher permeability of lipophilic component and better hydrophobic interaction of particles with cell membranes. Compared to the free DOX, the DOX.HCl and DOX base loaded LPHNPs showed higher antiproliferation effects in MDA-MB231 and PC3 cells. Conclusion: Therefore, LPHNPs have provided a potential drug delivery strategy for safe, controlled delivery of both hydrophilic and lipophilic form of DOX in cancer cells.
Biopolymer based nanosystem for doxorubicin targeted delivery
American journal of cancer research, 2017
This study describes formation of an actively and passively targeted, water-soluble drug delivery system (DDS) which contains doxorubicin (DOX). The system comprises two biocompatible and biodegradable polymers: poly-γ-glutamic acid (PGA) and chitosan (CH). Self-assembly of these biopolymers in aqueous medium results stable nanoparticles (NPs) with a hydrodynamic size of 80-150 nm and slightly negative surface charge. Folic acid (FA) was used as targeting agent bonded to the polyanion (PA) and also to the surface of the NPs. The NP's physical stability, active targeting effect, cellular toxicity, release profile and in vivo anti-tumor efficacy were investigated. It was found that the targeted, self-assembled nanoparticles are stable at 4°C for several months, cause better in vitro toxicity effect on folate receptor (FR) positive cell lines than the doxorubicin or the non-targeted nanosystem and based on its release profile it is expected, that the nanosystem will remain stable d...
Pharmaceutical Research, 2008
Purposes. To develop multifunctional RGD-decorated poly(ethylene oxide)-b-poly(ester) based micelles and assess their pH-triggered core degradation and targeted drug release in tumor cells that overexpress RGD receptors. Methods. Novel poly(ethylene oxide)-b-poly(ε-caprolactone) (PEO-b-PCL) based copolymers modified with RGD ligands on PEO and pendent functional groups on PCL, i.e., GRGDS-PEO-b-poly(αbenzylcarboxylate-ε-caprolactone) (GRGDS-PEO-b-PBCL) and GRGDS-PEO-b-poly(α-carboxyl-ε-caprolactone) (GRGDS-PEO-b-PCCL), were synthesized. Chemical conjugation of doxorubicin (DOX) to PCCL core produced GRGDS-PEO-b-P(CL-DOX) micellar conjugates, while GRGDS-PEO-b-PBCL were used to physically encapsulate DOX. For both systems, micellar core degradation, drug release, intracellular drug uptake/disposition, and cytotoxicity against B16F10 metastatic cells were investigated. Results. The PBCL and P(CL-DOX) cores were found resistant to degradation in pH 7.2, but showed 10% and 40% loss in core molecular weight in pH 5.0 within 144 h, respectively. Preferential release of DOX and DOX derivatives from PBCL and P(CL-DOX) cores was noted in pH 5.0, respectively. The GRGDS-modified micelles showed enhanced cellular internalization through endocytosis, increased intracellular DOX release, nuclear localization, and improved cytotoxicity against metastatic B16F10 cells compared to their unmodified counterparts. Conclusions. The results clearly suggest a promise for the development of multifunctional polymeric micelles with RGD ligand decorated shell and endosomal pH-triggered degradable core for selective DOX delivery to metastatic cancer cells.
Advances in nano delivery systems for doxorubicin an updated insight.pdf
Doxorubicin (DOX) is the most effective chemotherapeutic drug developed against broad range of cancers such as solid tumours, transplantable leukemias and lymphomas. Conventional DOX-induced cardiotoxicity has limited its use. FDA approved drugs i.e. non-pegylated liposomal (Myocet V R ) and pegylated liposomal (Doxil V R ) formulations have no doubt shown comparatively reduced cardiotoxicity, but has raised new toxicity issues. The entrapment of DOX in biocompatible, biodegradable and safe nano delivery systems can prevent its degradation in circulation minimising its toxicity with increased half-life, enhanced pharmacokinetic profile leading to improved patient compliance. In addition, nano delivery systems can actively and passively target the tumour resulting increase in therapeutic index and decreased side effects of drug. Foreseeing the need of a comprehensive review on DOX nanoformulations, in this article we for the first time have given an updated insight on DOX nano delivery systems.
Polymeric Nanocarriers: A Transformation in Doxorubicin Therapies
Materials, 2021
Doxorubicin, a member of the anthracycline family, is a common anticancer agent often used as a first line treatment for the wide spectrum of cancers. Doxorubicin-based chemotherapy, although effective, is associated with serious side effects, such as irreversible cardiotoxicity or nephrotoxicity. Those often life-threatening adverse risks, responsible for the elongation of the patients’ recuperation period and increasing medical expenses, have prompted the need for creating novel and safer drug delivery systems. Among many proposed concepts, polymeric nanocarriers are shown to be a promising approach, allowing for controlled and selective drug delivery, simultaneously enhancing its activity towards cancerous cells and reducing toxic effects on healthy tissues. This article is a chronological examination of the history of the work progress on polymeric nanostructures, designed as efficient doxorubicin nanocarriers, with the emphasis on the main achievements of 2010–2020. Numerous pu...