Sterically stabilized polymeric nanoparticles with a combinatorial approach for multi drug resistant cancer: In vitro and in vivo investigations (original) (raw)
Related papers
International Journal of Nanomedicine, 2018
Background: Successfully overcoming obstacles due to anticancer drugs' toxicity and achieving effective treatment using unique nanotechnology is challenging. The complex nature of breast tumors is mainly due to chemoresistance. Successful docetaxel (DTX) delivery by nanoparticles (NPs) through inhibition of multidrug resistance (MDR) can be a bridge to enhance intracellular dose and achieve higher cytotoxicity for cancer cells. Purpose: This study tested primary patient breast cancer cells in vitro with traditional free DTX in comparison with polymeric nanocarriers based on poly lactic co-glycolic acid (PLGA) NPs. Materials and methods: Establishment of primary cell line from breast malignant tumor depends on enzymatic digestion. Designed DTX-loaded PLGA NPs were prepared with a solvent evaporation method; one design was supported by the use of folic acid (FA) conjugated to PLGA. The physical properties of NPs were characterized as size, charge potential, surface morphology, DTX loading, and encapsulation efficiency. In vitro cellular uptake of fluorescent NPs was examined visually with confocal fluorescence microscopy and quantitatively with flow cytometry. In vitro cytotoxicity of all DTX designed NPs against cancer cells was investigated with MTT assay. RT-PCR measurements were done to examine the expression of chemoresistant and apoptotic genes of the tested DTX NPs. Results: Cellular uptake of DTX was time dependent and reached the maximum after loading on PLGA NPs and with FA incorporation, which activated the endocytosis mechanism. MTT assay revealed significant higher cytotoxicity of DTX-loaded FA/PLGA NPs with higher reduction of IC50 (8.29 nM). In addition, PLGA NPs, especially FA incorporated, limited DTX efflux by reducing expression of ABCG2 (3.2-fold) and MDR1 (2.86-fold), which were highly activated by free DTX. DTX-loaded FA/PLGA NPs showed the highest apoptotic effect through the activation of Caspase-9, Caspase-3, and TP53 genes by 2.8-, 1.6-, and 1.86-fold, respectively. Conclusion: FA/PLGA NPs could be a hopeful drug delivery system for DTX in breast cancer treatment.
Biomacromolecules, 2018
A multifunctional nanoparticulate system composed of methoxy poly(ethylene glycol)-poly(l-histidine)-d-α-vitamin E succinate (MPEG-PLH-VES) copolymers for encapsulation of doxorubicin (DOX) was elaborated with the aim of circumventing the multidrug resistance (MDR) in breast cancer treatment. The MPEG-PLH-VES nanoparticles (NPs) were subsequently functionalized with biotin motif for targeted drug delivery. The MPEG-PLH-VES copolymer exerts no obvious effect on the P-gp expression level of MCF-7/ADR but exhibited a significant influence on the loss of mitochondrial membrane potential, the reduction of intracellular ATP level, and the inhibition of P-gp ATPase activity of MCF-7/ADR cells. The constructed MPEG-PLH-VES NPs exhibited an acidic pH-induced increase on particle size in aqueous solution. The DOX-encapsulated MPEG-PLH-VES/biotin-PEG-VES (MPEG-PLH-VES/B) NPs were characterized to possess high drug encapsulation efficiency of approximate 90%, an average particle size of approxi...
Journal of Pharmacology and Experimental Therapeutics, 2006
The objectives of this study were to evaluate the potential of a polymer-lipid hybrid nanoparticle (PLN) system to enhance cellular accumulation and retention of doxorubicin (Dox), a widely used anticancer drug and an established P-glycoprotein (Pgp) substrate, in Pgp-overexpressing cancer cell lines and to explore the underlying mechanisms. Nanoparticles containing Dox complexed with a novel anionic polymer (Dox-PLN) were prepared using an ultrasound method. Two Pgp-overexpressing breast cancer cell lines (a human cell line, MDA435/LCC6/ MDR1, and a mouse cell line, EMT6/AR1) were used to investigate the effect of nanoparticles on cellular uptake and retention of Dox. Endocytosis inhibition studies and fluorescence microscopic imaging were performed to elucidate the mechanisms of cellular drug uptake. Treatment of Pgp-overexpressing cell lines with Dox-PLNs resulted in significantly en
ACS Biomaterials Science & Engineering, 2019
A multifunctional triblock copolymer intended for targeted drug delivery applications has been designed and successfully synthesized. Following various controlled polymerization and modification steps a saccharide end-functionalized polyoxyethylene block was attached through Page 1 of 46 ACS Paragon Plus Environment ACS Biomaterials Science & Engineering 2 a cleavable in slightly acidic conditions aromatic imine bond to amphiphilic diblock copolymer comprising biodegradable hydrophobic and modified with mitochondria targeting groups polycationic blocks. The micelles formed from the triblock copolymer in aqueous media possess key functions (cleavable "stealth" shield, targeting groups) needed for the safe extracellular transport, successful cell internalization and drug delivery to the target cellular organelles. The multifunctional nanocarriers were loaded with the plant-derived anticancer drug curcumin and the in vitro analyses revealed their superior cytotoxic, apoptogenic and NF-kB-inhibitory effects on target cells over the free drug and non-functionalized polymer micelles of similar composition. Moreover, the enhanced cellular internalization and mitochondrial accumulation of the multifunctional nanocarriers compared to their non-functionalized analogues was visualized by fluorescence microscopy. The results obtained indicate that the presented multifunctional micelles have a potential for application in nanomedicine for enhanced organelle-specific drug delivery.
Nanoscale Research Letters, 2015
Background Since aggressive cancer cells highly express the CD44 receptor compared to normal cells, hyaluronic acid (HA) can be used for CD44 targeting molecule. Since glutathione (GSH) level is normally elevated in the intracellular compartment and in the tumor cell, the fact that disulfide bond can be cleaved by GSH is widely used for intracellular drug delivery. Methods HA was connected with poly(dl-lactide-co-glycolide) (PLGA) using disulfide linkage, and then a diblock copolymer (HAssLG) was prepared. Doxorubicin (DOX)-loaded HAssLG nanoparticles were prepared by dialysis procedures. Results and Discussion DOX-loaded HAssLG nanoparticles have spherical shapes with small particle size of less than 300 nm. In fluorescence measurement, DOX was dose-dependently liberated from nanoparticles by the addition of GSH. DOX release rate from HAssLG nanoparticles was increased by the addition of GSH. To confirm CD44 receptor-mediated endocytosis of nanoparticles, CD44-positive MDA-MB231 ce...
Journal of Biomedical Materials Research Part A, 2008
Folate (FA) conjugated tri-block copolymers were prepared by bioconjugation of poly e-caprolactone diol and various molecular weights of diamine polyethylene glycol. The synthetic tri-block copolymers were characterized by 1 H-NMR. Three types of nanoparticles were prepared by nanoprecipitation. Their size and morphology were verified by laser scattering and transmission electron microscopy, respectively. The colloidal stability of the nanoparticles was evaluated by turbidity test. The anticancer drug doxorubicin (DOX) was encapsulated in the nanoparticles during preparation. Drug loading amounts and release behavior from prepared nanoparticles were investigated. Fluorescent-acti-vated cell sorting analysis and epi-fluorescencic microscopic imaging of prepared nanoparticles exhibited good cellular uptake against target cells. FA receptor expressed OVCAR3 cells that showed higher mean fluorescence intensity than FA receptor defect A549 cells at specific polyethylene glycol chain lengths. The cell cytotoxicity of prepared nanoparticles was evaluated for receptor mediated drug delivery.
Multicomponent Polymeric Nanoparticles Enhancing Intracellular Drug Release in Cancer Cells
ACS Applied Materials & Interfaces, 2014
Three kinds of amphiphilic copolymer i.e. Poly(ε-caprolactone)-SS-Poly(ethylene glycol) (PCL-SS-PEG), Poly(ε-caprolactone)-Polyethylenimine (PCL-PEI) and Poly(ε-caprolactone)-Polyethylenimine-Folate (PCL-PEI-Fol) were synthesized and self-assembled into surface engineered hybrid nanoparticles (NPs). Morphological studies elucidated the stable, spherical and uniform sandwich structure of NPs. PCL-PEI and PCL-SS-PEG segments have introduced pH and reduction responsive characteristics in these NPs, while PCL-PEI-FA copolymers could provide specific targeting capability to cancer cells. The stimuli responsive capabilities of these NPs were carried out. Negative-to-positive charge reversible property, in response to the pH change, was investigated by Zeta potential and Nuclear Magnetic Resonance (NMR). The structure cleavage, due to redox gradient, was studied by Dynamic Light Scattering (DLS) and Transmission Electron Microscope (TEM). These NPs showed controlled degradation, better drug release, less toxicity and effective uptake in MCF-7 breast cancer cells. These multifunctional NPs showed promising potential in the treatment of cancer.
Pharmaceutical research, 2014
Approaches for the synthesis of biomaterials to facilitate the delivery of "biologics" is a major area of research in cancer therapy. Here we designed and characterized a hyaluronic acid (HA) based self-assembling nanoparticles that can target CD44 receptors overexpressed on multidrug resistance (MDR) ovarian cancer. The nanoparticle system is composed of HA-poly(ethyleneimine)/HA-poly(ethylene glycol) (HA-PEI/HA-PEG) designed to deliver MDR1 siRNA for the treatment of MDR in an ovarian cancer model. HA-PEI/HA-PEG nanoparticles were synthesized and characterized, then the cellular uptake and knockdown efficiency…
ACS Nano, 2014
Resistance to anticancer drugs is considered a major cause of chemotherapy failure. One of the major mediators of resistance is the multidrug extrusion pump protein, P-glycoprotein (P-gp), an ATP-binding cassette (ABC) transporter with broad substrate specificity. In order to bypass this drug resistance mechanism, we have devised phospholipid-based nanoparticle clusters coated with the glycosaminoglycan hyaluronan, the major ligand of CD44, which is upregulated and undergoes different splice variations in many types of cancer cells. These particles, termed glycosaminoglycan particle nanoclusters or gagomers (GAGs), were self-assembled into ∼500 nm diameter clusters, with zeta-potential values of ∼À70 mV. Flow cytometry analysis provided evidence that, unlike free doxorubicin (DOX), a model chemotherapy, DOX entrapped in the GAGs (DOX-GAGs) accumulated in P-gpoverexpressing human ovarian adenocarcinoma cell line and dramatically decreased cell viability, while drug-free GAGs and the commercially available drug DOXIL (PEGylated liposomal DOX) did not produce therapeutic benefit. Furthermore, by using RNA interference strategy, we showed that DOX-GAGs were able to overcome the P-gp-mediated resistant mechanism of these cells. Most importantly, DOX-GAGs showed a superior therapeutic effect over free DOX in a resistant human ovarian adenocarcinoma mouse xenograft model. Taken together, these results demonstrated that GAGs might serve as an efficient platform for delivery of therapeutic payloads by bypassing P-gp-mediated multidrug resistance.