DOX-loaded Particles Research Articles

A polyampholyte core-shell microgel as an environmentally sensitive drug carrier

In this study, we investigate a polyampholyte degradable core-shell (CS) microgel, with an anionic pH-sensitive core and a cationic pH- and temperature-sensitive shell, as a model system for drug delivery. The core was based on crosslinked poly(acrylic acid) and was synthesized through distillation precipitation polymerization. Then, the shell, based on cross-linked poly(poly(ethylene glycol) methyl ether methacrylate - N-(3-aminopropyl)methacrylamide), were built over the core via the seed polymerization. N,N′-bis(acryloyl)cystamine was used as the linker for cross-linking both core and shell to give the core-shell particles the ability to degrade in the presence of reducing agent. The swelling characteristics of the core-shell microgels were studied using dynamic light scattering (DLS). The core-shell particles exhibited sensitivity to pH due to the presence of carboxylic and amine groups in the core and shell, respectively. The degradation of the core-shell particles was examined using electron microscopy and DLS. In the presence of glutathione, which acts as a reducing agent for the -S-S- bridges, commonly found in cancer cells, the particles underwent complete degradation. Our findings also demonstrate that the presence of the positively charged shell still enables efficient uptake of a drug in the form of a cation (doxorubicin DOX) into the anionic core and the drug can be released through the cationic shell. The release of DOX from the carrier was studied under different pH conditions to mimic the environment found in cancer cells. The results showed that at pH 7.4, the carrier exhibited the lowest release of DOX. However, under conditions mimicking the acidic and reducing environment typically for tumor microenvironment (pH 5.0 and cGSH = 40 mM), the CS particles demonstrated the highest cumulative and sustained release of DOX. The results showed that the DOX-loaded particles exhibited increased cytotoxicity against MCF-7 cells, indicating enhanced anti-cancer activity. At the same time, these particles demonstrated reduced toxicity towards healthy MCF-10A cells, which suggests improved selectivity and reduced side effects. It is worth noting that the gel nanoparticles alone did not inhibit cell growth. Overall, these findings suggest that the DOX-loaded core-shell particles hold promise as a targeted drug delivery system, capable of preferentially releasing the drug in the acidic and reducing tumor microenvironment while minimizing toxicity towards healthy cells.

Degradation and drug release profile of degradable core-corona type particles under acidic condition for cancer treatment

Biodegradable particles are potential drug delivery carriers for cancer treatment because the drugs existed in inner core are released during the degradation of the particles. In this study, graft copolymers were prepared by radical copolymerization of 2-methylene-1,3-dioxepane and poly(ethylene glycol) monomethacrylate. Under acidic condition (pH 1.3), the graft copolymers were degraded through hydrolysis, and after 50-days of hydrolysis, they were converted to hydrophilic oligomers. Degradable core-corona-type particles were prepared by reprecipitation of the graft copolymer solution against water. Under acidic conditions, the diameter of the prepared particles decreased for one day due to the hydrolysis of the particles. The diameter increased after three days due to the swelling of the partially degraded particle cores containing poly(ethylene glycol) chains. Doxorubicin (DOX) release profile was evaluated in a PBS (pH 7.4) and acidic conditions (pH 1.3, 5.4). DOX was not released in PBS, whereas it was released under acidic conditions. The release of DOX increased at lower pH conditions. HeLa cells were cultured in the presence of DOX-loaded particles. Non-DOX-loaded particles showed no cytotoxicity whereas a decrease in cell viability was observed with increasing amounts of DOX-loaded particles. The prepared particles are expected to be useful as degradable drug delivery system carriers for cancer treatment.

Synthesis of Multi-Functional Nano-Vectors for Target-Specific Drug Delivery.

Magnetic nanoparticles have gained attention in cancer therapy due to their non-toxic properties and high bio-compatibility. In this report, we synthesize a dual-responsive magnetic nanoparticle (MNP) that is sensitive to subtle pH and temperature change as in the tumor microenvironment. Thus, the functional doxorubicin (DOX)-loaded MNP (DOX-PNIPAM-PMAA@Fe3O4) can perform specific DOX releases in the cancer cell. The particle was characterized by scanning electron microscopy (SEM), dynamic light scattering (DLS), zeta-potential, Fourier-transform infrared spectroscopy (FTIR), and thermogravimetric analysis (TGA). The microscopy data revealed the particle as having a spherical shape. The zeta-potential and size distribution analysis data demonstrated the difference for the stepwise modified MNPs. The FTIR spectrum showed characteristic absorption bands of NH2-SiO2@Fe3O4, CPDB@Fe3O4, PMAA@Fe3O4, and PNIPAM-PMAA@Fe3O4. Drug-loading capacity and releasing efficiency were evaluated under different conditions. Through an in vitro analysis, we confirmed that PNIPAM-PMAA@Fe3O4 has enhanced drug releasing efficiency under acidic and warmer conditions. Finally, cellular uptake and cell viability were estimated via different treatments in an MDA-MB-231 cell line. Through the above analysis, we concluded that the DOX-loaded particles can be internalized by cancer cells, and such a result is positive and prospective.

A pH-controlled approach to fabricate electrolyte/non-electrolyte janus particles with low cytotoxicity as carriers of DOX

Seeded emulsion polymerizations of 2-(dimethylamino)ethyl methacrylate (DMAEMA) and methacrylic acid (MAA) were performed in presence of poly(2-hydroxyehtyl methacrylate) (PHEMA) particles as seed to fabricate Janus particles. By tuning the pH value of solution before polymerization, various solutions of protonated and deprotonated monomers were obtained. Then, different morphologies such as core-shell and dumbbell-like were fabricated as a result of pH variations. These composite particles were then used as carriers of DOX in different conditions. All samples showed high loading capacity and long-time release process. Although all morphologies showed insignificant cumulative release at pH = 7.4, release amount was increased to 50–75% at pH = 1. Finally, neat and DOX-loaded particles were introduced to cytotoxicity studies via an MTT assay. According results, PMAA-based particles had no mentionable cell toxicity whereas PDMAEMA-based ones had moderate cytotoxicity. Also, all drug-loaded particles prohibited cell growth significantly. However, DMAEMA-based particles killed more cells than PMAA-based composite particles.

One-step fabrication of low cytotoxic anisotropic poly(2-hydroxyethyl methacrylate-co-methacrylic acid) particles for efficient release of DOX

Herein, we report a one-step process of distillation precipitation polymerization (DPP) to fabricate anisotropic particles in which no stabilizing agent is used. This method is based on in situ crosslinking of poly(2-hydroxyethyl methacrylate-co-methacrylic acid) random copolymers with variety of feed composition that determine morphology of resultant particles. As a result, variation of feed composition led to formation of spherical, spherical with a lobe and a lobed spherical (multiple lobes) particles. These morphologies are discussed according to thermodynamics of colloids and polymerization-induced phase separation. As one of the most important applications, selected morphologies are used as carriers of anti-cancer DOX drug. Results showed high drug loading amount for all carriers those released DOX significantly at pH = 1 whereas no mentionable release was observed at pH = 7.4. Also, release profiles were fitted by well-known mathematical models to understand kinetics of release. Finally, cytotoxicity of carriers are measured by an MTT assay that showed all carriers are biocompatible whereas DOX-loaded particles were significantly cytotoxic.

Investigation of magnetic silica with thermoresponsive chitosan coating for drug controlled release and magnetic hyperthermia application

In this study, a drug delivery system for chemo-hyperthermia applications is proposed and fabricated. The delivery system consists of magnetic-silica (MagSi) particles being encapsulated within a pH/thermo-responsive chitosan‑g‑N‑isopropylacrylamide (Chi-g-NIPAAm) polymer matrix. The as-prepared MagSi@Chi-g-NIPAAm particles exhibit superparamagnetic behavior with a saturation magnetization (Ms) of 20.14 emu/g. In addition, the MagSi@Chi-g-NIPAAm particles can act as a heat source when subject to an alternating magnetic field (AMF) and have a specific absorptions rate (SAR) of 8.36 Wg−1. The release of the drug DOX from the synthesized particles is sensitive to both the pH and temperature of its environment. We have compared the drug release when the solution is externally heated up and when it is heated up by the AMF (internal heating). For external heating (when the pH/temperature is 4.0/45 °C), 83.30 ± 2.92% of the DOX were released within the first 5 h. The release of the DOX by the particles in pH 7.4 (temperature of 37 °C) was much slower (around 25.87 ± 1.30% after 25 h). The release of the DOX was much higher (under an acidic condition pH = 4.0) around 57.13 ± 2.36% within 1 h in the presence of AMF heating. The in vitro cytotoxicity tests of the of DOX-loaded MagSi@Chi-g-NIPAAm particles towards HeLa cancer cells. In general, the toxicities of the drug DOX as part of a MagSi@Chi-g-NIPAAm particles were less than those of the standalone DOX until the concentration of DOX-loaded particles reached 250 μg/mL, after which the toxicity of DOX in both forms were the same.

Colloidal properties and in vitro evaluation of Hydroxy ethyl cellulose coated iron oxide particles for targeted drug delivery

In this study, superparamagnetic iron oxide (Fe3O4) nanoparticles were prepared for the targeted drug delivery applications by controlling the colloidal properties with a cellulosic polymer that is Hydroxy ethyl cellulose (HEC). Fe3O4 particles were treated with HEC in a variable range of polymer concentration. Rheological, electrokinetic, magnetorheological and morphological properties of the dispersions were investigated to have stable and fully covered surfaces of Fe3O4 particles by coating with HEC and obtaining non-toxic biocompatible multifunctional magnetic particles. Fully coated HEC and iron-oxide particles were characterized thermally, magnetically and tested for toxicity in vitro. Then Doxorubicin hydrochloride (DOX), which is an anticancer drug widely used for cancer therapies, was loaded onto nanoparticles and their drug loading efficiency was determined. Finally, effects of DOX-loaded particles on the cancer cells were examined to report a nano drug system which can potentially open up new possibilities in the design of therapeutic agents. Results indicated that the synthesized nanoparticles in this study could be suitable to magnetically manipulated targeted delivery systems, imaging, magnetic hyperthermia treatments.

A reduction-sensitive carrier system using mesoporous silica nanospheres with biodegradable polyester as caps

Mesoporous silica nanoparticles (MSN)-polymer hybrid combined with the aliphatic biodegradable polyester caps on the surface were first developed in order to manipulate the smart intracellular release of anticancer drugs. First, poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-PCL) was successfully grafted on the surface of MSN via disulfide bonds which could cleave under a reduction environment in tumor cells. The anticancer drug doxorubicin (DOX) was encapsulated into the particle pores. The in vitro drug release profile showed that DOX release was significantly restricted by the polymer caps at pH 7.4, while it was greatly accelerated upon the addition of GSH. Cytotoxicity evaluation showed good biocompatibility with the hybrid particles. Fast endocytosis and intracellular DOX release were observed by confocal laser scanning microscopy (CLSM). The DOX-loaded particles exhibited comparable antitumor activity with free DOX towards HeLa cells and showed in a time-dependent manner. This work developed an extensive method of utilizing aliphatic biodegradable polyesters as polymer caps for MSN to control drug delivery. The paper might offer a potential option for cancer therapy.

M13 bacteriophage-polymer nanoassemblies as drug delivery vehicles

Poly(caprolactone-b-2-vinylpyridine) (PCL-P2VP) coated with folate-conjugated M13 (FA-M13) provides a nanosized delivery system which is capable of encapsulating hydrophobic antitumor drugs such as doxorubicin (DOX). The DOX-loaded FA-M13-PCL-P2VP assemblies had an average diameter of approximately 200 nm and their structure was characterized using transmission electron microscopy, scanning electron microscopy, and dynamic light scattering. The particles were stable at physiological pH but could be degraded at a lower pH. The release of DOX from the nanoassemblies under acidic conditions was shown to be significantly faster than that observed at physiological pH. In addition, the DOX-loaded FA-M13-PCL-P2VP particles showed a distinctly greater cellular uptake and cytotoxicity against folate-receptor-positive cancer cells than folate-receptor-negative cells, indicating that the receptor facilitates folate uptake via receptor-mediated endocytosis. Furthermore, the DOX-loaded particles also had a significantly higher tumor uptake and selectivity compared to free DOX. This study therefore offers a new way to fabricate nanosized drug delivery vehicles.