Yanna Zhao

Methotrexate Nanoparticles Prepared with Codendrimer from Polyamidoamine (PAMAM) and Oligoethylene Glycols (OEG) Dendrons: Antitumor Efficacy in Vitro and in Vivo

The novel methotrexate-loaded nanoparticles (MTX/PGD NPs) prepared with amphiphilic codendrimer PGD from polyamidoamine and oligothylene glycol dendrons were obtained via antisolvent precipitation method augmented by ultrasonication. Based on the excellent hydrophility of PGD, the drug-loaded nanoparticles could be investigated easily with the high drug-loading content (~85.2%, w/w). The MTX/PGD NPs possessed spherical morphology, nanoscaled particle size (approximately 182.4 nm), and narrow particle size distribution. Release of MTX from MTX/PGD NPs showed a sustained release manner and completed within 48 h. Hemolytic evaluation indicated MTX/PGD NPs presented good blood compatibility, and the cytotoxicity of nanoparticles against breast cancer cells in vitro, biodistribution in tumor tissue, and antitumor efficacy in vivo were enhanced significantly compared to MTX injection. According to the higher drug-loading content, enhanced antitumor efficacy, and appropriate particle size, MTX/PGD NPs as the drug delivery systems could have potential application for cancer chemotherapy in clinic.

Codendrimer (PAG) from polyamidoamine (PAMAM) and oligoethylene glycols (OEG) dendron: evaluation as drug carrier

Based on the successful synthesis of codendrimer PAMAM-co-OEG (PAG) from polyamidoamine (PAMAM) and oligoethylene glycols (OEG) dendron, the aim of this paper was to prepare drug-loaded aggregates and evaluate the ability of PAG as the drug carrier. A series of hydrophobic drugs with different functional groups were selected as model drugs. The drug-loading procedures were optimized by single factor exploration with resveratrol. From the results of drug-loading content (DLC) and entrapment efficiency (EE), MTX was proved to be the most suitable drug. Moreover, higher loading capacity and slower in vitro release of MTX were observed, which was due to the hydrophobic interactions and electrostatic interactions between MTX and PAG. In summary, PAG exhibited great potential for modifications in the stability, drug solubilization, and release properties of drug-loaded aggregates.

Well-defined podophyllotoxin polyprodrug brushes: preparation via RAFT polymerization and evaluation as drug carriers

Novel poly(triethylene glycol methacrylate)-b-poly(podophyllotoxin methacrylate) copolymers (PTP) with a well-defined structure were designed and synthesized by direct RAFT polymerization with the hydrophobic monomer derivative from the anticancer drug podophyllotoxin. After optimizing the hydrophilic/hydrophobic ratio, the polyprodrug brush PT45P14 was utilized as a carrier to prepare polyprodrug nanoparticles (PT45P14 NPs) via the dialysis method. The polyprodrug nanoparticles presented a drug-loading content of approximately 40% and excellent storage and medium stabilities. The release of POD from PT45P14 NPs showed a sustained and pH-dependent release manner within 72 h; the release rate was increased under acidic conditions because ester bonds cleaved faster in a low pH environment. PT45P14 NPs presented higher cytotoxicity against Hela cells compared with free POD, the antitumor efficacy in vitro was enhanced 5-fold, and the cellular uptake mechanism was proven to be sucrose-blocking clathrin-mediated endocytosis. According to their great drug-loading content, moderate hydrophilicity, appropriate particle size, pH-sensitive release, and enhanced antitumor efficacy, PT45P14 NPs as efficient drug delivery systems could have potential application in pH-sensitive cancer therapy.

Honokiol nanoparticles stabilized by oligoethylene glycols codendrimer: in vitro and in vivo investigations

Nanoparticles based on dendrimers were explored as excellent candidates for nanoscale drug delivery system. In this study, the fluorescently labeled amphiphilic codendrimer PGC from PAMAM G4.0 and oligoethylene glycol dendron was utilized as a carrier to prepare honokiol-loaded nanoparticles (HK NPs) via an evaporation method augmented by ultrasonication with an optimized drug-loading content (∼60%, wt%). The release of HK NPs showed a sustained release manner and was completed within 120 h. The HK NPs presented higher cytotoxicity against 4T1 cells, and the cellular uptake mechanism was proven to be caveolae-mediated endocytosis and clathrin-mediated endocytosis. Importantly, the HK NPs resulted in a strong antitumor efficacy on the 4T1 breast tumor model in vivo, and no significant adverse effects were observed. In addition, in vivo studies also showed that the HK NPs possessed better tumor accumulation over HCPT injection. According to the higher drug-loading content, enhanced antitumor efficacy, and appropriate particle size, HK NPs were shown to be safe and efficient drug delivery systems and could have potential application in cancer chemotherapy.

Self-assembled thermosensitive nanoparticles based on oligoethylene glycol dendron conjugated doxorubicin: preparation, and efficient delivery of free doxorubicin

An amphiphilic dendron–drug conjugate was synthesized via oligoethylene glycol (OEG) dendrons coupled with anticancer drug doxorubicin (DOX). The amphiphilic conjugate OEG–DOX (GD) self-assembled into spherical nanoparticles in aqueous solution, with mean diameters of approximately 212.5 nm. As an effective drug carrier, DOX was entrapped into GD to form drug-loaded nanoparticles (GD/D) with high drug loading content (24%, wt%), due to the enhanced hydrophobic/aromatic interactions between the DOX moiety in GD and free DOX. Besides, GD nanoparticles exhibited thermo-induced collapse and aggregation, therefore, the temperature-dependent drug release profiles of DOX from GD/D nanoparticles were measured and the possible mechanism was proposed. Moreover, hemolytic activity of GD/D revealed the good blood compatibility, and the cytotoxicity of DOX in GD/D was enhanced significantly in vitro against HepG2 cells. Overall, amphiphilic conjugate GD was considered to be potentially feasible to overcome formulation challenges for drug delivery and to be used in clinic.

A series of codendrimers from polyamidoamine (PAMAM) and oligoethylene glycols (OEG) dendrons as drug carriers: the effect of OEG dendron decoration degree

A series of codendrimers (co-D64, co-D48, co-D32, and co-D16) from polyamidoamine (PAMAM) decorated by oligoethylene glycol (OEG) dendrons with similar structures but different decoration degrees (DDs) were prepared, and their properties in aqueous solution, including particle size and morphology, were investigated. To explore the interactions between the codenderimers and drug, then find the effects of OEG dendron decoration degree, these codendrimers were utilized as drug carriers to load methotrexate (MTX). Although these drug-loaded nanoparticles presented similar particle size, morphology, thermal transition, and physical state, it was proved that codendrimers with lower DDs (co-D32, 50%; co-D16, 25%) were the most suitable carriers to load MTX from the drug-loading content (DLC), entrapment efficiency (EE), and cytotoxicity results. This was due to the stronger hydrophobic and electrostatic interactions between the free amine groups of the codendrimers and MTX. The results from the drug release profiles indicated that the release kinetics were not controlled only by these interactions, but that the steric hindrance of the OEG dendrons should be considered. Overall, co-D32 with a moderate decoration degree could be a promising drug delivery system.

A codendrimer of PAMAM decorated with oligoethylene glycol dendrons: synthesis, self-assembly, and application as a drug carrier

A codendrimer of PAMAM covered with oligoethylene glycol (OEG) dendrons (PGD) was prepared, and its conjugation with the anti-cancer drug, vincristine (VCR), via the pH-sensitive imine bond (PGV), was investigated. Dynamic light scattering, transmission electron microscopy, and cryo-transmission electron microscopy demonstrated that PGD and PGV self-assembled into spherical aggregates with a mean diameter of approximately 120 nm, in aqueous solutions. The application of these two codendrimers as drug carriers was studied, with both PGD and PGV demonstrating a good capacity for the loading of VCR, exhibiting drug-loadings (DLs) as high as 43% (physical encapsulation) and 32% (reversible conjugation), respectively. The cytotoxicity of PGD and PGV were evaluated in vitro. Specifically, PGV behaved as a prodrug, releasing VCR at a nearly constant rate during a long period of 16 days, with no burst release in pH 5.5 PBS. Moreover, the in vitro drug release from PGV indicated a relatively faster VCR release in acidic environments. All of these properties revealed that PGV has good potential to be used for IV injectable anti-cancer drug release, especially in long-acting interventional chemotherapy.

Hydroxycamptothecin Nanorods Prepared by Fluorescently Labeled Oligoethylene Glycols (OEG) Codendrimer: Antitumor Efficacy in Vitro and in Vivo

Nanorods based on dendrimers were explored as excellent candidates for nanoscale drug delivery system. In this study, fluorescently labeled PAMAM-b-oligoethylene glycols codendrimer (POC) was utilized as carrier to prepare 10-hydroxycamptothecin (HCPT) loaded nanorods (HCPT NRs) via antisolvent precipitation method augmented by ultrasonication with the optimized drug-loading content (∼90.6%) and positive charged surface. The nanorods presented high stability, and the release of HCPT nanorods showed a sustained release manner and was completed within 48 h. The nanorods presented higher cytotoxicity against HepG2 and 4T1 cells than HCPT injections, and the cellular uptake mechanism was proved to involve clathrin-mediated endocytosis and macropincytosis-dependent endobytosis. Importantly, the HCPT nanorods resulted in strong antitumor efficacy on the H22 liver tumor model, and no significant adverse effects was observed. Besides, in vivo studies also showed that HCPT NRs possessed better tumor accumulation over HCPT injection at the equivalent concentration. According to the high drug-loading content, enhanced antitumor efficacy, and appropriate particle size, HCPT NRs as the safe and efficient drug delivery systems could have potential application for cancer chemotherapy in clinic.

A stabilizer-free and organic solvent-free method to prepare 10-hydroxycamptothecin nanocrystals: in vitro and in vivo evaluation

10-Hydroxycamptothecin (10-HCPT) is a promising anticancer drug with a wide spectrum of antitumor activities. Due to its poor solubility, the carboxylate form that shows high water solubility but minimal anticancer activity and pharmacokinetic defects is used in the marketed 10-HCPT injections, resulting in its limited clinical application. To develop a simple, safe, and highly effective drug delivery system, a modified acid–base microprecipitation combined with a high-pressure homogenization technique was adopted to prepare 10-HCPT nanocrystals. Neither organic solvents nor stabilizers were employed throughout the preparation process. The in vitro and in vivo performances of the resulting10-HCPT nanocrystals were investigated systematically. The nanocrystals were spherical with a small size of ~130 nm, and the actual drug-loading content was as high as 75%. The nanocrystals displayed a sustained release pattern and were proven to have a higher cell uptake and antiproliferative activity than the 10-HCPT injections. The 10-HCPT nanocrystals also showed enhanced drug accumulation in tumors and better anticancer efficacy in 4T1-bearing mice. In summary, the 10-HCPT nanocrystals prepared in this study seem to be a promising delivery system for a new form of 10-HCPT dosages.

Shape of Nanoparticles as a Design Parameter to Improve Docetaxel Antitumor Efficacy

It was reported that the shape of nanocarriers played an important role in achieving a better therapeutic effect. To optimize the morphology and enhance the antitumor efficacy, in this study based on the amphiphilic PAMAM- b-OEG codendrimer (POD), docetaxel-loaded spherical and flake-like nanoparticles (DTX nanospheres and nanosheets) were prepared via an antisolvent precipitation method with similar particle size, surface charge, stability, and release profiles. The feed weight ratio of DTX/POD and the branched structure of OEG dendron were suggested to influence the shapes of the self-assembled nanostructures. As expected, DTX nanospheres and nanosheets exhibited strong shape-dependent cellular internalization efficiency and antitumor activity. The clathrin-mediated endocytosis and macropincytosis-dependent endocytosis were proven to be the main uptake mechanism for DTX nanospheres, while it was clathrin-mediated endocytosis for DTX nanosheets. More importantly, DTX nanosheets presented obviously superior antitumor efficacy over nanospheres, the tumor inhibition rate was increased 2-fold in vitro and 1.3-fold in vivo. An approximately 2-fold increase in pharmacokinetic parameter (AUC, MRT, and T1/2) and tumor accumulation were observed in the DTX nanosheets group. These results suggested that the particle shape played a key role in influencing cellular uptake behavior, pharmacokinetics, biodistribution, and antitumor activity; the shape of drug-loaded nanoparticles should be considered in the design of a new generation of nanoscale drug delivery systems for better therapeutic efficacy of anticancer drug.