Sai Li

Nanoparticles generated by PEG-Chrysin conjugates for efficient anticancer drug delivery.

Nanoparticle-based drug delivery systems promise the safety and efficacy of anticancer drugs. Herein, we presented a facile approach to fabricate novel nanoparticles generated by PEG-Chrysin conjugates for the delivery of anticancer drug doxorubicin. Chrysin was immobilized on the terminal group of methoxy poly(ethylene glycol) (mPEG) to form mPEG-Chrysin conjugate. The conjugates were self-assembled into nanoparticles. Doxorubicin (DOX) was loaded in the nanoparticles. The self-assembly, drug release profiles, interactions between nanoparticle and drug, cellular uptake and in vitro anticancer activity of the DOX loaded nanoparticles were investigated. The results showed that the mean diameters of drug loaded nanoparticles were below 200 nm. Strong π-π stacking interaction was tested within the drug loaded nanoparticles. The drug release rate was closely related to the chain length of PEG, shorter PEG chain resulted faster release. The mPEG-Chrysin conjugate was non-toxic to both 3T3 fibroblasts and HepG2 cancer cells. The cellular uptake measurements demonstrated that the mPEG1000-Chrysin nanoparticles exhibited higher capability in endocytosis. The IC50 of drug loaded mPEG1000-Chrysin nanoparticles was 4.4 μg/mL, which was much lower than that of drug loaded mPEG2000-Chrysin nanoparticles (6.8 μg/mL). These nanoparticles provided a new strategy for fabricating antitumor drug delivery systems.

Ultrasound accelerated gelation of novel L-lysine based hydrogelators

We reported a novel hydrogelator with L-lysine as a linker to connect 7-carboxyl methoxycoumarin and hydrazine as lipophilic and water-soluble moieties. Ultrasound accelerated the gelation and induced homogenous self-assembly of fibrils into entangled 3D networks. The hydrogel exhibits great potential for future biomedical applications.

Anticancer drug delivery of PEG based micelles with small lipophilic moieties.

Herein, we reported a new type of self-assembly micelles based on amphiphilic polymers of cinnamate and coumarin derivatives modified PEG for drug delivery applications. Lipophilic cinnamic acid (CIN) and 7-carboxyl methoxycoumarin (COU) were immobilized on the terminal groups of poly(ethylene glycol) (PEG) to prepare amphiphiles. The amphiphiles self-assembled into micelles. The amphiphiles and micelles were characterized by (1)H NMR, FT-IR, DLS and TEM. Doxorubicin (DOX) was used as a model drug to investigate the lipophilic moieties effects on the drug release behaviors. The DOX loaded micelles were incubated with HepG2 liver cancer cells to study the in vitro anticancer activities. The results showed that DOX could be encapsulated in the micelles efficiently. The mean diameter of the drug loaded micelles was around 100 nm. Drug release profile revealed that the release rate of DOX loaded COU-PEG-COU micelles was significantly slower than that of CIN-PEG-CIN micelles. The DOX loaded micelles could be internalized in HepG2 cells. Both CLSM and flow cytometry results showed that the DOX loaded CIN-PEG-CIN micelles exhibited better anticancer efficacy.

Polymeric micelles with π–π conjugated moiety on glycerol dendrimer as lipophilic segments for anticancer drug delivery

Polymeric micelles are important nanovehicles for anticancer drug delivery. The lipophilic segment in polymeric micelles is an important factor to affect the drug loading properties. In our previous work, we found that small molecules with π-π conjugated structures could be used to replace hydrophobic polymeric chains as lipophilic segments for anticancer drug delivery. Herein, we report a novel polymeric micelle with π-π conjugated cinnamate moiety on glycerol dendrimer as lipophilic segment, the modified dendritic segment was connected to poly(ethylene glycol) (PEG) via click chemistry. The received amphiphiles self-assembled into micelles in aqueous medium. The properties of the polymeric micelles such as critical micelle concentration (CMC), mean size and morphology were investigated. Anticancer drug doxorubicin (DOX) was loaded in the polymeric micelles. The π-π interaction, drug release profile and in vitro anticancer efficiency of the DOX loaded micelles were studied. The results showed that the micelles with more cinnamate moieties exhibited a lower CMC. The drug loading content and release rate of the micelles increased with increasing generation of glycerol dendrimer. Strong π-π stacking interaction was detected between DOX and carriers. The DOX loaded polymeric micelles exhibited efficient anticancer activity in vitro.

Arginine modified polymeric micelles as a novel drug delivery system with enhanced endocytosis efficiency.

A new drug delivery system with improved endocytosis efficiency based on arginine modified poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-PCL) diblock copolymers was developed successfully. The structures of amphiphilic copolymers were verified by proton Nuclear Magnetic Resonance (1H NMR), Fourier Transform Infrared (FTIR) and Gel Permeation Chromatography (GPC). The amphiphilic copolymers could self-assemble into spherical micelles with critical micelle concentration (CMC) at approximately 0.03mg/mL. Biocompatibility, cellular internalization efficiency and in vitro antitumor effect of the polymeric micelles were studied. Results showed that drug-free micelles were nontoxic to cells. The Confocal Laser Microscopy (CLSM) and the flow cytometry as well as the antitumor activity tests all revealed that drug-loaded micelles modified by arginine groups (guanidino) exhibited higher endocytosis efficiency than those without modification, resulting in a lower IC50 value to kill tumor cells and meanwhile averting the competitive binding problem. Also, in vivo results demonstrated that arginine modified polymeric micelles could deliver the drug to tumor site more efficiently than ones without any modification, thus indicating guanidino in polymeric micelles could benefit the internalization of micelles to fully exert the function of killing tumors. In general, guanidinylation strategy in this splendid novel micelle system has a great potential to improve the therapeutic effect of nanoparticle-based drug delivery system for cancer therapy in the future.

Studies on the degradation of poly(L-lactide-r-trimethene carbonate) copolymers

Biodegradable poly(L-lactide-r-trimethene carbonate) copolymers (P(LLA-co-TMC)) with different compositions were synthesized. The degradation of the copolymers was carried out in phosphate buffer saline solutions (pH = 7.4) at 37 °C. The compositions, structure and properties of the copolymers in degradation were characterized with 1H-NMR, DSC, XRD, GPC, and SEM. The weight loss of the P(LLA-co-TMC) 50/50 was much faster than that of P(LLA-co-TMC) 85/15 and PLLA homopolymer. Interestingly, though the molecular weight of the compolymers decreased greatly during degradation, the compositions were rarely varied. After long time degradation, the PLLA segments were induced to crystallize in the P(LLA-co-TMC) 85/15 copolymer. The SEM observation of the surface and cross-section of P(LLA-co-TMC) 85/15 copolymer films found it was similar to the bulk degradation of PLLA homopolymer.

A reactive oxygen species–responsive prodrug micelle with efficient cellular uptake and excellent bioavailability

Stimuli-responsive polymeric drug delivery systems are of great interest in anticancer research. Here, a reactive oxygen species (ROS)-responsive prodrug was prepared by thioketal linkage of poly(ethylene glycol) (PEG) and the anticancer drug doxorubicin (DOX). The ROS-responsive property of the prodrug was confirmed by dynamic light scattering and 1H NMR. The prodrug was then used as a drug carrier to further load DOX, to form a DOX-loaded prodrug micelle, which showed dual ROS and pH-responsive release behaviors. The prodrug micelle exhibited rapid intracellular uptake. Interestingly, the in vitro anticancer activity of the ROS-responsive prodrug micelle was better than that of the DOX-loaded prodrug micelle because of its faster cellular uptake and better bioavailability. However, both the ROS-responsive prodrug and drug-loaded prodrug micelles showed better anticancer efficacy than a non-responsive DOX-loaded poly(ethylene glycol)-block-polycaprolactone (PEG2k-PCL5k) micelle. Consistent results were obtained in in vivo animal experiments as the antitumor efficacy of the prodrug micelle was superior to that of the DOX-loaded prodrug micelle. Both micelles showed negligible systemic toxicity in vivo.

A reactive oxygen species (ROS)-responsive low molecular weight gel co-loaded with doxorubicin and Zn(II) phthalocyanine tetrasulfonic acid for combined chemo-photodynamic therapy

Low molecular weight gels (LMWGs) have significant advantages in drug delivery such as high drug loading capacity, in situ delivery of drug to the lesion site, sustaining drug release with excellent bioavailability, and minimized side effects. Here, we synthesized a reactive oxygen species (ROS)-responsive gelator to prepare an injectable gel. An anticancer drug, doxorubicin hydrochloride (DOX), and a photosensitizer, Zn(ii) phthalocyanine tetrasulfonic acid (ZnPCS4), were loaded into the gel for combined chemo-photodynamic therapy. The ROS-responsive gelator was characterized by proton nuclear magnetic resonance (1H NMR) and the morphology of gels was investigated by scanning electron microscopy (SEM). The rheological properties and destruction-recovery capability of both blank and drug-loaded gels were studied. The cytotoxicity of LMWGs against 3T3 fibroblasts and 4T1 breast cancer cells was tested. The in vitro drug release of both drugs was studied and the in vivo anticancer activities of DOX-ZnPCS4-coloaded LMWGs were investigated in tumor-bearing mice. The results revealed that the injectable ROS-responsive DOX-ZnPCS4-coloaded LMWGs exhibited excellent anti-tumor efficacy by a synergistic therapy.

Synthesis, characterization, and crystallization of biodegradable poly(ε-caprolactone)-poly(L-lactide) diblock copolymers

Abstract Three diblock copolymers of PCL6k-PLLA2k, PCL6k-PLLA4k, and PCL6k-PLLA6k were prepared and their crystallization behaviors were investigated. The molecular weights of the copolymers calculated from 1H nuclear magnetic resonance spectra were equivalent to the designed molecular weights. The gel permeation chromatography spectra of the copolymers showed one peak, which revealed that the copolymers were monodisperse. The crystallization capability of poly(ε-caprolactone) (PCL) decreased and that of poly(L-lactide) (PLLA) increased when the molecular weight of the PLLA block was increased from 2k to 6k. PCL spherulites in the PCL6k-PLLA2k copolymer film were smaller than those in PCL6k-PLLA4k or PCL6k-PLLA6k copolymer film. PCL spherulites in the PCL6k-PLLA2k copolymer film grew fastest within all three diblock copolymers. An obvious phase separation phenomenon was observed on the surface of PCL6k-PLLA6k copolymer film in atomic force microscopy images.

Synthesis, characterization, and property of biodegradable PEG-PCL-PLA terpolymers with miktoarm star and triblock architectures as drug carriers

A series of amphiphilic terpolymers with miktoarm star and triblock architectures of poly(ethylene glycol) (PEG), poly(ε-caprolactone) (PCL) and poly(l-lactide acid) (PLLA) or poly(DL-lactide acid) (PDLLA) terpolymers were synthesized as carriers for drug delivery. The architecture, molecular weight and crystallization behavior of the terpolymers were characterized. Anticancer drug doxorubicin was encapsulated in the micelles to investigate their drug loading properties. The miktoarm star terpolymers exhibited stronger crystallization capability, smaller size and better stability than that of triblock polymeric micelle, owing to the lower CMC values of miktoarm star polymeric micelle. Furthermore, the drug-loaded miktoarm star polymeric micelles showed the cumulative DOX release account of the micelles with PDLLA blocks was 65.3% while the release account of the corresponding micelles containing PLLA blocks was 45.2%. The IC50 values of drug-loaded miktoarm star polymeric micelle were lower than triblock polymeric micelle. Meanwhile, Confocal laser scanning microscopy (CLSM) and Flow Cytometry results demonstrated that the miktoarm star micelles were more favorable for cellular internalization. The miktoarm star micelles with PDLLA blocks were promising carriers for anticancer drug delivery.