Rui Wang

Co-delivery of daunomycin and oxaliplatin by biodegradable polymers for safer and more efficacious combination therapy

An oxaliplatin pro-drug (Oxa(IV)-COOH) with an axial carboxyl group was synthesized and conjugated to biodegradable polymers with pendant hydroxyl groups to prepare polymer-Oxa(IV) conjugates. A hydrophobic anthracycline-based drug, daunorubicin (DRB) was conjugated to similar biodegradable polymers with carboxyl groups to synthesize polymer-DRB conjugates. The two drug conjugates have the similar polymer backbone and are amphiphilic; thus, they can co-assemble into composite micelles. In the composite micelles, the polymer-Oxa(IV) conjugates can release clinically widely used water soluble anticancer drug oxaliplatin (Oxa(II)) upon reduction, while polymer-DRB conjugate is thought to release DRB via acid hydrolysis in the cancer cells. In this way, combination of the hydrophilic platinum drug Oxa(II) and hydrophobic drug DRB can be realized by delivering them in one platform. Moreover, the composite micelles showed reduced systematic toxicity and greater synergistic effect than combination of small molecules of the two anticancer drugs both in vitro and in vivo; thus, this polymer based combination therapy can be useful in future clinic application.

A novel nanosilica/graphene oxide hybrid and its flame retarding epoxy resin with simultaneously improved mechanical, thermal conductivity, and dielectric properties

Graphene is regarded as a prominent multi-functional flame retardant for use in halogen-free flame retardant polymers with simultaneously improved integrated properties and special functionalities. However, its flame retardant efficiency is not impressive enough due to the weak resistance to thermo-oxidative decomposition. In order to overcome this problem, the surface of graphene oxide was covered with large amounts of non-flammable silicas through a sol–gel and surface treatment process, and then used to modify the epoxy (EP) resin. Results show that the incorporation of the as-prepared nanosilica/graphene oxide (m-SGO) hybrid into EP resin not only obviously increases the flame retardancy, mechanical, and thermal stability properties, but also endows EP resin with high thermal conductivity, low dielectric loss, and high dielectric constant. Specifically, the peaks of the heat release rate and total heat release of the modified EP resin with 1.5% m-SGO decrease by 39% and 10% of those of neat EP resin, respectively. These attractive features of m-SGO/EP nanocomposites are attributed to the unique structure and high resistance to oxidative degradation of m-SGO as well as its good interactions with EP resin. The investigation provides a new approach for the preparation of novel core–shell flame retardants through surface wrapping with other flame retardants on SGO and related high performance flame retardant resins.

Transferrin-Conjugated Micelles: Enhanced Accumulation and Antitumor Effect for Transferrin-Receptor-Overexpressing Cancer Models

As the transport protein for iron, transferrin can trigger cellular endocytosis once binding to its receptor (TfR) on the cell membrane. Using this property, we conjugated transferrin onto the surface of biodegradable polymeric micelles constructed from amphiphilic block copolymers. The core of micelle was either labeled with a near-infrared dye (NIR) or conjugated with a chemotherapeutic drug paclitaxel (PTX) to study the biodistribution or antitumor effect in nude mice bearing subcutaneous TfR-overexpressing cancers. DLS and TEM showed that the sizes of Tf-conjugated and Tf-free micelles were in the range of 85-110 nm. Confocal laser scanning microscopy and flow cytometry experiments indicated that the uptake efficiency of the micelles by the TfR-overexpressing cells was enhanced by Tf conjugation. Semiquantitative analysis of the NIR signals collected from the tumor site showed that the maximum accumulation was achieved at 28 h in the M(NIR) group, while at 22 h in Tf-M(NIR) groups; and the area under the intensity curve in the Tf-M(NIR) groups was more than that in M(NIR) group. Finally, the tumor inhibition effects of targeting micelles were studied with the gastric carcinoma model which overexpressed TfR. The analysis of tumor volumes and the observation of H&E-stained tumor sections showed that Tf-M(PTX) had the best antitumor effect compared with the control groups (saline, PTX, and M(PTX)). The results of this study demonstrated the potential application of Tf-conjugated polymeric micelles in the treatment of TfR-overexpressing cancers.

The use of polymeric platinum(IV) prodrugs to deliver multinuclear platinum(II) drugs with reduced systemic toxicity and enhanced antitumor efficacy

Two dinuclear platinum(IV) prodrugs were prepared from cisplatin and oxaliplatin, and tethered to amphiphilic biodegradable block copolymers. The polymeric dinuclear platinum(IV) prodrugs were allowed to self-assemble into nanomicelles, which showed reduced systemic toxicity, relatively long blood circulation, and enhanced antitumor efficacy. In this way, the bottleneck of present multinuclear platinum drugs, especially their severe systemic toxicity, might be overcome.

Reduction-responsive shell-crosslinked micelles prepared from Y-shaped amphiphilic block copolymers as a drug carrier

Biodegradable Y-shaped amphiphilic block copolymer mPEG-b-PLG-b-(PLA)2 was synthesized and characterized by 1H NMR and FTIR. The amphiphilic property of the copolymer with a mPEG-b-PLG segment as the hydrophilic arm and two PLA segments as the hydrophobic arms endows the copolymer with the ability to form core–shell nanoparticles in aqueous solution. Co-assembly of doxorubicin (Dox) and the block copolymer in selective solvent was carried out to prepare Dox-loaded micelles. The inner-shell (PLG) of the micelle was crosslinked through a carbodiimide coupling method with cystamine as the crosslinker. The crosslinked micelles exhibit reduction-responsive release of Dox and the stability in vitro was much better than non-crosslinked micelles. In acidic release condition, the total amount of Dox released could be increased due to the increased solubility of Dox. The blood clearance of Dox in different form of micelles was studied and the results show that Dox loaded in the crosslinked micelles with PEG5K as the outer shell exhibit the longest blood circulation after intravenous injection.

Targeting and anti-tumor effect of folic acid-labeled polymer–Doxorubicin conjugates with pH-sensitive hydrazone linker

Multifunctional micelles were successfully prepared by co-assembling a Doxorubicin-conjugated copolymer (mPEG-b-P(LA-co-ME/Dox), for antitumor properties) and a Rhodamine B-conjugated copolymer (mPEG-b-P(LA-co-ME/RhB), for imaging) with a folic acid (FA)-conjugated copolymer (FA-PEG-b-PLA, for targeting), respectively. DLS showed that the sizes of these micelles were in the range of 150–300 nm. Fluorescent imaging analysis based on the RhB signals of the isolated visceral organs showed that the micelles with or without FA moieties were mainly accumulated in the liver and in the tumor from 2 h post drug administration, maximized at ca. 6 h, and decayed afterwards. More FA-carrying micelles were accumulated in the tumor for a longer time compared to the micelles without FA moieties. Dox-containing micelles were used for tumor inhibition experiments in vivo and the results showed that the micelles with FA moieties exhibited better antitumor efficacy than those without FA and free Dox.

Multifunctional Pt(IV) pro-drug and its micellar platform: to kill two birds with one stone

A multifunctional hybrid platinum(iv) drug which has both DCA and Pt in one molecule was synthesized and tethered to polymers to further self-assemble into micelles. This micelle-mediated delivery of platinum(iv) prodrug aims to target both nuclear DNA and mitochondria.

Biological Characterization of Folate-Decorated Biodegradable Polymer–Platinum(II) Complex Micelles

A biodegradable and amphiphilic copolymer, poly(ethylene glycol)-block-poly(l-lactide-co-2-methyl-2-carboxyl-propylene carbonate) (mPEG-b-P(LA-co-MCC)), which contains pendant carboxyl groups, was chosen as a drug carrier for the active anticancer part (diaminocyclohexane platinum, DACH-Pt) of oxaliplatin to form mPEG-b-P(LA-co-MCC/Pt) complex. A folic acid-conjugated copolymer, folic acid-poly(ethylene glycol)-block-poly(L-lactide) (FA-PEG-PLA), with similar chemical structure was chosen for targeting. Multifunctional micelles were successfully prepared by a coassembling method. In vitro evaluation was performed by using SKOV-3 and MCF-7 cancer cells. In vivo blood clearance of platinum was studied, and the results show that micelles exhibit longer blood circulation after iv injection. Pt biodistribution was studied by measuring its levels in plasma, organs, and tumors, especially in tumor cell DNA, by atomic absorption and inductively coupled plasma mass spectrometry. Antitumor activity was assessed in mice bearing H22 liver cancers, and the results showed that the micelles with FA moieties exhibited greater antitumor efficacy than those without FA or oxaliplatin. Therefore, these novel multifunctional platinum micelles have great potential in future clinical application.

A cross-linked polymeric micellar delivery system for cisplatin(IV) complex

A polymeric cisplatin(IV) prodrug in the form of cross-linked micelles (M(Pt(IV)) was prepared by first constructing MPEG-b-PCL-b-PLL micelles and then attaching a cisplatin(IV) complex with two axial succinic moieties to the lysine residues of the carrier polymer in aqueous medium. The micelles obtained were characterized by TEM, DLS, and zeta potential measurement. Their in vitro release experiments were carried out at pH 7.4 and 5.0 or in the presence of 5mM sodium ascorbate (NaAsc). Results showed that the micelles were sensitive to both acidic hydrolysis and mild reducing agents; in the presence of 5mM NaAsc, cisplatin(II) was directly released and the released cisplatin(II) could chelate with nucleobases; the micelles displayed comparable cytotoxicities to cisplatin; and the micelles were much more efficiently internalized by the cells than cisplatin(II) and cisplatin(IV) counterparts. Moreover, in vivo study showed accumulation of more Pt species in the tumor site and lower systematic toxicity compared to free cisplatin(II) and cisplatin(IV). This polymeric prodrug of cisplatin is expected to be used more for future study and applications.

Folate-targeted paclitaxel-conjugated polymeric micelles inhibits pulmonary metastatic hepatoma in experimental murine H22 metastasis models

Hepatocellular carcinoma shows low response to most conventional chemotherapies; additionally, extrahepatic metastasis from hepatoma is considered refractory to conventional systemic chemotherapy. Target therapy is a promising strategy for advanced hepatoma; however, targeted accumulation and controlled release of therapeutic agents into the metastatic site is still a great challenge. Folic acid (FA) and paclitaxel (PTX) containing composite micelles (FA-M[PTX]) were prepared by coassembling the FA polymer conjugate and PTX polymer conjugate. The main purpose of this study is to investigate the inhibitory efficacy of FA-M(PTX) on the pulmonary metastasis of intravenously injected murine hepatoma 22 (H22) on BALB/c mice models. The lung metastatic burden of H22 were measured and tissues were analyzed by immunohistochemistry and histology (hematoxylin and eosin stain), followed by survival analysis. The results indicated that FA-M(PTX) prevented pulmonary metastasis of H22, and the efficacy was stronger than pure PTX and simple PTX-conjugated micelles. In particular, the formation of lung metastasis colonies in mice was evidently inhibited, which was paralleled with the downregulated expression of matrix metalloproteinase-2 and matrix metalloproteinase-9. Furthermore, the mice bearing pulmonary metastatic hepatoma in the FA-M(PTX) group gained significantly prolonged survival time when compared with others given equivalent doses of PTX of 30 mg/kg. The enhanced efficacy of FA-M(PTX) is theoretically ascribed to the target effect of FA; moreover, the extensive pulmonary capillary networks may play a role. In conclusion, FA-M(PTX) displayed great potential as a promising antimetastatic agent, and the FA-conjugated micelles is a preferential targeted delivery system when compared to micelles without FA.