Ruogu Qi

Biodegradable polymer - cisplatin(IV) conjugate as a pro-drug of cisplatin(II)

A Pt(IV) complex was covalently conjugated to a new biodegradable amphiphilic tri-block copolymer, MPEG-b-PCL-b-PLL, which contains pendant amino groups, to form a polymeric pro-drug of cisplatin(II), MPEG-b-PCL-b-PLL/Pt(IV). The conjugate was assembled into nano-micelles. The Pt(IV) complex, the polymer carrier and the conjugate were characterized systematically. In vitro release experiments showed that drug release from the polymer-Pt(IV) micelles follows an acid responsive and oxidation-reduction sensitive kinetics. HPLC-ICP-MS analysis revealed that cisplatin(II) can be released from the conjugate under an acidic plus a reductive condition which is available inside a cancerous cell. In vitro MTT assay demonstrated that the polymer-Pt(IV) micelles display higher cytotoxicity against SKOV-3 tumor cells than both cisplatin(II) and Pt(IV) complex. This enhanced cytotoxicity is attributed to effective internalization of the micelles by the cells via endocytosis mechanism, which was observed by fluorescence imaging and by direct determination of the platinum uptake by the cells. This polymer-Pt(IV) conjugate is a promising polymeric pro-drug of cisplatin in micellar form. It can protect the Pt(IV) complex against blood clearance. It can enter cancerous cells via endocytosis mechanism and then cisplatin(II) can be released. Therefore, this polymeric pro-drug of cisplatin is expected to find clinical applications in the future.

A prodrug strategy to deliver cisplatin(IV) and paclitaxel in nanomicelles to improve efficacy and tolerance

A strategy of preparing composite micelles containing both cisplatin(IV) prodrug and paclitaxel was developed, i.e., synthesizing a cisplatin(IV) conjugate and a paclitaxel conjugate starting with the same biodegradable and amphiphilic block copolymer, and co-assembling the two conjugates. The composite micelles could release effective anticancer drug cisplatin(II) upon cellular reduction and PTX via acid hydrolysis once they came into the cancerous cells. Moreover, the composite micelles displayed synergistic effect in vitro and the combination therapy in micellar dosage-form led to reduced systematic toxicity and enhanced antitumor efficacy in vivo.

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.

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.

Porous heterogeneous organic photocatalyst prepared by HIPE polymerization for oxidation of sulfides under visible light

A porous heterogeneous photocatalyst was prepared by high internal phase emulsion (HIPE) polymerization. Such porous materials have interconnected pores and enough active moieties for photocatalysis. The material demonstrated a very high catalytic efficiency and can be reused for photocatalyzed oxidation of thioanisole under visible light.

Iodo-BODIPY: a visible-light-driven, highly efficient and photostable metal-free organic photocatalyst

Boron-dipyrromethene (BODIPY) compounds have been used extensively. However, their application in photocatalysis has not been well-studied. In this report, iodo-BODIPYs were utilized as visible-light-driven photocatalysts. They demonstrated very high catalytic efficiencies and reaction rates for the photocatalyzed oxidation of thioanisole under visible light.

Design and delivery of camplatin to overcome cisplatin drug resistance

Camplatin, a prodrug formed via coining camphoric anhydride and cisplatin, was delivered in biodegradable nanoparticles. This camphoric acid and cisplatin co-delivery system exhibited enhanced anticancer activity compared to cisplatin and has successfully overcome cisplatin drug resistance.

Delivery of active DACH-Pt anticancer species by biodegradable amphiphilic polymers using thiol-ene radical addition.

A biodegradable and amphiphilic copolymer, mPEG-b-P(LA-co-MAC/TMA) that contains pendant 1,2-bidentate carboxyl groups is synthesized by thiol-ene radical addition and is further used to chelate with the active anticancer species (DACH-Pt) of oxaliplatin to form an mPEG-b-P(LA-co-MAC/TMA-Pt-DACH) complex. The polymer platinum complex can self-assemble into micelles. In vitro studies show that the DACH-Pt micelles display enhanced or comparable cytotoxicity against SKOV-3 and MCF-7 cancer cells, while they show reduced toxicity to HeLa cells compared with oxaliplatin.

Guanidinated amphiphilic cationic copolymer with enhanced gene delivery efficiency

The lack of safe and effective carriers for RNA interference therapeutics remains a barrier for its wide clinical application. In this study, guanidino groups were incorporated into poly(ethylene glycol)-block-poly(e-caprolactone)-block-poly(L-lysine) (mPEG-b-PCL-b-PLL, AG0) by simple replacement of the amino groups on PLL segments by the guanidino groups to enhance the transfection performance by mimicking the transmembrane function of cell penetrating peptides, such as TAT or other arginine-rich peptides. The guanidinated copolymers (AG1–AG3) displayed similar siRNA-binding capacity to AG0, but less cytotoxicity and higher silencing efficiency than AG0. Typically, AG3 with full replacement of the amino groups by guanidino groups exhibited higher silencing efficiency than PEI-25k and Lipofectamine 2000. Cell uptake and cell imaging experiments showed that the enhanced silencing efficiency of AG3–siRNA complex was due to the enhanced endocytosis cross the cell-membrane and the enhanced escape from the endosomes/lyosomes. The guanidino groups on the polylysine units were responsible for these enhancements although they are attached to the polymer backbone with a spacer of (CH2)4, in comparison with (CH2)3 in polyarginine. In conclusion, guanidination of mPEG-b-PCL-b-PLL resulted in a less toxic and more efficient siRNA vector and contribution of the guanidine groups to cell-membrane penetration and endosome/lyosome-membrane penetration was demonstrated. Therefore, replacement of the amino groups in conventional gene delivery vectors with guanidine groups might be a useful strategy of developing novel gene or drug delivery vectors.

A biodegradable polymer platform for co-delivery of clinically relevant oxaliplatin and gemcitabine

Anticancer drugs of gemcitabine and oxaliplatin combined in a clinic regimen (GEMOX regimen) were co-loaded to a biodegradable polymer platform for drug delivery.