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• A novel multifunctional bioreductive linker based on 2-nitroimidazole was designed and synthesized. • It's application in SN-38 prodrug design was proven to be successful. • Preliminary screening for reduction-mediated cleavage and specific hypoxia cytotoxity. Tumor hypoxia has been widely explored over the years as a diagnostic and therapeutic marker. Herein, we designed, optimized and synthesized a new multifunctional bioreductive linker (12) containing an alkynyl group (potential click chemistry fragment); the linker is based on 2-nitroimidazole which was expected to simultaneously overcome the drawbacks of hypoxia-activated prodrugs (poor selectivity and unsatisfactory water solubility). Furthermore, a hypoxia-activated, water-soluble SN-38 prodrug was obtained, and it was stable under physiological conditions and was rapidly released as an active drug under hypoxic conditions. [ABSTRACT FROM AUTHOR]

Graphical abstract In vitro hydrolysis, co-prodrug 1a could release PTX and SAHA more efficiently and was further prepared to nanomicelles with mPEG2000-PLA1750. 1a nanomicelles had a comparable or even better cytotoxicity than PTX especially in the drug-resistant MCF-7/ADR cells. Highlights • Design of PTX and SAHA co-prodrugs are based on the synergistic antitumor effect. • In this study, we successfully bound PTX and SAHA to form co-prodrugs 1a and 1b. • 1a was further prepared to nanomicelles with mPEG 2000 -PLA 1750 as the carrier. • PTX-SAHA co-prodrug nanomicelles are promising for treatment of drug-fast cancer. Abstract Paclitaxel (PTX) is the first-line treatment drug for breast cancer. However, drug resistance after a course of treatment and low selectivity restricted its clinical utility sometimes. In this study, we successfully bound PTX and vorinostat (SAHA) to form co-prodrugs based on the synergistic anticancer effects. The PTX-SAHA co-prodrugs were conjugated by glycine (1a) and succinic acid (1b) respectively and the former has shown better activity in cytotoxicity, cell cycle arrest and western-blot experiments. Therefore, 1a was further prepared to nanomicelles with mPEG 2000 -PLA 1750 as the carrier by using thin film method. PTX-SAHA co-prodrug nanomicelles were spherical with a particle size of 20–100 nm. In vitro drug release test showed 1a nanomicelles had sustained release effect, which could reduce the resistance of PTX. In vitro cytotoxicity was evaluated by SRB assay in HCT-116 cells, MCF-7 cells and drug-resistant MCF-7/ADR cells. The results showed 1a nanomicelles had comparable or even better cytotoxicity than PTX especially in the MCF-7/ADR cells. All the results suggested that PTX-SAHA co-prodrug nanomicelles were promising treatment for PTX resistance cancer. [ABSTRACT FROM AUTHOR]

Graphical abstract Schematic diagram of the self-delivery of Janus nano-prodrug CPT-SS-GEM nanoparticles. Abstract A carrier-free and reduction-degradable Janus prodrug, termed as CPT-SS-GEM, was fabricated by redox-sensitive disulfide bond linked gemcitabine and camptothecin. This amphiphilic prodrug showed high drug loading capacity, 42.6% of CPT and 32.2% of GEM, respectively. Benefiting from its amphiphilic property, CPT-SS-GEM prodrug could self-assemble into Janus nano-prodrug in water without aid of any excipient. The morphology of the nano-prodrug was spherical particle confirmed by TEM. The rapid drug release from the nano-prodrug proceeded in a reduction-dependent manner, more than 90% of the native CPT and GEM were released in the mimic microenvironment of tumor cells (pH 6.5 PBS containing 2 mM DTT) within a period of 3 h. The concurrent and ratio-metric release of CPT and GEM endowed the Janus nano-prodrug CPT-SS-GEM with pronounced in vitro synergistic antiproliferative effect in multiple cancer cell lines when the inhibition rate of cancer cell proliferation exceeded 50%, including A549, NCI-H460, HCT116, HT-29, and MCF-7/ADR. The combination index values showed as followings, 1.04–0.4 (A549), 0.24–0.60 (NCI-H460), 0.42–0.16 (HCT116), 1.98–0.15 (HT-29), 0.36–0.19 (MCF-7/ADR). Taken together, the carrier-free, redox-sensitive Janus nano-prodrug CPT-SS-GEM is a promising candidate as synergistic combination of chemotherapeutics. [ABSTRACT FROM AUTHOR]

A novel pH-sensitive polymeric prodrug of camptothecin (CPT) by polymerizing γ-camptothecin-glutamate N-carboxyanhydride (Glu (CPT)-NCA) on boronate ester-linked poly (ethyleneglycol) (PEG) directly via the amine-initiated ring open polymerization (ROP) has been developed. The resulting amphiphilic prodrug (mPEG-BC-PGluCPT) could self-assemble into nanoparticles and encapsulate doxorubicin (Dox) simultaneously in aqueous solution for dual-drug delivery. The formation of polymeric prodrug micelles (mPEG-BC@PGluCPT) was confirmed by the measurements of critical aggregation concentration (CAC), particle size, and morphology observations. The mPEG-BC@PGluCPT micelles were colloidally stable in solutions for two weeks. Polymeric prodrug micelles mPEG-BC@PGluCPT and Dox-loaded micelles mPEG-BC@PGluCPT⋅Dox showed sustained drug release profiles over 48 h. As expected, drug release was accelerated by the decreasement of pH value from 7.4 to 6.0, which demonstrated pH-dependent manner of drug release. Additionally, it was found that cellular uptake of mPEG-BC@PGluCPT⋅Dox micelles on HepG2 cells was higher than that on HL-7702 cells, especially in culture medium at pH 6.0. The enhanced cellular uptake of mPEG-BC@PGluCPT⋅Dox micelles under acidic condition on HepG2 cells resulted in the higher cytotoxicity of mPEG-BC@PGluCPT⋅Dox micelles at acidic pH than that at pH 7.4. [ABSTRACT FROM PUBLISHER]

Gemcitabine, 2′,2′-difluoro-2′-deoxycytidine (dFdC), is the first-line antitumor agent in the treatment of pancreatic tumors. However, it possesses certain drawbacks, such as poor biological half-life resulted from rapid metabolism and the induction of resistance, leading to its restricted therapeutic potential. With the purpose of overcoming the above drawbacks, we developed a novel VESylated gemcitabine (VES-dFdC) prodrug by coupling the N 4 -amino group of the pyrimidine ring of dFdC to the carboxylic group of vitamin E succinate (VES). The resulting amphiphilic compound could protect the N 4 -amino group of the pyrimidine ring of dFdC from being degraded by cytidine deaminase. What is more, the prodrug was able to form nanocapsules in aqueous media (similar to the structure of cytomembrane), confirmed by transmission electron microscope (TEM). Their average particle size is about 107 nm with zeta potential of −33.4 mV measured by dynamic light scattering (DLS). VES-dFdC nanocapsules showed accelerated accumulative drug release profile in simulated lysosome environment (sodium acetate buffer pH 5 + cathepsin B, an enzyme in lysosome), due to the easily hydrolyzed property of amide bond by cathepsin B, while rather stable in PBS (pH 7.4) or sodium acetate buffer (pH 5.0) without cathepsin B, indicating their enhanced intracellular drug controlled release manner. Besides, VES-dFdC prodrug nanocapsules showed enhanced cellular uptake ability, and the amount of cellular uptake of the nanocapsules by the pancreatic cancer cell line BxPC-3 is seventy times higher than that of native gemcitabine in the first 1.5 h. Compared with free gemcitabine, VES-dFdC nanocapsules showed essentially increased growth inhibition activity against BxPC-3 cells, indicating its great potential as prodrug for pancreatic tumor therapy with improved antitumor activity. [ABSTRACT FROM AUTHOR]

Highlights: [•] mPEGylated artesunate amphiphilic conjugate was prepared through esterification. [•] The mPEG–ART conjugate was inclined to form nanocapsules in aqueous media. [•] The nanocapsules was biodegradation due to the easily hydrolyzed property of ester bond by esterase, which is abundant in cells. [•] The nanocapsules showed decreased cytotoxicity against L1210 and MCF7 cell line compared with free ART. [ABSTRACT FROM AUTHOR]

Abstract: Surface modification of nanoparticles with poly (ethylene glycol) (PEG) shows poor cellular uptake, although it affords long circulation time and passive targeting potential to the tumor tissue. In this research, poly(ethylene glycol) shell-sheddable nanomicelle prodrug of camptothecin (CPT) was developed, in order to enhance the cellular uptake ability, achieve the passive targeting potential to tumor tissue and long circulation time, and to improve the stability of CPT in aqueous media. Firstly, the five-member rings in poly (l-succinimide) (PSI) were successively opened by the amino terminated disulfide-linked poly (ethylene glycol) monomethyl ether (mPEG-SS-NH2) and 6-aminocaproic acid to produce the graft copolymer of mPEG-SS-NH-g-PHAsp. And then, the resultant prodrug of mPEG-SS-NH-g-PHAsp-CPT was obtained by the esterification between carboxylic groups of mPEG-SS-NH-g-PHAsp and 20-OH of CPT. The prodrug was able to form spherical micelles in aqueous media because of its amphiphilic nature with average particle size of about 100nm measured by dynamic light scattering (DLS), suggesting its passive targeting potential to tumor tissue. Due to the detachment of PEG shell in the presence of dithiothreitol (DTT), the nanomicelle showed a tendency to aggregation, intense release of CPT, and enhanced cellular uptake ability. Also, the mPEG-SS-NH-g-PHAsp-CPT nanomicelle effectively protected the active lactone ring of CPT from hydrolysis under physiological condition. Compared with free CPT, mPEG-SS-NH-g-PHAsp-CPT nanomicelle showed essentially decreased cytotoxicity against L929 cell line in 24h, especially at high dosage, indicating its great potential as tumor tissue targeted prodrug. [Copyright &y& Elsevier]

Abstract: To enhance the stability and long-term circulation of camptothecin (CPT), mPEGylated α,β-poly (l-aspartic acid)-CPT conjugates were synthesized, and used to fabricate nanomicelle. Firstly, α,β-poly (l-aspartic acid) derivative (PAA-der) containing alkyne groups was synthesized via the ring-opening of PSI with propargyl amine. And then, azide-functionalized CPT derivatives (CPT-N3) and azide-terminated poly (ethylene glycol) methyl ether (mPEG-N3) were conjugated with PAA-der by click cycloaddition to give mPEG-graft-PAA-CPT conjugates. The formation of mPEG-graft-PAA-CPT nanomicelles was confirmed by fluorescence spectrophotoscopy and particle size measurements. It was found that all the nanomicelles showed spherical shapes with size about 178nm. MPEG-graft-PAA-CPT nanomicelles showed good storage stability, even incubation at 37°C for 60 days, and improved the stability of CPT lactone form in aqueous media. A steady release rate of CPT was kept for 72h, suggested the great potential of mPEG-graft-PAA-CPT nanomicelles as polymer prodrug of CPT. [ABSTRACT FROM AUTHOR]

Abstract: This research is aimed to develop a nanomicelle delivery system in order to enhance the solubility and stability of camptothecin (CPT) in aqueous media. In this case, α,β-poly[(N-carboxybutyl)-l-aspartamide] (PBAsp)–CPT was conjugated by the esterification between PBAsp and 20-OH of CPT, and hence used to fabricate nanomicelles with a particle size between the pore size of blood capillary in normal tissue and that in tumor tissue. It was worthy of note that the drug-loaded system of PBAsp–CPT nanomicelle improved the solubility and stability of CPT in aqueous media. However, with an increase of the CPT loading in PBAsp–CPT, the solubility sharply decreased. Meanwhile, the sizes of PBAsp–CPT nanomicelles showed a tendency of increase. Moreover, the drug release of PBAsp–CPT nanomicelles displayed a linear sustaining profile, and hence resulted in the essential decrease of cytotoxicity to L929 cell line. The assembled nanomicelles based on the PBAsp–CPT conjugates showed a great potential as polymer prodrug of tumor therapy, and the controlled nano-scale might achieve the passive tumor targeting. [Copyright &y& Elsevier]