Cleavability of Non-multiplicative Spaces and Arhangel'skii Problems

Arhangel' skit posed the problem:How a class of topological spaces has the orthogonality or cleavability? The partial solution on this problem has been obtained for the class of spaces which are multiplicative by Arhangel' skit, Bella and the others. In this paper we shall prove that some classes of generalized metric spaces which are non-multiplicative also have the orthogonality or cleavability.

Recent advances in construction of small molecule-based fluorophoredrug conjugates

As a powerful tool to advance drug discovery,molecular imaging may provide new insights into the process of drug effect and therapy at cellular and molecular levels.When compared with other detection methods,fluorescence-based strategies are highly attractive and can be used to illuminate pathways of drugs’transport,with multi-color capacity,high specificity and good sensitivity.The conjugates of fluorescent molecules and therapeutic agents create exciting avenues for real-time monitoring of drug delivery and distribution,both in vitro and in vivo.In this short review,we discuss recent developments of small molecule-based fluorophore-drug conjugates,including non-cleavable and cleavable ones,that are capable of visualizing drug delivery.

Cellular processing determinants for the activation of damage signals in response to topoisomerase I-linked DNA breakage

Recent studies have suggested an involvement of processing pathways for the initiation of cellular responses induced by topoisomerase-targeting drugs. Here, we showed that cellular exposure to camptothecin （CPT） induced formation of topoisomerase I cleavable complex （TOPlcc）, degradation of TOP1 and activation of DNA damage responses （DDR）. Transcription and proteasome-dependent proteolysis, but not replication, were involved in CPTo indneed TOPl degradation, while none of above three processing activities affected TOPlcc formation. Replication- and transcription-initiated proeessing （RIP and TIP） of TOPlee were identified as two independent pathways, which contribute distinctly to various CPT-activated DDR. Specifically, in cycling cells, RIP-processed TOPlec triggered the CPT-induced RPA pbosphorylation. At higher CPT dosages, the TIP pathway is required for other DDR activation, including ATM, p53 and Chkl/2 phosphorylation. The TIP pathway was further demonstrated to be S-phase independent by using three nonreplicating cell models. Furthermore, the effect of proteasome inhibitors mimicked that of transcription inhibition on the CPT-induced activation of DDR, suggesting the involvement of proteasome in the TIP pathway. Interestingly, the TIP pathway was important for TOPlcc-activated, but not ionization radiationactivated ATM, p53 and Chk2 phosphorylation. We have also found that pharmacological interferences of TIP and RIP pathways distinctively modulated the CPT-induced cell killing with treatments at low and high dosages, respec- tively. Together, our results support that both RIP and TIP pathways of TOPlcc are required for the activation of CPT-induced DDR and cytotoxicity.

Modular synthesis of a block copolymer with a cleavable linkage via “click” chemistry

A diblock copolymer poly(ethylene glycol)-block-polystyrene or PEG-b-PS with an olefinic double bond at the PEG and PS junction has been prepared by modular synthesis via"click"chemistry.This involved the synthesis of PS by atom transfer radical polymerization and the nucleophilic substitution of the terminal bromide group with azide to yield azide-terminated PS. PEG with an alkynyl terminal group was prepared from reacting carboxyl-end-functionalized PEG with 4-hydroxybut-2-enyl prop-2-ynyl succinate,which contained an alkynyl group as well as an olefin group.The PS and PEG polymers were linked via the 1,3-dipolar cycloaddition of the end azide and alkyne groups.The obtained copolymer was characterized by 1H NMR spectroscopy and size exclusion chromatography(SEC).SEC analysis indicated that the diblock copolymer produced could be readily cleaved by ozonolysis to regenerate the constituent homopolymers.

Synthesis of cleavable multi-functional mikto-arm star polymer by RAFT polymerization: example of an anti-cancer drug 7-ethyl-10-hydroxycamptothecin(SN-38) as functional moiety

Multi-functional mikto-arm star polymers containing three different arms [hydrophilic, SN-38-P（OEGMAs_9）11, cationizable, SN-38-P（DMAEMA）3s and hydrophobic, SN-38-P（BMA）26] were prepared by RAFT polymerization via an arm-first approach using a cleavable cross-linker. The star polymers were cleaved to the linear arms with tributylphosphine as a reducing agent. The decrease in molecular weight observed is consistent with the initial stars having approximately five arms, Blue fluorescence was observed when a solution of mikto-arm star was irradiated under a 365 nm light proving the retention of the SN-38 moiety during star formation by RAFT polymerization. Thus these polymer-drug conjugates can be considered as potential delivery vehicles for cancer therapy. The P（DMAEMA） arms can be quaternized using iodomethane, allowing star polymers to bind negatively charged small interfering RNA （siRNA） and potentially be used as a carrier for that material.