Platinum-based anticancer drugs occupy a crucial role in the treatment of various malignant tumours. However, the efficacy and applicability of platinum drugs are heavily restricted by severe ...systemic toxicities and drug resistance. Different drug targeting and delivery (DTD) strategies have been developed to prevent the shortcomings of platinum-based chemotherapy. These approaches can be roughly categorized into two groups; namely, active and passive tactics. Active DTD is realized through specific molecular interactions between the drugs and cell or tissue elements, while passive DTD is achieved by exploiting the enhanced permeability and retention effect in tumour tissues. The principal methods for active DTD include conjugation of platinum drugs with selective targeting moieties or encapsulation of platinum drugs in host molecules. Bioactive substances such as hormones, carbohydrates, bisphosphonates, peptides and proteins are commonly used in active DTD. Passive DTD generally involves the fabrication of functionalized polymers or nanoparticles and the subsequent conjugation of platinum drugs with such entities. Polymeric micelles, liposomes, nanotubes and nanoparticles are frequently used in passive DTD. In some cases, both active and passive mechanisms are involved in one DTD system. This review concentrates on various targeting and delivery techniques for improving the efficacy and reducing the side effects of platinum-based anticancer drugs. The content covers most of the related literatures published since 2006. These innovative tactics represent current state-of-the-art developments in platinum-based anticancer drugs.
Platinum-based anticancer drugs are the mainstay of chemotherapy regimens in clinic. Nevertheless, the efficacy of platinum drugs is badly affected by serious systemic toxicities and drug resistance, ...and the pharmacokinetics of most platinum drugs is largely unknown. In recent years, a keen interest in functionalizing platinum complexes with bioactive molecules, targeting groups, photosensitizers, fluorophores, or nanomaterials has been sparked among chemical and biomedical researchers. The motivation for functionalization comes from some of the following demands: to improve the tumor selectivity or minimize the systemic toxicity of the drugs, to enhance the cellular accumulation of the drugs, to overcome the tumor resistance to the drugs, to visualize the drug molecules in vitro or in vivo, to achieve a synergistic anticancer effect between different therapeutic modalities, or to add extra functionality to the drugs. In this Account, we present different strategies being used for functionalizing platinum complexes, including conjugation with bisphosphonates, peptides, receptor-specific ligands, polymers, nanoparticles, magnetic resonance imaging contrast agents, metal chelators, or photosensitizers. Among them, bisphosphonates, peptides, and receptor-specific ligands are used for actively targeted drug delivery, polymers and nanoparticles are for passively targeted drug delivery, magnetic resonance imaging contrast agents are for theranostic purposes, metal chelators are for the treatment or prevention of Alzheimer's disease (AD), and photosensitizers are for photodynamic therapy of cancers. The rationales behind these designs are explained and justified at the molecular or cellular level, associating with the requirements for diagnosis, therapy, and visualization of biological processes. To illustrate the wide range of opportunities and challenges that are emerging in this realm, representative examples of targeted drug delivery systems, anticancer conjugates, anticancer theranostic agents, and anti-AD compounds relevant to functionalized platinum complexes are provided. All the examples exhibit new potential of platinum complexes for future applications in biomedical areas. The emphases of this Account are placed on the functionalization for targeted drug delivery and theranostic agents. In the end, a general assessment of various strategies has been made according to their major shortcomings and defects. The original information in this Account comes entirely from literature appearing since 2010.
Mitochondria-lysosome interactions are essential for maintaining intracellular homeostasis. Although various fluorescent probes have been developed to visualize such interactions, they remain unable ...to label mitochondria and lysosomes simultaneously and dynamically track their interaction. Here, we introduce a cell-permeable, biocompatible, viscosity-responsive, small organic molecular probe, Coupa, to monitor the interaction of mitochondria and lysosomes in living cells. Through a functional fluorescence conversion, Coupa can simultaneously label mitochondria with blue fluorescence and lysosomes with red fluorescence, and the correlation between the red-blue fluorescence intensity indicates the progress of mitochondria-lysosome interplay during mitophagy. Moreover, because its fluorescence is sensitive to viscosity, Coupa allowed us to precisely localize sites of mitochondria-lysosome contact and reveal increases in local viscosity on mitochondria associated with mitochondria-lysosome contact. Thus, our probe represents an attractive tool for the localization and dynamic tracking of functional mitochondria-lysosome interactions in living cells.
The evolution of the "Maotai" liquor brand was closely related to market changes and evolving state-business networks at different junctures in modern China. In the early Republican era, Maotai ...liquor was especially popular within the top military and political circles of Guizhou Province and became a hallmark of Guizhou after it won a list of specialty exposition prizes. After the Sino-Japanese War, the exodus of government officials and teachers into the southwest China and the trade embargo imposed by the Japanese changed the structure of premium liquor consumption. Maotai liquor became a famous independent brand after it became widely known in the area under Wartime Guomindang (GMD) control. After 1945, a commercial network was established introducing Maotai liquor to the major Chinese cities. The market share of Maotai liquor thus grew exponentially, making it a household brand throughout China. The history of Maotai liquor sheds light on how the Wartime experience, the market and the state-business network shaped the evolution of a commercial brand. Furthermore, it helps explain the evolutionary logic of a niche commodity in China's modern economy.
To minimize the concomitant cell damage in the capture process of circulating tumor cells(CTCs) in conventional methods, Zuo
et al.
proposed to use aptamer-trigger-clamped hybridization chain ...reaction method to encapsulate CTCs by
in-situ
forming 3D DNA hydrogel. The 3D porous DNA hydrogel on cell membrane minimizes cell damage, and the CTCs can be readily released by the ATP triggered dis-assembly of DNA hydrogel for subsequent culture and live cell analysis. This work has been published online in the
Nature Protocols
in June 22, 2020.
Golgi apparatus (GA) oxidative stress induced by in situ reactive oxygen species (ROS) could severely damage the morphology and function of GA, which may open up an avenue for effective photodynamic ...therapy (PDT). However, due to the lack of effective design strategy, photosensitizers (PSs) with specific GA targeting ability are in high demand and yet quite challenging. Herein, we report an aggregation-induced emission luminogen (AIEgen) based PS (TPE-PyT-CPS) that can effectively target the GA via caveolin/raft mediated endocytosis with a Pearson correlation coefficient up to 0.98. Additionally, the introduction of pyrene into TPE-PyT-CPS can reduce the energy gap between the lowest singlet state (S
) and the lowest triplet state (T
) (ΔE
) and exhibits enhanced singlet oxygen generation capability. GA fragmentation and cleavage of GA proteins (p115/GM130) are observed upon light irradiation. Meanwhile, the apoptotic pathway is activated through a crosstalk between GA oxidative stress and mitochondria in HeLa cells. More importantly, GA targeting TPE-T-CPS show better PDT effect than its non-GA-targeting counterpart TPE-PyT-PS, even though they possess very close ROS generation rate. This work provides a strategy for the development of PSs with specific GA targeting ability, which is of great importance for precise and effective PDT.
Vitrimers have been emerged as a new class of polymers with many attractive properties of material processing such as reshaping, recycling and repairing. Herein, a new type of vitrimers (BDSER) based ...on thermosetting dynamic epoxy network with double disulfide bonds was synthesized by the reaction of a difunctional epoxy monomer containing disulfide bonds with 4,4′-disulfanediyldianiline (4-AFD). Our results demonstrated that the relaxation time of BDSER at 200 °C was as short as 9 s without any catalyst. The storage modulus of BDSER was up to about 2.2 GPa and its glass transition temperature was higher than 130 °C. Additionally, the thermodynamic and chemical properties of BDSER were no significant loss after 3 cycles of continuous breaking/compression molding. Furthermore, the resistance of CNT/PPy/Vitrimer composites (CPV), synthesized by doped BDSER with the polypyrrole (PPy) decorated multi-walled carbon nanotubes (WMCNTs), was decreased to 109 Ω even the mass ratio was only 1%wt, which could be used a promising candidate as self-repairing materials in the field of antistatic.
Abstract
Zn
2+
plays important roles in metabolism and signaling regulation. Subcellular Zn
2+
compartmentalization is essential for organelle functions and cell biology, but there is currently no ...method to determine Zn
2+
signaling relationships among more than two different organelles with one probe. Here, we report simultaneous Zn
2+
tracking in multiple organelles (Zn-STIMO), a method that uses structured illumination microscopy (SIM) and a single Zn
2+
fluorescent probe, allowing super-resolution morphology-correlated organelle identification in living cells. To guarantee SIM imaging quality for organelle identification, we develop a new turn-on Zn
2+
fluorescent probe, NapBu-BPEA, by regulating the lipophilicity of naphthalimide-derived Zn
2+
probes to make it accumulate in multiple organelles except the nucleus. Zn-STIMO with this probe shows that CCCP-induced mitophagy in HeLa cells is associated with labile Zn
2+
enhancement. Therefore, direct organelle identification supported by SIM imaging makes Zn-STIMO a reliable method to determine labile Zn
2+
dynamics in various organelles with one probe. Finally, SIM imaging of pluripotent stem cell-derived organoids with NapBu-BPEA demonstrates the potential of super-resolution morphology-correlated organelle identification to track biospecies and events in specific organelles within organoids.
Breast cancer (BC) is one of the most common malignancies in women and often accompanied by inflammatory processes. Cyclooxygenase‐2 (COX‐2) plays a vital role in the progression of BC, correlating ...with the expression of programmed death‐ligand 1 (PD‐L1). Overexpression of PD‐L1 contributes to the immune escape of cancer cells, and its blockade would stimulate anticancer immunity. Two multispecific platinum(IV) complexes DNP and NP were prepared using non‐steroidal antiinflammatory drug naproxen (NPX) as axial ligand(s) to inhibit the BC cells. DNP exhibited high cytotoxicity and antiinflammatory properties superior over NP, cisplatin and NPX; moreover, it displayed potent antitumor activity and almost no general toxicity in mice bearing triple‐negative breast cancer (TNBC). Mechanistic studies revealed that DNP could downregulate the expression of COX‐2 and PD‐L1 in vitro and vivo, inhibit the secretion of prostaglandin, reduce the expression of BC‐associated protein BRD4 and phosphorylation of extracellular signal‐regulated kinases 1/2 (Erk1/2), and block the oncogene c‐Myc in BC cells. These findings demonstrate that DNP is capable of intervening in inflammatory, immune, and metastatic processes of BC, thus presenting a new mechanism of action for anticancer platinum(IV) complexes. The multispecificity offers a special superiority for DNP to treat TNBC by combining chemotherapy and immunotherapy in one molecule.
A platinum(IV) complex (DNP) modified by the non‐steroidal antiinflammatory drug naproxen downregulated the expression of cyclooxygenase‐2 (COX‐2) and programmed death‐ligand 1 (PD‐L1) in vitro and vivo, retarded the metastasis of breast cancer cells, and showed potent antitumor activity in cancer‐bearing mice. Suppression on inflammatory cytokines and immune checkpoint is the unique character of DNP as a drug candidate.
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