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.
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.
Platinum-based anticancer drugs represented by cisplatin play important roles in the treatment of various solid tumors. However, their applications are largely compromised by drug resistance and side ...effects. Much effort has been made to circumvent the drug resistance and general toxicity of these drugs. Among multifarious designs, monofunctional platinum(II) complexes with a general formula of Pt(3A)Cl
(A: Ammonia or amine) stand out as a class of "non-traditional" anticancer agents hopeful to overcome the defects of current platinum drugs. This review aims to summarize the development of monofunctional platinum(II) complexes in recent years. They are classified into four categories: fluorescent complexes, photoactive complexes, targeted complexes, and miscellaneous complexes. The intention behind the designs is either to visualize the cellular distribution, or to reduce the side effects, or to improve the tumor selectivity, or inhibit the cancer cells through non-DNA targets. The information provided by this review may inspire researchers to conceive more innovative complexes with potent efficacy to shake off the drawbacks of platinum anticancer drugs.
The success of platinum-based anticancer agents has motivated the exploration of novel metal-based drugs for several decades, whereas problems such as drug-resistance and systemic toxicity hampered ...their clinical applications and efficacy. Stimuli-responsiveness of some metal complexes offers a good opportunity for designing site-specific prodrugs to maximize the therapeutic efficacy and minimize the side effect of metallodrugs. This review presents a comprehensive and up-to-date overview on the therapeutic stimuli-responsive metallodrugs that have appeared in the past two decades, where stimuli such as redox, pH, enzyme, light, temperature, and so forth were involved. The compounds are classified into three major categories based on the nature of stimuli, that is, endo-stimuli-responsive metallodrugs, exo-stimuli-responsive metallodrugs, and dual-stimuli-responsive metallodrugs. Representative examples of each type are discussed in terms of structure, response mechanism, and potential medical applications. In the end, future opportunities and challenges in this field are tentatively proposed. With diverse metal complexes being introduced, the foci of this review are pointed to platinum and ruthenium complexes.
Platinum complexes are potential antitumor drugs in chemotherapy. Their impact on tumor treatment could be greatly strengthened by combining with immunotherapy. Increasing evidences indicate that the ...antitumor activity of platinum complexes is not limited to chemical killing effects, but also extends to immunomodulatory actions. This review introduced the general concept of chemoimmunotherapy and summarized the progress of platinum complexes as chemoimmunotherapeutic agents in recent years. Platinum complexes could be developed into inducers of immunogenic cell death, blockers of immune checkpoint, regulators of immune signaling pathway, and modulators of tumor immune microenvironment, etc. The synergy between chemotherapeutic and immunomodulatory effects reinforces the antitumor activity of platinum complexes, and helps them circumvent the drug resistance and systemic toxicity. The exploration of platinum complexes for chemoimmunotherapy may create new opportunities to revive the discovery of metal anticancer drugs.
Chemoimmunotherapy is a novel treatment for cancers via synergy between chemotherapy and immunotherapy. Pt complexes could be developed into chemoimmunotherapeutic agents as inducers of immunogenic cell death, inhibitors of immune checkpoint, stimulators of immune response, relievers of immunosupression, or modulators of immune signal. They reshape the tumor microenvironment and reinforce the antitumor activity.
► A facile and efficient approach for surface modification of PU was introduced. ► MPC was grafted onto the surface of PU film by RATRP. ► Some free La3+ ions reacted with CPTM and the product served ...as mixed ligand complex. ► The obtained PUs had good blood compatibility and a possible usage in biomedicine.
Low grafting density is a disadvantage both in reverse atom transfer radical polymerization (RATRP) and ATRP. In this work, the surfaces of polyurethane (PU) were treated by LaCl3·6H2O to obtain modified surfaces with hydrated layers. The reaction of surface-initiated RATRP was carried out easily, which may be attributed to the enriched hydroxyl groups on the hydrated layers. An innovation found in this work is that some free lanthanum ions (La3+) reacted with the silane coupling agent (CPTM) and the product served as mixed ligand complex. The mixed ligand complex instead of conventional 2,2′-bipyridine was adopted to serve as a ligand in the process of RATRP. As a result, PU surfaces grafted with well-defined polymer brushes (MPC) were obtained. PU substrates before and after modification were characterized by FTIR, XPS, AFM, SEM, SCA, respectively. The results showed that zwitterionic brushes were successfully fabricated on the PU surfaces (P(MPC)), and the content of the grafted layer increased gradually with polymerization time with the grafting density as high as 97.9%. The blood compatibility of the PU substrates was evaluated by plasma recalcification profiles test and platelet adhesion tests in vitro. It was found that all PU functionalized with zwitterionic brush showed improved resistance to nonspecific protein adsorption and platelet adhesion.
Mitophagy is a selective autophagic process that degrades dysfunctional mitochondria. Monofunctional platinum(II) complexes are candidates for anticancer drugs with the potential to circumvent the ...drug resistance and side effects of cisplatin and its analogues, but their mechanism of action is elusive. Complex Mono-Pt kills cancer cells through a mitophagic pathway. The mechanism involves the stimulation of endoplasmic reticulum stress (ERS) and activation of the unfolded protein response. Mono-Pt severely impairs the structure and function of mitochondria, including disruption of morphological integrity, dissipation of membrane potential, elevation of reactive oxygen species, inhibition of mtDNA transcription, and reduction of adenosine triphosphate (ATP), which ultimately leads to mitophagy. Mono-Pt does not react with nuclear DNA but exhibits potent antiproliferative activity against cancer cells, thus breaking the DNA-binding paradigm and classical structure-activity rules for platinum drugs. The ERS-mediated mitophagy provides an alternative mechanism for platinum complexes, which broadens the way for developing new platinum anticancer drugs.
Alzheimer's disease (AD) is a neurodegenerative illness accompanied by severe memory loss, cognitive disorders and impaired behavioral ability. Amyloid β-peptide (Aβ) aggregation and ...nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome play crucial roles in the pathogenesis of AD. Aβ plaques not only induce oxidative stress and impair neurons, but also activate the NLRP3 inflammasome, which releases inflammatory cytokine IL-1β to trigger neuroinflammation. A bifunctional molecule, 2-2-(benzo
thiazol-2-yl)phenylaminobenzoic acid (BPBA), with both Aβ-targeting and inflammasome-inhibiting capabilities was designed and synthesized. BPBA inhibited self- and Cu
- or Zn
-induced Aβ aggregation, disaggregated the already formed Aβ aggregates, and reduced the neurotoxicity of Aβ aggregates; it also inhibited the activation of the NLRP3 inflammasome and reduced the release of IL-1β
and
. Moreover, BPBA decreased the production of reactive oxygen species (ROS) and alleviated Aβ-induced paralysis in transgenic
with the human Aβ
gene. BPBA exerts an anti-AD effect mainly through dissolving Aβ aggregates and inhibiting NLRP3 inflammasome activation synergistically.
Platinum(IV) complexes are prodrugs of cisplatin with multiple potential advantages over platinum(II) drugs. Mitochondria play pivotal roles in producing energy and inducing death of cancer cells. ...Two platinum(IV) complexes, namely, c,c,t-Pt(NH
)
Cl
(OH)(OCOCH
CH
CH
CH
PPh
)Br and c,c,t-Pt(NH
)
Cl
(OCOCH
CH
CH
CH
PPh
)
Br
, were designed to explore the effect of mitochondrion-targeting group(s) on the bioactivity and cytotoxicity of platinum(IV) complexes. The complexes were characterized by electrospray ionization mass spectrometry, reverse-phase high-performance liquid chromatography, and multinuclear (
H,
C,
P, and
Pt) NMR spectroscopy. The introduction of triphenylphosphonium targeting group(s) markedly influences the reactivity and cytotoxicity of the Pt(IV) complexes. The targeted complex displays more potent disruptive effect on mitochondria but less inhibitory effect on cancer cells than cisplatin. The lipophilicity of the Pt(IV) complexes is enhanced by the targeting group(s), while their reactivity to DNA is decreased. As a result, the mitochondrial morphology and adenosine triphosphate producing ability are impaired, which constitutes an alternative pathway to inhibit cancer cells. This study shows that both the reactivity of platinum(IV) center and the property of axial targeting ligand exert influences on the cytotoxicity of targeted Pt(IV) complexes. For targeting groups with pharmacological activities, their intrinsic function could enrich the anticancer mechanism of Pt(IV) complexes.
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