Targeted Engineering of Medicinal Chemistry for Cancer Therapy: Recent Advances and Perspectives

Chen, Weihua; Sun, Zhen; Lu, Lehui

doi:10.1002/anie.201914511

Cited by 53 publications

(33 citation statements)

References 198 publications

(142 reference statements)

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“…The approach consists of dual tumortargeting specificity: first, the polymer encapsulated-NPs can passively accumulate in the tumor tissues via the enhanced permeability and retention (EPR) effect; second, biotin (vitamin H or coenzyme R) as an essential micronutrient is mainly taken up by cells through its receptor sodium dependent multivitamin transporter (SMVT), which is overexpressed in a variety of tumors than in normal tissues. [54][55][56][57][58] The two molecules were respectively assembled into NPs by using a nanoprecipitation method in which two copolymers DSPE-mPEG2000 and DSPE-PEG2000-Biotin with a weight ratio of 95%:5% are utilized as the coating matrix (Figure 1). Dynamic light scattering (DLS) measurement reveals that the hydrodynamic diameters of IDT and IDT-TPE NPs are 78 and 81 nm, respectively.…”

Section: Resultsmentioning

confidence: 99%

Add the Finishing Touch: Molecular Engineering of Conjugated Small Molecule for High‐Performance AIE Luminogen in Multimodal Phototheranostics

et al. 2021

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Among the multiple diagnostic imaging, fluorescence imaging (FLI) possesses several distinct advantages including minimal invasiveness, superb sensitivity, and high spatiotemporal resolution. [8][9][10] However, conventional organic fluorophores usually suffer from the aggregation-caused quenching (ACQ) effect due to intermolecular π-π stacking caused by the planar molecule conformation, thereby resulting in weakened or vanished fluorescence emission upon the formation of aggregates in the physiological environment, which seriously hampers their biological applications. [11,12] Given the circumstances, emerging research interest is the aggregation-induced emission (AIE), which refers to a photophysical phenomenon wherein a novel family of propeller-shaped luminogens with twisted structural conformation are weakly emissive or nonemissive in the single-molecule state, but are induced to emit intensely in the aggregates through a mechanism of the restriction of intramolecular motions (RIM). [13][14][15][16][17][18][19][20][21][22][23] AIE luminogens (AIEgens) have triggered state-ofthe-art developments in FLI, thanks to their intrinsic properties including high signal-to-noise ratio and high photostability. Phototheranostics based on luminogens with aggregation-induced emission (AIE) characteristics is captivating increasing research interest nowadays. However, AIE luminogens are inherently featured by inferior absorption coefficients (ε) resulting from the distorted molecular geometry. Besides, molecular innovation of long-wavelength light-excitable AIE luminogens with highly efficient phototheranostic outputs is an appealing yet significantly challenging task. Herein, on the basis of a fused-ring electron acceptor-donator-acceptor (A-D-A) type molecule (IDT) with aggregation-caused quenching (ACQ)properties, molecular engineering smoothly proceeds and successfully yields a novel AIE luminogen (IDT-TPE) via simply modifying tetraphenylethene (TPE) moieties on the sides of IDT backbone. The AIE tendency endows IDT-TPE nanoparticles with enhanced fluorescence brightness and far superior fluorescence imaging performance to IDT nanoparticles for mice tumors. Moreover, IDT-TPE nanoparticles exhibit near-infrared light-excitable features with a high ε of 8.9 × 10 4 m −1 cm −1 , which is roughly an order of magnitude higher than that of most previously reported AIE luminogens. Combining with their reactive oxygen species generation capability and extremely high photothermal conversion efficiency (59.7%), IDT-TPE nanoparticles actualize unprecedented performance in multimodal phototheranostics. This study thus brings useful insights into the development of versatile phototheranostic materials with great potential for practical cancer theranostics.

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Section: Resultsmentioning

confidence: 99%

Add the Finishing Touch: Molecular Engineering of Conjugated Small Molecule for High‐Performance AIE Luminogen in Multimodal Phototheranostics

et al. 2021

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“…Owing to the critical biological functions of various organelles, proper cancer therapeutic can be enhanced by targeting specific organelles . Mitochondria provide energy for cell growth and also afford considerable flexibility for tumor growth and viability in severe environments, − thus constitute important targeted sites for cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Mitochondria-Targeting Enhanced Phototherapy by Intrinsic Characteristics Engineered “One-for-All” Nanoparticles

Sun

Liu

et al. 2021

ACS Appl. Mater. Interfaces

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Mitochondria-targeted synergistic therapy, including photothermal (PTT) and photodynamic therapy (PDT), has aroused wide attention due to the high sensitivity to reactive oxygen species (ROS) and heat shock of mitochondria. However, most of the developed nanosystems for the combinatorial functions require the integration of different components, such as photosensitizers and mitochondria-targeted molecules. Consequently, it indispensably requires sophisticated design and complex synthetic procedures. In this work, a well-designed Bi2S3-based nanoneedle, that localizes to mitochondria and produces extra ROS with inherent photothermal effect, was reported by doping of Fe (denoted as FeBS). The engineered intrinsic characteristics certify the capacity of such “one-for-all” nanosystems without additional molecules. The lipophilicity and surface positive charge are demonstrated as crucial factors for specifical mitochondria targeting. Significantly, Fe doping overcomes the disadvantage of the narrow band gap of Bi2S3 to prevent the fast recombination of electron–hole, hence resulting in the generation of ROS for PDT. The “one-for-all” nanoparticles integrate with mitochondria-targeting and synergistic effect of PDT and PTT, thus exhibit enhanced therapeutic effect and inhibit the growth of tumors observably. This strategy may open a new direction in designing the mitochondria-targeted materials and broadening the properties of inorganic semiconductor materials for satisfactory therapeutic outcomes.

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“…Targeted drugs have passed multicenter clinical trials and been marketed in the last 20 years, with various drug classes (small molecules, peptides, proteins, antibodies) and also various molecular targets (generally cell signaling), ranging from angiogenesis (VEGF, VEGFR, αvβ3 integrin) and cell proliferation (EGFR, HER2) up to certain specific receptors (folic acid receptors, biotin D, LDL, CD20, etc.) [6,14]. However, their clinical application so far shows that achieving long-lasting therapeutic effects remains difficult due to subsequent drug resistance.…”

Section: Targeted Drugs and Targeting Abnormal Metabolism Of Cancermentioning

confidence: 99%

Highly Specific L-Type Amino Acid Transporter 1 Inhibition by JPH203 as a Potential Pan-Cancer Treatment

et al. 2021

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Accelerated cancer cell growth requires a massive intake of amino acids. Overexpression of L-type (large) amino acid transporter 1 (LAT1) on the cancer cell membrane facilitates such a demand, which is limited in normal organs. Therefore, LAT1 overexpression is ideal as a molecular cancer therapeutic target. JPH203, a LAT1-selective non-transportable blocker, had demonstrated LAT1 inhibition in <10 µM IC50 values and effectively suppressed cancer cell growth in studies involving several types of cancer cell lines and tumor xenograft models. A limited phase I clinical trial was performed on five different solid tumors and showed that JPH203 is well-tolerated and has a promising activity for the treatment of bile duct cancer. This review details the development and prospect of JPH203 as a LAT1-targeting cancer therapy.

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Targeted Engineering of Medicinal Chemistry for Cancer Therapy: Recent Advances and Perspectives

Cited by 53 publications

References 198 publications

Add the Finishing Touch: Molecular Engineering of Conjugated Small Molecule for High‐Performance AIE Luminogen in Multimodal Phototheranostics

Add the Finishing Touch: Molecular Engineering of Conjugated Small Molecule for High‐Performance AIE Luminogen in Multimodal Phototheranostics

Mitochondria-Targeting Enhanced Phototherapy by Intrinsic Characteristics Engineered “One-for-All” Nanoparticles

Highly Specific L-Type Amino Acid Transporter 1 Inhibition by JPH203 as a Potential Pan-Cancer Treatment

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