Due to the advantages in efficacy and safety compared with traditional chemotherapy drugs, targeted therapeutic drugs have become mainstream cancer treatments. Since the first tyrosine kinase inhibitor imatinib was approved to enter the market by the US Food and Drug Administration (FDA) in 2001, an increasing number of small-molecule targeted drugs have been developed for the treatment of malignancies. By December 2020, 89 small-molecule targeted antitumor drugs have been approved by the US FDA and the National Medical Products Administration (NMPA) of China. Despite great progress, small-molecule targeted anti-cancer drugs still face many challenges, such as a low response rate and drug resistance. To better promote the development of targeted anti-cancer drugs, we conducted a comprehensive review of small-molecule targeted anti-cancer drugs according to the target classification. We present all the approved drugs as well as important drug candidates in clinical trials for each target, discuss the current challenges, and provide insights and perspectives for the research and development of anti-cancer drugs.
Photodynamic therapy (PDT), using a combination of chemical photosensitizers (PS) and light, has been successfully applied as a noninvasive therapeutic procedure to treat tumors by inducing apoptosis or necrosis of cancer cells. However, most current clinically used PS have suffered from the instability in physiological conditions which lead to low photodynamic therapy efficacy. Herein, a highly biocompatible poly(dopamine) (PDA) nanoparticle conjugated with Chlorin e6 (referenced as the PDA-Ce6 nanosphere) was designed as a nanotherapeutic agent to achieve simultaneous photodynamic/photothermal therapy (PDT/PTT). Compared to the free Ce6, the PDA-Ce6 nanosphere exhibited significantly higher PDT efficacy against tumor cells, because of the enhanced cellular uptake and subsequently greater reactive oxygen species (ROS) production upon laser irradiation at 670 nm. Meanwhile, the PDA-Ce6 nanosphere could be also used as a photoabsorbing agent for PTT, because of the excellent photothermal conversion ability of PDA nanoparticle under laser irradiation at 808 nm. Moreover, our prepared nanosphere had extremely low dark toxicity, while excellent phototoxicity under the combination laser irradiation of 670 and 808 nm, both in vitro and in vivo, compared to any single laser irradiation alone. Therefore, our prepared PDA-Ce6 nanosphere could be applied as a very promising dual-modal phototherapeutic agent for enhanced cancer therapy in future clinical applications.
In this paper, a core–shell nanocomposite of clusters of superparamagnetic iron oxide nanoparticles coated with poly(dopamine) (SPION clusters@PDA) is fabricated as a magnetic field-directed theranostic agent that combines the capabilities of highly sensitive magnetic resonance imaging (MRI) and photothermal cancer therapy. The highly concentrated SPION cluster core is suitable for sensitive MRI due to its superparamagnetic properties, and the poly(dopamine) coating layer can induce cancer cell death under near-infrared (NIR) laser irradiation because of the photothermal conversion ability of PDA. MRI scanning reveals that the nanocomposite has relatively high r2 and r2(*) relaxivities, and the r2(*) values are nearly threefold higher than the r2 values because of the clustering of the SPIONs in the nanocomposite core. Due to the rapid response to magnetic field gradients, enhanced cellular uptake of our nanocomposite mediated by an external magnetic field can be achieved, thus producing significantly enhanced local photothermal killing efficiency against cancer cells under NIR irritation.
Multifunctional theranostic nanoparticles represent an emerging agent with the potential to offer extremely sensitive diagnosis and targeted cancer therapy. Herein, we report the synthesis and characterization of a multifunctional theranostic agent (referred to as LA-LAPNHs) for targeted magnetic resonance imaging/computed X-ray tomography (MRI/CT) dual-mode imaging and photothermal therapy of hepatocellular carcinoma. The LA-LAPNHs were characterized as having a core-shell structure with the gold nanoparticles (AuNPs)@polydopamine (PDA) as the inner core, the indocyanine green (ICG), which is electrostatically absorbed onto the surface of PDA, as the photothermal therapeutic agent, and the lipids modified with gadolinium-1,4,7,10-tetraacetic acid and lactobionic acid (LA), which is self-assembled on the outer surface as the shell. The LA-LAPNHs could be selectively internalized into the hepatocellular cell line (HepG2 cells) but not into HeLa cells due to the specific recognition ability of LA to asialoglycoprotein receptor. Additionally, the dual-mode imaging ability of the LA-LAPNH aqueous solution was confirmed by enhanced MR and CT imaging showing a shorter T1 relaxation time and a higher Hounsfield unit value, respectively. In addition, the LA-LAPNHs showed significant photothermal cytotoxicity against liver cancer cells with near-infrared irradiation due to their strong absorbance in the region between 700 and 850 nm. In summary, this study demonstrates that LA-LAPNHs may be a promising candidate for targeted MR/CT dual-mode imaging and photothermal therapy of hepatocellular carcinoma.
Photodynamic therapy (PDT) usually aggravates tumor hypoxia, which promotes the survival and metastasis of residue cancer cells; furthermore, although PDT‐induced immunogenic death of cancer cells can induce host antitumor responses, such responses are generally weak and not enough to eliminate the residue cancer cells. Here, metal–organic framework (MOF)‐based nanoparticles to combine PDT, antihypoxic signaling, and CpG adjuvant as an in situ tumor vaccine to boost host anticancer responses after PDT are designed. The MOF‐based nanoparticles are self‐assembled from H2TCPP and zirconium ions with hypoxia inducible factor (HIF) signaling inhibitor (ACF) and immunologic adjuvant (CpG) loading, and hyaluronic acid (HA) coating on the surface. The final nanoparticles (PCN‐ACF‐CpG@HA) can specifically target cancer cells overexpressing CD44 receptor though HA; the aggravated hypoxic survival signaling after PDT can be blocked by ACF to inhibit the HIF‐1α induced survival and metastasis. With the help of CpG adjuvant, the tumor associated antigens generated from PDT‐based cancer cell destruction can initiate strong antitumor immune responses to eliminate residue cancer cells. Taken together, a novel in situ immunostimulatory strategy is designed to synergistically enhance therapeutic effects of PDT by activating host antitumor immune‐responses both in vitro and in vivo, which may have great potential for clinical translation in future.
Three new monotetrahydrofuran annonaceous acetogenins, muricin H (1), muricin I (2), and cis-annomontacin (3), along with five known acetogenins, annonacin, annonacinone, annomontacin, murisolin, and xylomaticin, were isolated from the seeds of Annona muricata. Additionally, two new monotetrahydrofuran annonaceous acetogenins, cis-corossolone (4) and annocatalin (5), together with four known ones, annonacin, annonacinone, solamin, and corossolone, were isolated from the leaves of this species. The structures of all new isolates were elucidated and characterized by spectral and chemical methods. These new acetogenins exhibited significant activity in in vitro cytotoxic assays against two human hepatoma cell lines, Hep G(2) and 2,2,15. Compound 5 showed a high selectivity toward the Hep 2,2,15 cell line.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.