Nucleic acid aptamers have minimal immunogenicity, high chemical synthesis production, low cost and high chemical stability when compared with antibodies. However, the susceptibility to nuclease ...degradation, rapid excretion through renal filtration and insufficient binding affinity hindered their development as drug candidates for therapeutic applications. In this review, we will discuss methods to conquer these challenges and highlight recent developments of chemical modifications and technological advances that may enable early aptamers to be translated into clinical therapeutics.
Antibody-drug conjugates (ADCs) have become a promising targeted therapy strategy that combines the specificity, favorable pharmacokinetics and biodistributions of antibodies with the destructive ...potential of highly potent drugs. One of the biggest challenges in the development of ADCs is the application of suitable linkers for conjugating drugs to antibodies. Recently, the design and synthesis of linkers are making great progress. In this review, we present the methods that are currently used to synthesize antibody-drug conjugates by using thiols, amines, alcohols, aldehydes and azides.
Paclitaxel (PTX) is among the most commonly used first-line drugs for cancer chemotherapy. However, its poor water solubility and indiscriminate distribution in normal tissues remain clinical ...challenges. Here we design and synthesize a highly water-soluble nucleolin aptamer-paclitaxel conjugate (NucA-PTX) that selectively delivers PTX to the tumor site. By connecting a tumor-targeting nucleolin aptamer (NucA) to the active hydroxyl group at 2' position of PTX via a cathepsin B sensitive dipeptide bond, NucA-PTX remains stable and inactive in the circulation. NucA facilitates the uptake of the conjugated PTX specifically in tumor cells. Once inside cells, the dipeptide bond linker of NucA-PTX is cleaved by cathepsin B and then the conjugated PTX is released for action. The NucA modification assists the selective accumulation of the conjugated PTX in ovarian tumor tissue rather than normal tissues, and subsequently resulting in notably improved antitumor activity and reduced toxicity.
Prodrug Strategies for Paclitaxel Meng, Ziyuan; Lv, Quanxia; Lu, Jun ...
International journal of molecular sciences,
05/2016, Volume:
17, Issue:
5
Journal Article
Peer reviewed
Open access
Paclitaxel is an anti-tumor agent with remarkable anti-tumor activity and wide clinical uses. However, it is also faced with various challenges especially for its poor water solubility and low ...selectivity for the target. To overcome these disadvantages of paclitaxel, approaches using small molecule modifications and macromolecule modifications have been developed by many research groups from all over the world. In this review, we discuss the different strategies especially prodrug strategies that are currently used to make paclitaxel more effective.
The IC50s of seven potent N,N′-arylurea compounds against juvenile and adult S. japonicum. Compounds 16 and 38 showed higher activities than the positive control MMV665852. Display omitted
Although ...the antischistosomal activities of N,N′-arylurea analogs were reported, systematic structure–activity relationships have not been conducted. In this Letter, we reported the design, synthesis and evaluation of 45 N,N′-arylurea analogs. Among these prepared compounds, 13 compounds were urea linker modified and 32 were N,N′-arylurea derivatives. The activity evaluation revealed 12 analogs exhibited IC50 values lower than 22.6μM, and 7 of them had IC50 less than 10μM against the juvenile Schistosoma japonicum in vitro. Their worm killing potency was even higher against adult worm. Unfortunately, low to moderate worm burden reduction of 0–33.4% was recorded after administration of a single oral dose of 200mg/kg or 400mg/kg to mice harboring S. japonicum.
Platinum drugs are widely used in clinics to treat various types of cancer. However, a number of severe side effects induced by the nonspecific binding of platinum drugs to normal tissues limit their ...clinical use. The conversion of platinum(II) drugs into more inert platinum(IV) derivatives is a promising strategy to solve this problem. Some platinum(IV) prodrugs, such as carboplatin-based tetracarboxylatoplatinum(IV) prodrugs, are not easily reduced to active platinum(II) species, leading to low cytotoxicity in vitro. In this study, we report the design and synthesis of a carboplatin-based platinum(IV) prodrug functionalized with a boron dipyrromethene (bodipy) ligand at the axial position, and the ligand acts as a photoabsorber to photoactivate the platinum(IV) prodrug. This compound, designated as BODI-Pt, is highly stable in the dark but quickly activated under irradiation to release carboplatin and the axial ligands. A cytotoxic study reveals that BODI-Pt is effective under irradiation, with cytotoxicity 11 times higher than that in the dark and 39 times higher than that of carboplatin in MCF-7 cells. Moreover, BODI-Pt has been proven to kill cancer cells by binding to the genomic DNA, arresting the cell cycle at the G2/M phase, inducing oncosis, and generating ROS upon irradiation. In summary, we report a green-light-activatable and carboplatin-based Pt(IV) prodrug with improved cytotoxicity against cancer cells, and our strategy can be used as a promising way to effectively activate carboplatin-based platinum(IV) prodrugs.
Platinum(IV) complexes containing carboxylate and carbamate ligands at the axial position have been reported previously. A better understanding of the similarity and difference between the two types ...of ligands will provide us with new insights and more choices to design novel Pt(IV) complexes. In this study, we systematically investigated and compared the properties of Pt(IV) complexes bearing the two types of ligands. Ten pairs of unsymmetric Pt(IV) complexes bearing axial carbamate or carboxylate ligands were synthesized and characterized. The stability of these Pt(IV) complexes in a PBS buffer with or without a reducing agent was investigated, and most of these complexes exhibited good stability. Besides, most Pt(IV) prodrugs with carbamate axial ligands were reduced faster than the corresponding ones with carboxylate ligands. Furthermore, the aqueous solubilities and lipophilicities of these Pt(IV) complexes were tested. All the carbamate complexes showed better aqueous solubility and decreased lipophilicity as compared to those of the corresponding carboxylate complexes, due to the increased polarity of carbamate ligands. Biological properties of these complexes were also evaluated. Many carbamate complexes showed cytotoxicity similar to that of the carboxylate complexes, which may derive from the lower cellular accumulation but faster reduction of the former. Our research highlights the differences between the Pt(IV) prodrugs containing carbamate and carboxylate axial ligands and may contribute to the future rational design of Pt-based anticancer prodrugs.
Five eremophilane sesquiterpenes including three new ones, named paraconions A–C (1–3), were isolated from an endophytic fungus, Paraconiothyrium sp. from Artemisia selengensis. The structures of ...these new compounds were established based on spectroscopic methods, including nuclear magnetic resonance (NMR), ultraviolet (UV), and infrared (IR) spectroscopy, as well as high resolution electrospray ionization mass spectrometry (HR‐ESI‐MS). An anti‐inflammatory assay indicated that paraconion B (2) inhibited lipopolysaccharide‐induced nitric oxide (NO) production in RAW 264.7 cells, with an IC50 value of 51.7 μM. The compounds discovered in this study will enrich the structural types of secondary metabolites of the endophytic fungus Paraconiothyrium sp.
The short circulatory half‐lives and low tumor accumulation of carboplatin greatly limit the drug's efficacy in vivo. Herein, we address these challenges by using a prodrug strategy and present the ...rational design of a novel platinum(IV) anticancer prodrug that can hitchhike on erythrocytes. This prodrug, designated as ERY1‐PtIV, can bind to erythrocytes efficiently and stably, possessing a circulatory half‐life 18.5 times longer than that of carboplatin in mice. This elongated circulatory half‐life enables platinum to accumulate at levels 7.7 times higher than with carboplatin, with steady levels in the tumors. As a consequence, the ERY1‐PtIV prodrug is proved to exhibit significantly enhanced antitumor activity and reduced side effects compared with carboplatin. Collectively, our novel approach highlights an efficient strategy to utilize intrinsic erythrocytes as auto‐binding carriers to enhance the tumor accumulation and subsequent antitumor efficacy of platinum drugs.
A carboplatin‐based platinum(IV) anticancer prodrug that can hitchhike on erythrocytes is reported. The as‐prepared prodrug ERY1‐PtIV has a prolonged circulatory half‐life, enhanced tumor accumulation, and improved antitumor effect compared to carboplatin in vivo via this erythrocyte‐anchored strategy.
Selective activation of prodrugs at diseased tissue through bioorthogonal catalysis represents an attractive strategy for precision cancer treatment. Achieving efficient prodrug photoactivation in ...cancer cells, however, remains challenging. Herein, we report two Pt(
iv
) complexes, designated as rhodaplatins {rhodaplatin
1
, Pt(CBDCA-
O
,
O
′)(NH
3
)
2
(RhB)OH; rhodaplatin
2
, Pt(DACH)ox(RhB)(OH), where CBDCA is cyclobutane-1,1-dicarboxylate, RhB is rhodamine B, DACH is (1
R
,2
R
)-1,2-diaminocyclohexane, and ox is oxalate}, that bear an internal photoswitch to realize efficient accumulation, significant co-localization, and subsequent effective photoactivation in cancer cells. Compared with the conventional platform of "external photocatalyst plus substrate", rhodaplatins presented up to 4.8 × 10
4
-fold increased photoconversion efficiency in converting inert Pt(
iv
) prodrugs to active Pt(
ii
) species under physiological conditions, due to the increased proximity and covalent bond between the photoswitch and Pt(
iv
) substrate. As a result, rhodaplatins displayed increased photocytotoxicity compared with a mixture of RhB and conventional Pt(
iv
) compound in cancer cells including Pt-resistant ones. Intriguingly, rhodaplatin
2
efficiently accumulated in the mitochondria and induced apoptosis without causing genomic DNA damage to overcome drug resistance. This work presents a new approach to develop highly effective prodrugs containing intramolecular photoswitches for potential medical applications.
The newly developed Pt(
iv
) prodrugs, rhodaplatins, contain an internal photoswitch and present up to 4.8 × 10
4
-fold increased photoconversion efficiency compared to the conventional "photocatalyst plus Pt(
iv
) prodrug" photocatalysis platform.
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