Drug-drug Conjugates Research Articles

Isoalantolactone/hydroxamic acid hybrids as potent dual STAT3/HDAC inhibitors and self-assembled nanoparticles for cancer therapy

Conventional chemotherapy, especially with natural anticancer drugs, usually suffers from poor bioavailability and low tumor accumulation. To address these limitations, we developed a novel approach for modifying natural products in which amphiphilic hydroxamic acid hybrids based on a natural product: isoalantolactone (IAL) were rationally designed. Compound 18 is identified as a highly potent dual signal transducer and activator of transcription 3 (STAT3)/histone deacetylases (HDAC) inhibitor and induces autophagy and apoptosis. 18 exhibits higher antitumor potency than IAL and the hydroxamic acid SAHA in vitro and in vivo. Furthermore, 18 self-assembled in water to form nanoparticles (18 NPs), which facilitated the accumulation of drugs in tumor tissues and promoted their cellular uptake, resulting in superior anticancer efficacy compared to free 18. Compared to drug-drug conjugates, hydroxamic acid hybrids have a smaller molecular weight and can synergize with various anticancer drugs. Overall, these findings indicate that 18 utilizing nanomedicines and dual-target drugs provide an efficient strategy for the rational design of dual-target drugs and the modification of natural products.

Drug-drug conjugates self-assembled nanomedicines triggered photo−/immuno- therapy for synergistic cancer treatments

Although immunotherapies have made progress in cancer treatment, their clinical response rates vary widely and are typically low due to sparse immune cell infiltration (immune “cold”) and suppressive tumor immune microenvironment (TIME). A simple yet effective approach that integrates a variety of immune-stimulating and TIME-modulating functions could potentially address this clinical challenge. Herein, we conjugate two small molecules, including a photosensitizer (pyropheophorbide-a, PA) and a Toll-like receptor 7/8 agonist (resiquimod, R848), into prodrug (PA-R848) that self-assembles into PA-R848 esterase responsive nanoparticles (PARE NPs) with 100% drug composition and synergistic photo−/immune- therapeutic effects. In PARE NPs, PA exhibits strong phototherapeutic effects which ablate the primary tumor directly and elicits immunogenic cell death (ICD) to promote the immune response. R848 effectively polarizes the M2-type tumor-associated macrophage (TAM) to M1-type TAM, consequently reversing the “cold” and suppressive TIME when working together with phototherapy. The PARE NPs can efficiently pare down the tumor development by two synergisms, including i) synergistic immunotherapy between ICD and TAM polarization; ii) and the antitumor effects between phototherapy and immunotherapy. On a head-neck squamous cell carcinoma mouse model, PARE NPs combined with PD-1 antibody eliminate primary tumors, and significantly inhibit the progress of distant tumors thanks to the robust antitumor immunity enhanced by the PARE NPs.

Computational Drug Shifting Towards Drug-Drug Conjugates and Monoclonal Antibody Conjugates in the Contradictory Excursion of Asthma

Background: Pandemic of COVID-19 has gathered up the surrounding respiratory diseases such as asthma. The need to combat asthma is an unanswerable question nowadays and about 20-30% of people are getting into the trap of asthma. Objectives: The mechanistic involvement of GPCR receptors in the protuberant signaling pathway such as Neuropeptide S receptor 1 (NPSR1 receptor) acts as a projected entry that needs to be inhibited for the prohibition of asthma. Methods: Exaggerative G-proteins of NPSR1 receptors are exposed as a target through GPCR modeling to point drug targeting. Three Drug-Drug Conjugates (DDCs) are designed through the combination of nine chemical compounds through methylene bridges and selection was done based on docking energy and ADMET profiling. Designation of three Monoclonal Antibody Conjugates (MACs) is expedited using single monoclonal antibodies, linked through EAAAK linkers and the best conjugate was valued based on docking energy, allergenicity, toxicity, and surface accessibility leading towards cloning and expression. Results: The best Drug-Drug Conjugate was Fluoroquinolone and 1-Indanone conjugate which possessed -7.7 Kcal/mol docking energy, lipophilicity 6.41, water solubility 1.19e-09 mg/ml, and pharmacokinetics -8.31 cm/s, indicating it to act as best drug candidate. The best Monoclonal Antibody Conjugate was Ustekinumab and Belimumab conjugate which retained -383.1 Kcal/mol docking energy, computed as non-allergen and nontoxic. Conclusion:: The use of MACs and DDCs may prove an effective treatment for lethal diseases like asthma and the future exertion will support the in vitro synthesis delivered in this study of conjugation against bronchial diseases.

Supramolecular self-assemblies based on water-soluble pillar[6]arene and drug-drug conjugates for the combination of chemotherapy

Although some co-drug delivery systems have been reported to treat cancer, how to optimal design these nano-systems with enhanced therapeutic efficacy is still a major challenge. As for the nitrogen mustard drugs chlorambucil (Cb), the overexpressed glutathione (GSH) in cancer tissue is responsible for their detoxification and reduced bioavailability. In this paper, chlorambucil-oxoplatin (Cb-Pt) was prepared to fabricate water-soluble pillar[6]arene (WP[6]) based supramolecular drug-drug self-assemblies (SDSAs). Remarkably, after the transcytosis by cancer cells, SDSAs was reduced by GSH to re lease Cb and higher toxic cisplatin, accompanying with the declining GSH level and ascending ROS level. Moreover, in vitro and in vivo experiments demonstrated that SDSAs with oxidative stress amplification strategy exhibited excellent therapeutic effect. This strategy might be useful for the synergistic co-drug based chemotherapy field.

Carrier-Free Nanomedicine for Cancer Immunotherapy.

With the rapid development of nanotechnology, carrier-based nano-drug delivery systems (DDSs) have been widely studied due to their advantages in optimizing pharmacokinetic and distribution profiles. However, despite those merits, some carrier-related limitations, such as low drug-loading capacity, systematic toxicity and unclear metabolism, usually prevent their further clinical transformation. Carrier-free nanomedicines with non-therapeutic excipients, are considered as an excellent paradigm to overcome these obstacles, owing to their superiority in improving both drug delivery efficacy and safety concern. In recent years, carrier-free nanomedicines have opened new horizons for cancer immunotherapy, and have already made outstanding progress. Herein, in this review, we are focusing on making an integrated and exhaustive overview of lately reports about them. Firstly, the major synthetic strategies of carrier-free nanomedicines are introduced, such as nanocrystals, prodrug-, amphiphilic drug-drug conjugates (ADDCs)-, polymer-drug conjugates-, and peptide-drug conjugates (PepDCs)-assembled nanomedicines. Afterwards, the typical applications of carrier-free nanomedicines in cancer immunotherapy are well-discussed, including cancer vaccines, cytokine therapy, enhancing T-cell checkpoint inhibition, as well as modulating tumor microenvironment (TME). After that, both the advantages and the potential challenges, as well as the future prospects of carrier-free nanomedicines in cancer immunotherapy, were discussed. And we believe that it would be of great potential practiced and reference value to the relative fields.

Integrating Epigenetic Modulators in Nanofibers for Synergistic Gastric Cancer Therapy via Epigenetic Reprogramming.

Epigenetic dysregulations resulting from the defects of epigenetic regulators are often reversible in tumorigenesis, making them promising cancer therapeutic targets. However, the limited specificity of action, short-term stability, and low retention of the epigenetic drugs greatly impede their clinical efficacy against solid tumors. Herein a method of combinatorial delivery of epigenetic modulatory drugs via a molecular self-assembly strategy was developed using inhibitors of DNA methyltransferases and histone deacetylases. The drug-drug conjugates can self-assemble into nanofibers with enhanced chemical stability. The nanofibers synergistically regulate aberrant DNA methylation and histone deacetylation, subsequently reprogram the gene expression profiles, and finally inhibit gastric cancer cell proliferation and promote cell apoptosis. The superior in vivo therapeutic efficacy of the nanofibers could be ascribed to the prolonged retention and accumulation in tumors and the minimized off-target effects. Therefore, this design of epigenetic-drug-based nanofiber formulation may provide a valuable paradigm for cancer therapy through epigenetic reprogramming.

Synergistic antimicrobial activity of N-methyl substituted pyrrolidinium-based ionic liquids and melittin against Gram-positive and Gram-negative bacteria.

In pharmaceutical industry, the prodrug approaches and drug-drug conjugates are being now vastly used to optimize the efficacy of the drugs for multipurpose. The combination or conjugation of antimicrobials agents with natural antimicrobials may lead to better synergistic antimicrobial activity. Currently, many publications show the potential of ionic liquids (ILs) as novel antimicrobials and even as active pharmaceutical ingredients. The current study showed the synthesis of novel pyrrolidinium-based ILs (Cx, x = 4, 6, 8, 10, 12) and their antibacterial activity alone and in combination with antimicrobial peptide, melittin (MEL), against clinically relevant microorganism, E. coli and S. aureus. The cytotoxicity of synthesized ILs was administered on HEK 293 cell line using MTT assay. The obtained results showed the dependency of antibacterial activity of ILs on alkyl chain length (C4 < C6 < C8 < C10 < C12). The remarkable improvement in the antibacterial efficiency of MEL was seen with ILs; however, antibacterial effect is more pronounced with IL having large alkyl chain length (C8, C10, and C12) at their minimal concentration with MEL to disrupt the cell membrane. In addition, the binding study and haemocompatibility results showed favourable biocompatibility and stability which could potentially improve its utility for the biomedical field. KEY POINTS: • The combination of melittin and pyrrolidinium-based ILs showed improved antibacterial activity against E. coli and S. aureus which may be used for developing new antibacterial agents. • Moreover, the cytotoxicity and haemocompatibility results showed excellent biocompatibility of the combinations on human cell line and human serum albumin, respectively, which could potentially improve its utility for the biomedical field.

Linked drug-drug conjugates based on triterpene and phenol structures. Rational synthesis, molecular properties, toxicity and bioactivity prediction

One of the tasks of modern medicinal chemistry is to produce new molecules that have interesting and desired biological effects. In addition, the synthetic procedure for obtaining these compounds should be at least partially smart and rational e.g. “Lego” and green approaches. The study focuses on the synthesis of several hybrid type compounds that are expected to be characterized by beneficial bioactivities. In order to hybridize natural triterpene oleanolic acid and phenol structures, the linker-mode concept was selected. The synthetic goal was achieved in two stages. The first concerns the rapid introduction of the halogenoacidic linker to active phenols selected as a result of microwave-ultrasonic (MW-US) assisted O-alkylation with the use of 2-halogenoacetic acid. The next stage of the synthetic studies involves the reaction of phenoxyacetic acid derivatives obtained containing an active carboxylic group with oleanolic acid/oxime units by the methods typical of triterpene chemistry. Novel linked ester- and iminoester-type triterpene derivatives with phenols (thymol, eugenol, paracetamol, nipagins, naphthols, curcumin and genistein) were obtained and characterized. Additionally, based on the analysis of numerous references and selected methods of computational chemistry (Molinspiration Cheminformatics, Osiris Property Explorer and PASS method) the molecular parameters and the preliminary anti-inflammatory and antinociceptive activity characterising these molecules as potential drugs were calculated and predicted.

β-Cyclodextrin-modified hyaluronic acid-based supramolecular self-assemblies for pH- and esterase- dual-responsive drug delivery

Although some drug-based supramolecular systems have been constructed to overcome multidrug resistance and enhance the bioavailability of chemical drugs, strengthening the specific stimuli-responsive and active targeting ability of these systems is still a major challenge. In this paper, the synthesis and self-assembly behaviour of supramolecular self-assemblies with active targeting β-cyclodextrin-modified hyaluronic acid (HA-CD) and drug-drug conjugates (curcumin-oxoplatin, Cur-Pt) as building moieties were carefully investigated. Notably, the curcumin was chosen not only as the chemical anti-cancer drug, but also acted as the guest molecule which could be included into CD cavity to form host-guest interaction-based supramolecular assemblies. The obtained self-assemblies exhibited pH- and esterase-responsive drug release behaviours. Furthermore, basic cell experiments were performed to prove their effective cellular toxicity based on A549 cells and PC3 cells with high expression of CD44 receptor but they showed no toxicity to normal LO-2 cells with low expression of CD44 receptor, which suggests their potential application in the targeted drug release field.

Nanomolar photodynamic activity of porphyrins bearing 1,4,7-trioxanonyl and 2-methyl-5-nitroimidazole moieties against cancer cells

Despite the continuous development of medicine, there is still a lack of effective and fully safe protocols for the treatment of neoplastic diseases. The drug-drug conjugates approach seems to give a chance to obtain more efficient molecules. New alkoxy and metronidazole substituted porphyrins were synthesized. Novel porphyrins were purified by flash column chromatography and characterized using NMR, MS, UV–Vis and HPLC. The Nuclear Magnetic Resonance study was performed to annotate experimentally observed 1H NMR and 13C NMR signals of new compounds. The 2D NMR techniques such as 1H-1H COSY (Correlation Spectroscopy), 1H-13C HSQC (Heteronuclear Single Quantum Correlation) and 1H-13C HMBC (Heteronuclear Multiple Bond Correlation) were used for the structure elucidation of the new compounds. In the range of 250–450 nm of the absorption spectra, the Soret band was observed, whereas the Q band was noted in the range of 500–650 nm. Compounds revealed a fluorescence quantum yield in the range 0.03–0.12. Singlet oxygen generation quantum yields up to 0.54 were determined. Electrochemical properties has also been studied. It has been noticed electropolymerization of compound bearing 5-nitroimidazole substituents. The photodynamic activity of the studied porphyrins against A549 and HEK001/HPV16 cancer cells were examined. The most active against A549 and HEK 001/HPV16 was light-excited trioxanonylporphyrin with the values of IC50 equal to 0.49 μM and 50 nM respectively.

Molecular Consortia-Various Structural and Synthetic Concepts for More Effective Therapeutics Synthesis.

The design and discovery of novel drug candidates are the initial and most probably the crucial steps in the drug development process. One of the tasks of medicinal chemistry is to produce new molecules that have a desired biological effect. However, even today the search for new pharmaceuticals is a very complicated process that is hard to rationalize. Literature provides many scientific reports on future prospects of design of potentially useful drugs. Many trends have been proposed for the design of new drugs containing different structures (dimers, heterodimers, heteromers, adducts, associates, complexes, biooligomers, dendrimers, dual-, bivalent-, multifunction drugs and codrugs, identical or non-identical twin drugs, mixed or combo drugs, supramolecular particles and various nanoindividuals. Recently much attention has been paid to different strategies of molecular hybridization. In this paper, various molecular combinations were described e.g., drug–drug or drug-non-drug combinations which are expressed in a schematic multi-factor form called a molecular matrix, consisting of four factors: association mode, connection method, and the number of elements and linkers. One of the most popular trends is to create small–small molecule combinations such as different hybrids, codrugs, drug–drug conjugates (DDCs) and small-large molecule combinations such as antibody-drug conjugates (ADCs), polymer-drug conjugates (PDCs) or different prodrugs and macromolecular therapeutics. A review of the structural possibilities of active framework combinations indicates that a wide range of potentially effective novel-type compounds can be formed. What is particularly important is that new therapeutics can be obtained in fast, efficient, and selective methods using current trends in chemical synthesis and the design of drugs such as the “Lego” concept or rational green approach.

Facile Approach To Construct Ternary Cocktail Nanoparticles for Cancer Combination Therapy.

Drug combinations have been widely used in cancer treatment. However, it remains a formidable challenge to deliver three or more therapeutic agents in one nanoparticle with a precise and tunable molar ratio because of differences in pharmacokinetics and biodistribution of various anticancer drugs. Herein, we reported a facile approach to construct ternary cocktail nanoparticles, which are composed of three different anticancer drugs, such as gemcitabine, chlorambucil, and irinotecan, through the molecular coassembly of two amphiphilic drug-drug conjugates. The component of these nanoparticles can be simply adjusted by changing the feed ratio of two amphiphilic drug-drug conjugates in the coassembly process. Without the help of any drug carriers, they can self-deliver, release three drugs synchronally, and obtain the optimal synergistic therapeutic effect. This facile strategy may open a new way for cancer combination therapy.