Small molecule nanodrugs for cancer therapy

Nanoscale drug delivery systems (DDSs) have emerged as promising candidates for cancer therapy. However, traditional nanoscale DDSs suffer from several inherent drawbacks, including sophisticated synthesis, uncontrolled structure, low drug loading capacity, high reticuloendothelial system (RES) accumulation, unpredicted metabolic mechanism, and so on. In order to solve these problems, nanodrugs self-assembled from small molecules containing anticancer drugs have received great attention in recent years. Different from traditional nanoscale DDSs, small molecule nanodrugs (SMNs) exhibit unique advantages, such as simple synthesis, defined structure, high drug loading capacity, excellent tumor accumulation and low-toxic metabolism pathway. Hence, with rational design, SMNs can achieve excellent cancer therapeutic efficacy as well as low side effects, extremely promising for the clinic translation. Up to now, significant progress has been made for the exploration of SMNs for cancer therapy. In this review, we briefly summarize the design and synthesis, biological properties, as well as their wide range of applications for cancer therapy.     

Synthesis of indole based novel small molecules and their in vitro anti-proliferative effects on various cancer cell lines

Indole based novel small molecules were designed as potential anticancer agents. Multi step synthesis of these compounds was carried out by using Pd/C–Cu mediated coupling–cyclization strategy as a key step. The single crystal X-ray diffraction study was used to confirm the molecular structure of a representative compound unambiguously. Many of these compounds were evaluated for their anti-proliferative properties in vitro against six cancer cell lines as well as noncancerous cells. All these compounds showed selective growth inhibition of cancer cells and several of them were found to be promising with IC₅₀ values in the range of 0.1–1.2 μM, comparable to the known anticancer drug doxorubicin.     

The anti-lung cancer activity of propylene tethered dihydroartemisinin-isatin hybrids

Nineteen propylene tethered dihydroartemisinin-isatin hybrids 5a-g and 6a-l were designed, synthesized, and screened for their in vitro antiproliferative activity against three lung cancer cell lines, inclusive of drug-sensitive (A549), doxorubicin-resistant A549 (A549/DOX) and cisplatin-resistant A549 (A549/DDP) cell lines. The cytotoxicity of the synthesized hybrids towards normal lung epithelial cell line (BEAS-2B) was also assessed to evaluate the selectivity. The structure-activity relationship (SAR) elucidated that (1) alkyloxylimino fragment at C-3 position of isatin moiety were more favorable than the carbonyl and benzoxylimino, and the relative contricution order was methoxylimino > ethoxylimino > carbonyl > benzoxylimino; halogen atom at C-5 or C-6 position of isatin fragment could enhance the activity. Among them, hybrid 6f (IC₅₀: 21.7–28.9 μM) showed promising activity against the three tested lung cancer cell lines, and the activity was not inferior to that of cisplatin (IC₅₀: 19.7 and 66.9 μM) and doxorubicin (IC₅₀: 54.3 and 15.1 μM) against multidrug-resistant A549/DOX and A549/DDP lung cancer cell lines. In addition, hybrid 6f (IC₅₀: >100 μM) was non-cytotoxic towards normal lung epithelial cell line (BEAS-2B), and the RI values of hybrid 6f were 1.12 and 1.33. Further, hybrid 6f also possessed acceptable stability in mouse and human microsomes. Accordingly, hybrid 6a was a promising anti-lung cancer chemotherapeutic candidate and merited further evaluations.     

Functional polymer/inorganic hybrid nanoparticles for macrophage targeting delivery of oligodeoxynucleotides in cancer immunotherapy

To efficiently deliver CpG oligodeoxynucleotides (ODN) in cancer immunotherapy, a multifunctional macrophage targeting delivery system was designed and prepared. Mannosylated carboxymethyl chitosan/protamine sulfate/CaCO₃/ODN (MCMC/PS/CaCO₃/ODN) nanoparticles were prepared using a facile self-assembly method. The functional components, including MCMC to endow the nanoparticles with macrophage targeting ability, PS to improve the ODN loading capacity and enhance the cell uptake, and CaCO₃ to encapsulate ODN and induce the favorable pH sensitivity, were introduced to the delivery systems by self-assembly. Due to the mannose mediated endocytosis and the favorable effects of PS in overcoming delivery barriers, MCMC/PS/CaCO₃/ODN nanoparticles exhibit a much higher ODN delivery efficiency and a significantly enhanced immune stimulation capacity as compared with Lipofectamine 2000/ODN complexes. The regulation of NF-κB activity by our ODN delivery system results in dramatically increased production of proinflammatory cytokines including IL-12, IL-6, and TNF-α in RAW264.7 cells. The significantly increased CD80 expression after stimulation by the ODN delivery systems indicates the successful modulation of the macrophage polarity to the anti-tumor M1 phenotype. The multifunctional macrophage targeting delivery system developed has promising applications in delivery of CpG ODN in cancer immunotherapy.     

Effect of falciparum malaria infection on blood cholesterol and platelets

The current study is a hospital based investigation, in which attempts were being made to establish the effect of falciparum malarial infection on cholesterol level and platelet counts. The level of parasitaemia and its correlation with cholesterol level and platelet count in malaria patients was investigated. Two hundred clinically diagnosed malaria patients and 200 age matched healthy blood donors were included in the current study. In each case, blood sample was analyzed for serum cholesterol level and platelet count to establish a correlation between such parameters with paraesitemia. Based on the results obtained, it was evident that there was a highly significant reduction in the serum cholesterol level and the platelet count in malaria patients having high levels of parasitaemia. The low levels of cholesterol and platelets in malaria patients provided basis for the possible use of such clinical data in the diagnosis of malaria in the absence of a positive blood film.     

A protein-targeted photosensitizer for highly efficient cancer therapy

Photodynamic therapy typically employs photo-triggered photosensitizers to generate reactive oxygen species to destroy cancer cells. However, the therapeutic effect of photodynamic therapy is often limited owing to the ultrashort diffusion distance of reactive oxygen species and easy efflux of photosensitizers. Herein, we design and synthesize a protein-targeted molecular photosensitizer for highly efficient photodynamic therapy. The designed photosensitizer can covalently bind with the sulfhydryl groups of intracellular proteins to achieve the protein targeting. Under irradiated with near infrared laser, the photosensitizer was locally activated, and the produced reactive oxygen species directly destroy intracellular bioactive proteins, causing cell dysfunction and ultimately inducing cell apoptosis. Significantly, the leakage of molecular photosensitizer is effectually avoided due to the protein targeting. In vivo experimental results indicated that the effect of treatment was efficiently enhanced with the protein-targeted strategy. This work can offer new insights for designing protein-based therapeutic drugs.     

Recent applications of near-infrared spectroscopy in cancer diagnosis and therapy

In recent years, near-infrared spectroscopy (NIRS) has gained importance for non-invasive or minimally invasive diagnostic applications in cancer. This technology is based on differences of endogenous chromophores between cancer and normal tissues using either oxy-haemoglobin or deoxy-haemoglobin, lipid or water bands, or a combination of two or more of these as diagnostic markers. These marker bands provide a basis for the diagnosis and therapy monitoring of several cancers. Various applications also use advances in NIR fluorescence spectroscopy which is based on exogenous contrast-enhancing agents. In this review the literature published during the last seven years has been assessed. It will provide an overview on the importance of the NIRS tools in cancer pathology, and in the near future it is envisaged to play a crucial role in cancer diagnosis, treatment decisions, and defining therapeutic drug levels.     

D-A-D structured selenadiazolesbenzothiadiazole-based near-infrared dye for enhanced photoacoustic imaging and photothermal cancer therapy

Near-infrared (NIR) small molecular organic dyes as photothermal agents for cancer photothermal therapy (PTT) have attracted considerable research attention. Herein, two donor-acceptor-donor (D-A-D) structured NIR dyes, BBTT and SeBTT, are rationally designed, where the only difference is one heteroatom within the acceptor unit varying from sulfur to selenium (Se). More importantly, SeBTT NPs exhibit stronger NIR absorbance and higher photothermal conversion efficiency (PTCE ≈ 65.3%). In vivo experiments illustrate that SeBTT NPs can be utilized as a high contrast photoacoustic imaging (PAI) agent, and succeed in tumor suppression without noticeable damage to main organs under NIR photoirradiation. This study presents an effective molecular heteroatom surgery strategy to regulate the photothermal properties of NIR small molecules for enhanced PAI and PTT.     

pH-Sensitive nanoscale materials as robust drug delivery systems for cancer therapy

Cancer is one of the diseases that have the highest mortality,which threatens the human health.Chemotherapy functions as the most widely used strategy in clinic to treat cancer,still exists urgent problems,like lacking selectivity and causing severe side effects.According to detailed researches on the metabolism,functions and histology of cancer tissues,many different features of cancer are uncovered,like lower pH in microenvironment,abnormal redox level in intracellular compartments and elevated expression level of several enzymes and receptors.Recently,the development of smart nanoparticles that response to tumor specific microenvironment has lighted up hope for selective cancer therapy.Herein,this review mainly focuses on pH-sensitive nano scale materials for anti-cancer drug delivery.We summarized the formation progress of acidic tumor microenvironment,the mechanism of pHresponsive drug delivery system and nanomaterials that responsive to acidic pH in tumor microenvironment.     

Dynamic covalent chemistry-regulated stimuli-activatable drug delivery systems for improved cancer therapy

Drug delivery systems(DDSs) are of paramount importance to deliver drugs at the intended targets,e.g.,tumor cells or tissue by prolonging blood circulation and optimizing the pharmaceutical profiles.However,the therapeutic efficacy of DDSs is severely impaired by insufficient or non-specific drug release.Dynamic chemical bonds having stimuli-liable prope rties are the refore introduced into DDSs for regulating the drug release kinetics.This review summarizes the recent advances of dynamic covalent chemistry in the DDSs for improving cancer therapy.The review discusses the constitutions of the major classes of dynamic covalent bonds,and the respective applications in the tumor-targe ted DDSs which are based on the different responsive mechanisms,including acid-activatable and reduction-activatable.Furthermore,the review also discusses combination strategies of dual dynamic covale nt bonds which can response to the complex tumor microenvironment much more accurately,and then summarizes and analyzes the prospects for the application of dynamic covalent chemistry in DDSs.     

Resealed erythrocytes: Towards a novel approach for anticancer therapy

Cancer is one of the deadliest diseases in the history of mankind, accounting for almost 10 million deaths per year. Even though significant advances in chemotherapy have been made however many challenges need the attention of scientists for providing a safe and economic treatment. As a result, oncological science is focusing on developing innovative and effective pharmacotherapy such as targeted therapy, immunotherapy, gene therapy, laser therapy, RNA interference therapy, nanoparticles, and biocarrier therapeutics that can mitigate serious side effects induced by traditional treatments. Targeted drug delivery is one approach in which the drug is concentrated selectively at a particular tissue and is able to deliver cytotoxic drugs safely and effectively by making use of various carriers such as lipidic nanocarriers, metallic nanoparticles, liposomes, niosomes, and cellular carriers. Resealed erythrocytes have emerged as one of the most effective biocarriers studied recently because of their easy preparation and drug loading, biodegradability, and possess long circulation half-life. This article gives an insight on the source and isolation of erythrocytes, merits and demerits of using erythrocytes as a carrier, methods of drug encapsulation and release kinetics, and storage methods of red blood cells with special attention on using resealed erythrocytes as carriers for anti-tumor drugs.     

Erythrocyte-derived drug delivery systems in cancer therapy

As natural blood components,erythrocytes were good candidates for being used as drug delive ry systems to improve the pharmacokinetics,biocompatibility and many other aspects of different drugs.The advantages brought by erythrocytes making erythrocyte-derived drug delivery systems,also known as erythrocyte carriers,suitable for various anti-cancer agents,especially newly invented agents like nanoparticles,which were characterized by their undesired systematic toxicity,anaphylactic reactions and poor biocompatibility.Current researches on erythrocyte carriers in ca ncer therapy showed inspiring results in four major aspects:cancer enzyme therapy,delivering chemotherapeutic agents,combining with nanoparticles,and several other anti-cancer agents for gene or immune therapy.This novel delivering system was now undergoing the translation process from laboratory to clinical practice.Erythrocyte carriers for cancer enzyme therapy have entered the stage of clinical trial and have showed promising outcomes,and others were still at pre-clinical stage.In summary,erythrocyte-derived drug delivery system might play an indispensable role in the management of cancer in the future.     

Chitosan coated molybdenum sulphide nanosheet incorporated with tantalum oxide nanomaterials for improving cancer photothermal therapy

In recent years, two-dimensional nanomaterials (2D) prominent for site specific photothermal treatment (PTT), which are one of the most interesting strategy due to their maximizing cancer cell killing efficiency without the normal cells. Several robust methods are established for 2D material synthesis and improving the photothermal conversion efficiency (PCE), biocompatibility, and photostability in cancer PTT. Such preferred mechanism like nanomaterial decoration on to their surface would enable access to tunable 2D nanomaterial properties to improve cancer PTT. Here, we first time report a robust route for deposition of tantalum (TaO₂) on to chitosan (CS) coated molybdenum sulphite (MoS₂) nanosheet surface via electrostatic interaction, which assists to improve cancer PTT efficiency. Detailed studies prove that prepared TaO₂-CS-MoS₂ nanomaterial shows lack of toxicity, photostability and PCE was calculated from 26 °C to 47.2 °C under the 808 nm irradiation/5 min. Therefore, the TaO₂ deposition particularly interest to promote the photostability, biocompatibility and PCE of bare MoS₂ nanosheets. Therefore, the possible mechanism is highly expected to improve biological features in cancer PTT.     

Mitochondria targeted cancer therapy using ethidium derivatives

In this study, we reported on two novel fluorescent ethidium derivatives of MTP1 and MTP2 for selective and efficient cancer therapy. MTP1 and MTP2 exhibited cancer cell targeting and subsequent mitochondria targeting and imaging abilities. Moreover, both MTP1 and MTP2 would induce mitochondria depolarization and so along with a series of cascaded biochemical effects including the reduction of ATP production, destruction of intracellular redox potential balance and release of mitochondria cytochrome C (Cyt C), which could finally trigger caspase-dependent cell apoptosis. More interestingly, both MTP1 and MTP2 demonstrated significant cancer suppression abilities in vitro and in vivo, which presented a new paradigm for the development of unique anti-cancer agent candidates in precise and efficient cancer theranostics.     

Fabrication of ordered metallic and magnetic heterostructured DNA-Nanoparticle hybrids

Here we provide a method based on enzymatically catalyzed reactions to cleave and ligate DNA molecules coated with nanoparticles to fabricate multi-component structures. This is done by simultaneously digesting two solutions of nanoparticle coated DNA, one with iron oxide particles the other gold particles, which yields short DNA fragments with complementary single stranded overhangs. When added together and re-attached using ligase enzymes multi-component nanoparticle coated structures are formed providing a novel method to fabricate complicated nanoparticle arrangements from the bottom up. We evaluated the fabrication by characterizing the samples with gel electrophoresis and magnetic force microscopy (MFM). The electrophoresis provides proof that the coated DNA molecules were digested with restriction enzymes and ligated by the T4 ligase enzymes. MFM experiments allow us to visualize the multi-component strands and analyze the magnetic versus metallic segments.     

Synthesis and structural characterization of rac-2-[(diphenylphosphino)methyl]ferrocenecarboxylic acid, its selected derivatives and some rhodium complexes

rac-2-[(Diphenylphosphino)methyl]ferrocenecarboxylic acid (1) was prepared in a good yield from rac-2-(N,N-dimethylaminomethyl)bromoferrocene (2) via rac-2-(hydroxymethyl)bromoferrocene (4) and rac-2-[(diphenylphosphino)methyl]bromoferrocene (5), and further converted to the respective phosphine oxide (6), phosphine sulfide (7) and methyl ester (8). The phosphines 1 and 8 were studied as ligands in rhodium complexes. The reaction of di-μ-chloro-bis[chloro-(η⁵-pentamethylcyclopentadienyl)rhodium(III)] with the stoichiometric amounts of 1 and 8 yielded the corresponding mononuclear complexes with P-monodentate ligands: [RhC₂(η⁵-C₅Me₅)(L-κP)], 9 and 10, respectively. Attempted deprotonation of 9 with LiBu or KOt-Bu gave intractable mixtures, in which the parent complex 9 as the major component was accompanied by two new compounds, likely the diastereoizomeric phosphinocarboxylate complexes. A defined O,P-chelating phosphinocarboxylate complex, [SP-4-2]-carbonyl-[rac-2-{(diphenylphosphino)methyl}ferrocenecarboxylato-κ²O,P]-tricyclohexylphosphinerhodium(I) (12), was obtained from the displacement of acetylacetonate(1−) (acac) ligand in [Rh(acac)(CO)(PCy₃)] (Cy = cyclohexyl) with acid 1. The structures of 1, 6 · CHCl₃, and 7 · 1/2 CH₂Cl₂, 10, and hydrated complexes 9 and 12 were determined by single-crystal X-ray diffraction.     

Microstructure and properties of polyamideimide/silica hybrids compatibilized with 3-aminopropyltriethoxysilane

In this work, we prepared and characterized polyamideimide (PAI)/silica hybrids compatibilized with 3-aminopropyltriethoxysilane (APTES). PAI/silica nanohybrid thin films were prepared using an in situ sol-gel process, followed by thermal imidization. We have investigated the microstructures and properties of the PAI/silica hybrids using FT-IR spectroscopy, X-ray diffraction, small-angle X-ray scattering (SAXS), and differential scanning calorimetry (DSC). We also measured their tensile properties, thermal properties, refractive indices, and dielectric constants. In general, the properties of the PAI/silica hybrids were optimized when the silica content was 6 wt.%.