This work demonstrates that targeting ligand density on nanoparticles can affect interactions between the nanoconstructs and cell membrane receptors. We discovered that when the separation between covalently grafted DNA aptamers on gold nanostars was comparable to the distance between binding sites on a receptor dimer (matched density; MD), nanoconstructs exhibited a higher selectivity for binding to the dimeric form of the protein. Single-particle dynamics of MD nanoconstructs showed slower rotational rates and larger translational footprints on cancer cells expressing more dimeric forms of receptors (dimer+) compared with cells having more monomeric forms (dimer-). In contrast, nanoconstructs with either increased (nonmatched density; NDlow) or decreased ligand spacing (NDhigh) had minimal changes in dynamics on either dimer+ or dimer- cells. Real-time, single-particle analyses can reveal the importance of nanoconstruct ligand density for the selective targeting of membrane receptors in live cells.

Specific interactions between ligands and receptors on cell surface play an important role in the cell biological process. Nucleic acid aptamers as commonly used ligands enable specific recognition and tight binding to membrane protein receptors for modulation of cell fate. Therefore, molecular probes with aptamers can be applied for cancer diagnosis and targeted therapy by targeting overexpression membrane proteins of cancer cells. However, because of their fast degradation and rapid glomerulus clearance in vivo, the applications of aptamers in physiological conditions remain challenged. Inspired by natural multivalent interactions, many approaches have been developed to construct multivalent aptamers to improve the performance of aptamers in complex matrices with higher binding affinity, more stability, and longer circulation time. In this review, we first introduce the aptamer generation from purified protein-based SELEX and whole cell-based SELEX for targeting the cell surface. We then highlight the approaches to fabricate multivalent aptamers and discuss their properties. By integrating different materials (including inorganic nanomaterials, diacyllipid, polymeric nanoparticles, and DNA nanostructures) as scaffolds with an interface modification technique, we have summarized four kinds of multivalent aptamers. After that, representative applications in biosensing and targeted therapy are illustrated to show the elevated performance of multivalent aptamers. In addition, we analyze the challenges and opportunities for the clinical practices of multivalent aptamers.

The usefulness of Marine-derived products as the source of anticancer agents has been explored for many decades. The objective of our study was to investigate the molecular mechanism by which C-PC induces apoptosis in monotherapy as well as in combination treatment with a known chemotherapeutic drug named Topotecan (TPT) using prostate cancer cells (LNCaP). To determine the intracellular mechanism of action, we analyzed the gene expression profile of C-PC treated cells using human apoptosis RT2 profiler PCR array, which indicated that C-PC was able to regulate both anti- and pro-apoptotic genes significantly. Detailed analysis revealed increases in the levels of Bax, Apaf-1 (pro-apoptotic proteins) along with the activation of the key apoptotic proteases such as caspase-8, caspase-9, and caspase-3. Similarly, analysis of anti-apoptotic proteins demonstrated a decrease in the expression of Bcl-2, Mcl-1, and survivin. Results from the whole-cell incubation studies indicated that C-PC was only binding to the plasma membrane-associated receptor proteins. LNCaP cells treated with C-PC alone and in combination with TPT showed increased expression of the death receptor FAS (also known as FAS or CD95) along with cleaved PARP, confirming its importance. Our study is significant since it is providing greater insight into the apoptotic mechanisms triggered by C-PC as well as emphasizing the involvement of FAS in mediating its effects. Furthermore, our results with combination treatments suggest that-PC could improve the anticancer effects of drugs such as TPT that are currently used for cancer treatments. In addition, use of C-PC in combination can also diminish the side effects resulting from conventional chemotherapeutic agents such as TPT.

Elucidation of the communication between metal complexes and cell membrane may provide useful information for rational design of metal-based anticancer drugs. Herein we synthesized a novel class of ruthenium (Ru) complexes containing phtpy derivatives (phtpy = phenylterpyridine), analyzed their structure-activity relationship and revealed their action mechanisms. The result showed that, the increase in the planarity of hydrophobic Ru complexes significantly enhanced their lipophilicity and cellular uptake. Meanwhile, the introduction of nitro group effectively improved their anticancer efficacy. Further mechanism studies revealed that, complex (2c), firstly accumulated on cell membrane and interacted with death receptors to activate extrinsic apoptosis signaling pathway. The complex was then transported into cell cytoplasm through transferrin receptor-mediated endocytosis. Most of the intracellular 2c accumulated in cell plasma, decreasing the level of cellular ROS, inducing the activation of caspase-9 and thus intensifying the apoptosis. At the same time, the residual 2c can translocate into cell nucleus to interact with DNA, induce DNA damage, activate p53 pathway and enhance apoptosis. Comparing with cisplatin, 2c possesses prolonged circulation time in blood, comparable antitumor ability and importantly, much lower toxicity in vivo. Taken together, this study uncovers the role of membrane receptors in the anticancer actions of Ru complexes, and provides fundamental information for rational design of membrane receptor targeting anticancer drugs.

The central issue of this review are inflammatory changes that take place in the mucous membranes of the respiratory tract as a result of inhaled pollutants. Of particular relevance are dusts, SO(2), ozone, aldehydes und volatile organic compounds. Bioorganic pollutants, especially fragments of bacteria and fungi, occur predominantly in indoor dusts. They activate the toll-like/IL-1 receptor and lead to the activation of the transcription factor NF-κB for the release of numerous proinflammatory cytokines. Metals are predominant in ambient air dust particles. They induce the release of reactive oxygen species that cause damage to lipids, proteins and the DNA of the cell. As well as NF-κB, transcription factors that foster proliferation are activated via stress activated protein kinases. Organic compounds such as polycyclic aromatic hydrocarbons and nitroso-compounds of incomplete combustion processes activate additional via the cytosolic arylhydrocarbon receptor for detoxification enzymes. Sulphur dioxide leads to acid stress, and ozone to oxidative stress of the cell. This is accompanied by the release of proinflammatory cytokines via stress activated protein kinases. Aldehydes and volatile organic compounds activate the vanilloid receptor of trigeminal nerve fibres and induce a hyperreactivity of the mucous membrane via the release of nerve growth factors. The mechanisms described work synergistically and lead to a chronic inflammatory reaction of the mucous membranes of the upper respiratory tract that is regularly demonstrable in inhabitants of western industrial nations. It is unclear whether we are dealing here with a physiological inflammation or with an at least partially avoidable result of chronic pollutant exposure.