Self-assembly inside cellular organelles: Aspects of functions and various strategies for cancer therapy

Self-assembly generates three-dimensional architectures through the non-covalent interactions of building blocks of various sizes, ranging from nanometers to micrometers, and the assembled structures may have new functions that the building blocks do not have. Cell self-assembly has attracted considerable attention in cancer treatment because it can overcome the side effects of conventional chemotherapy and the low therapeutic effect on drug-resistant cells. In addition, the trigger in the building block reacts with the specific environment of the cancer, such as pH, ions, redox reactions, enzymes, or receptors, facilitating cancer-targeted therapy. However, the precise control of self-assembly for the construction of nanostructures is difficult in harsh intracellular environments. To overcome this challenge, various researchers have investigated intracellular self-assembly. In particular, the self-assembly in cellular organelles is of great interest. Compared with self-assembly in the cytoplasm of cells, organelle-targeting self-assembly has the advantage of being able to self-assemble without side effects under more stable conditions with a relatively low concentration of building blocks. In this mini-review, we discuss the latest research on self-assembly inside or near organelles for cancer treatment

Spatiotemporal Self-Assembly of Peptides Dictates Cancer-Selective Toxicity

The intracellular or pericellular self-assembly of amphiphilic peptides is emerging as a potent cancer therapeutic strategy. Achieving the self-assembly of amphiphilic peptides inside a cell or cellular organelle is challenging due to the complex cellular environment, which consists of many amphiphilic biomolecules that may alter the self-assembling propensity of the synthetic peptides. Herein, we show that the hydrophobic-hydrophilic balance of the amphiphilic peptides determines the self-assembling propensity, thereby controlling the fate of the cell. A series of peptides were designed to target and self-assemble inside the mitochondria of cancer cells. The hydrophobicity of the peptides was tuned by varying their N-terminus capping. The analysis showed that the largest hydrophobic peptide was self-assembled before reaching the mitochondria and showed no selectivity toward cancer cells, whereas hydrophilic peptides could not self-assemble inside the mitochondria. Optimum balance between hydrophobicity and hydrophilicity is a critical factor for achieving self-assembly inside the mitochondria, thereby providing greater selectivity against cancer cells

Intra-mitochondrial self-assembly to overcome the intracellular enzymatic degradation ofl-peptides

The design of peptide-based therapeutics is generally based on the replacement ofl-amino acids withd-isomers to obtain improved therapeutic efficiency. However,d-isomers are expensive and frequently induce undesirable immune responses. In the present work, we demonstrate that an intra-mitochondrially self-assembling amphiphilic peptide exhibits analogous activity in bothd- andl-isomeric forms. This outcome is in contrast to the general observation considering higher therapeutic efficiencies ofd-isomers compared withl-analogues. This suggests thatl-peptides overcome proteolytic degradation during intra-mitochondrial self-assembly bothin vitroandin vivo

Supramolecular protection-mediated one-pot synthesis of cationic gold nanoparticles

Despite the extended use of cationic gold nanoparticles (AuNPs) in biomedical applications, direct one-pot synthesis of AuNPs with tunable size in aqueous media is limited due to the deleterious electrostatic attraction between AuCl4-anions and positively charged ligands. This paper describes the one-pot synthesis of cationic gold nanoparticles with size tunability based on host-guest chemistry. As the host molecule, cucurbit[7]uril inhibits self-aggregation in aqueous solution by threading positively charged guest ligands, which provides a shielding effect on the ligands. Reduction of the mixtures by directly adding NaBH4 generates cationic AuNPs with narrow size distributions. Furthermore, their potential in biomedical applications is demonstrated by siRNA transfection experiments. This approach relying on supramolecular-mediated interactions may provide new insights into organic/inorganic reactions that involve electrostatic disturbance

Targeting senescent retinal pigment epithelial cells facilitates retinal regeneration in mouse models of age-related macular degeneration

Although age-related macular degeneration (AMD) is a multifactorial disorder with angiogenic, immune, and inflammatory components, the most common clinical treatment strategies are antiangiogenic therapies. However, these strategies are only applicable to neovascular AMD, which accounts for less than 20% of all AMD cases, and there are no FDA-approved drugs for the treatment of dry AMD, which accounts for ~ 80% of AMD cases. Here, we report that the elimination of senescent cells is a potential novel therapeutic approach for the treatment of all types of AMD. We identified senescent retinal pigment epithelium (RPE) cells in animal models of AMD and determined their contributions to retinal degeneration. We further confirmed that the clearance of senescent RPE cells with the MDM2-p53 inhibitor Nutlin-3a ameliorated retinal degeneration. These findings provide new insights into the use of senescent cells as a therapeutic target for the treatment of AMD

CFD Simulation of Microchannel Reactor Block for Fischer–Tropsch Synthesis: Effect of Coolant Type and Wall Boiling Condition on Reactor Temperature

Computational fluid dynamic (CFD) simulation of heat transfer in a microchannel reactor block for low temperature Fischer–Tropsch (FT) synthesis was considered. Heat generation profiles for different operating conditions (GHSV 5000 h^–1; catalyst loading 60%–120%, where 100% loading equals 1060 kg/m³ of cobalt based catalyst from Oxford Catalyst Ltd.) were obtained from a single channel model. Simulations on a reactor block quantified the effects of three coolant types: cooling oil (Merlotherm SH), subcooled water and saturated water, on reactor temperature, and also evaluated the effect of wall boiling conditions. At process conditions of GHSV 5000 h^–1 and catalyst loading of 120%, predicted temperature gradients along channel length were 32, 17 and 12 K for cooling oil, subcooled water and saturated water, respectively. A modified reactor block showed improved thermal performance as well as heat transfer enhancement due to wall boiling conditions

Self???Assembly of Mitochondria???Targeted Photosensitizer to Increase Photostability and Photodynamic Therapeutic Efficacy in Hypoxia

The development of photosensitizers for cancer photodynamic therapy has been challenging due to their low photostability and therapeutic inefficacy in hypoxic tumor microenvironments. To overcome these issues, we have developed a mitochondria-targeted photosensitizer consisting of an indocyanine moiety with triphenylphosphonium arms, which can self-assemble into spherical micelles directed to mitochondria. Self-assembly of the photosensitizer resulted in a higher photostability by preventing free rotation of the indoline ring of the indocyanine moiety. The mitochondria targeting capability of the photosensitizer allowed it to utilize intramitochondrial oxygen. We found that the mitochondria-targeted photosensitizer localized to mitochondria and induced apoptosis of cancer cells both normoxic and hypoxic conditions through generation of ROS. The micellar self-assemblies of the photosensitizer were further confirmed to selectively localize to tumor tissues in a xenograft tumor mouse model through passive targeting and showed efficient tumor growth inhibition

Computational Fluid Dynamics Based Optimal Design of Guiding Channel Geometry in U‑Type Coolant Layer Manifold of Large-Scale Microchannel Fischer–Tropsch Reactor

A microchannel Fischer–Tropsch reactor retaining high heat and mass transfer performance requires uniform flow distribution on the coolant side to induce isothermal condition for controllable and sustainable operation. The present work improved the flow performance of a large-scale layer of over 100 channels by introducing an extremely simple guiding fin in the inlet and outlet rectangular manifolds. Case studies with three-dimensional computational fluid dynamics (CFD) were carried out where the upper and bottom lengths of the guiding fin were the main geometric variables. Then the optimization work was conducted to estimate the performance of the optimal design. The robustness for the proposed geometry was tested with varying the flow rate, fluid type, and temperature. The result showed that the proposed design can retain uniform distribution over a wide operation range (500 ≤ <i>Re</i>_GF ≤ 10800)