Size-dependent secondary nucleation and amplification of α-synuclein amyloid fibrils

The size of the amyloid seeds is known to modulate their autocatalytic amplification and cellular toxicity. However, the seed size-dependent secondary nucleation mechanism, toxicity, and disease-associated biological processes mediated by α-synuclein (α-Syn) fibrils are largely unknown. Using the cellular model and in vitro reconstitution, we showed that the size of α-Syn fibril seeds not only dictates its cellular internalization and associated cell death; but also the distinct mechanisms of fibril amplification pathways involved in the pathological conformational change of α-Syn. Specifically, small-sized fibril seeds showed elongation possibly through monomer addition at the fibril termini; whereas longer fibrils template the fibril amplification by surface-mediated nucleation as demonstrated by super-resolution microscopy. The distinct mechanism of fibril amplification, and cellular uptake along with toxicity suggest that breakage of fibrils into different sizes of seeds determine the underlying pathological outcome of synucleinopathies.

Targeted Photodynamic Diagnosis and Therapy for Esophageal Cancer: Potential Role of Functionalized Nanomedicine

Esophageal cancer is often diagnosed at the late stage when cancer has already spread and is characterized by a poor prognosis. Therefore, early diagnosis is vital for a better and efficient treatment outcome. Upper endoscopy with biopsy is the standard diagnostic tool for esophageal cancer but is challenging to diagnose at its premalignant stage, while conventional treatments such as surgery, chemotherapy, and irradiation therapy, are challenging to eliminate the tumor. Photodynamic diagnosis (PDD) and therapy (PDT) modalities that employ photosensitizers (PSs) are emerging diagnostic and therapeutic strategies for esophageal cancer. However, some flaws associated with the classic PSs have limited their clinical applications. Functionalized nanomedicine has emerged as a potential drug delivery system to enhance PS drug biodistribution and cellular internalization. The conjugation of PSs with functionalized nanomedicine enables increased localization within esophageal cancer cells due to improved solubility and stability in blood circulation. This review highlights PS drugs used for PDD and PDT for esophageal cancer. In addition, it focuses on the various functionalized nanomedicine explored for esophageal cancer and their role in targeted PDD and PDT for diagnosis and treatment.

Glimpse into Cellular Internalization and Intracellular Trafficking of Lipid-Based Nanoparticles in Cancer Cells

: Lipid-based nanoparticles as drug delivery carriers have been mainly used for delivery of anti-cancer therapeutic agents. Lipid-based nanoparticles, due to their smaller particle size and similarity to cell membranes, are readily internalized into cancer cells. Interestingly, cancer cells also overexpress receptors for specific ligands including folic acid, hyaluronic acid, and transferrin on their surface. This allows the use of these ligands for surface modification of the lipid-based nanoparticle. These modifications then allow the specific recognition of these ligand-coated nanoparticles by their receptors on cancer cells allowing the targeted gradual intracellular accumulation of the functionalized nanoplatforms. These interactions could eventually enhance the internalization of desired drugs via increasing ligand-receptor mediated cellular uptake of the nanoplatforms. The cellular internalization of the nanoplatforms also varies and depends on their physicochemical properties including particle size, zeta potential, and shape. The cellular uptake is also influenced by the types of ligand internalization pathway utilized by cells such as phagocytosis, macropinocytosis, and multiple endocytosis pathways. In this review, we will classify and discuss lipid based nanoparticles engineered to express specific ligands, and are recognized by their receptors on cancer cell, and their cellular internalization pathways. Moreover, the intracellular fate of nanoparticles decorated with specific ligands and the best internalization pathways (caveolae mediated endocytosis) for safe cargo delivery will be discussed.