Polysaccharides are natural biological molecules that have numerous advantages for theranostics, the integrated approach of therapeutics and diagnostics. Their derivable reactive groups can be leveraged for functionalization with a nanoparticle-enabling conjugate, therapeutics (small molecules, proteins, peptides, photosensitizers) and/or diagnostic agents (imaging agents, sensors). In addition, polysaccharides are diverse in size and charge, biodegradable and abundant and show low toxicity in vivo. Polysaccharide-based nanoparticles are increasingly being used as platforms for simultaneous drug delivery and imaging and are therefore becoming popular theranostic nanoparticles. The review focuses on the method of nanoparticle formation (self-assembled, physical or chemical cross-linked) when engineering polysaccharide-based nanoparticles for theranostic nanomedicine. We highlight recent examples of polysaccharides-based theranostic systems from literature and their potential for use in the clinic, particularly chitosan- and hyaluronic acid-based NPs.

The non-invasive photodynamic therapy has been limited to treat superficial tumours, primarily ascribed to poor tissue penetration of light as the energy source. Herein, we designed a long-circulating hydrophilized titanium dioxide nanoparticle (HTiO2 NP) that can be activated by ultrasound to generate reactive oxygen species (ROS). When administered systemically to mice, HTiO2 NPs effectively suppressed the growth of superficial tumours after ultrasound treatments. In tumour tissue, the levels of proinflammatory cytokines were elevated several fold and intense vascular damage was observed. Notably, ultrasound treatments with HTiO2 NPs also suppressed the growth of deeply located liver tumours at least 15-fold, compared to animals without ultrasound treatments. This study provides the first demonstration of the feasibility of using HTiO2 NPs as sensitizers for sonodynamic therapy in vivo.

Cell based therapeutics are emerging as powerful regimens. To better understand the migration and proliferation mechanisms of implanted cells, a means to track cells in living subjects is essential, and to achieve that, a number of cell labeling techniques have been developed. Nanoparticles, with their superior physical properties, have become the materials of choice in many investigations along this line. Owing to inherent magnetic, optical or acoustic attributes, these nanoparticles can be detected by corresponding imaging modalities in living subjects at a high spatial and temporal resolution. These features allow implanted cells to be separated from host cells; and have advantages over traditional histological methods, as they permit non-invasive, real-time tracking in vivo. This review attempts to give a summary of progress in using nanotechnology to monitor cell trafficking. We will focus on direct cell labeling techniques, in which cells ingest nanoparticles that bear traceable signals, such as iron oxide or quantum dots. Ferritin and MagA reporter genes that can package endogenous iron or iron supplement into iron oxide nanoparticles will also be discussed.

Conventional chemotherapy is plagued with adverse side effects because cancer treatments are subject to numerous variations, most predominantly from drug resistance. Accordingly, multiple or multistage chemotherapeutic regimens are often performed, combining two or more drugs with orthogonal and possibly synergistic mechanisms. In this respect, glycol chitosan (GC)-based nanoparticles (CNPs) serve as an effective platform vehicle that can encapsulate both chemotherapeutics and siRNA to achieve maximal efficacy by overcoming resistance. Herein, DOX-encapsulated CNPs (DOX-CNPs) or Bcl-2 siRNA-encapsulated CNPs (siRNA-CNPs) exhibited similar physicochemical properties, including size, surface properties and pH sensitive behavior, regardless of the different physical features of DOX and Bcl-2 siRNA. We confirmed that the CNP platform applied to two different types of drugs results in similar in vivo biodistribution and pharmacokinetics, enhancing treatment in a dose-dependent fashion.

TNF-related apoptosis-inducing ligand (TRAIL) is a promising anti-cancer agent because of its selective ability to induce apoptosis in activated immune cells or cancer cells with minimal toxicity in normal cells. However, a short biological half-life and the development of inherent TRAIL resistance in a variety of cancer cells, including colorectal cancer cells (CRC), results in the poor performance of TRAIL as a chemotherapeutic agent. To overcome these limitation, we developed PEGylated TRAIL (PEG-TRAIL) to compensate the short half-life of TRAIL offering improved pharmacokinetics in non-human primates. In parallel, we found that pre-sensitization with doxorubicin resulted in the upregulated expression of the functional TRAIL receptor, DR5, in highly TRAIL-resistant HT-29 cells by Western blotting and qRT-PCR. Although neither individual treatment of doxorubicin nor TRAILPEG induced apoptosis, pre-sensitization with doxorubicin followed by PEG-TRAIL induced significant apoptosis through the activation of both extrinsic and intrinsic apoptotic pathways promoted by the cleavage of caspases 8, 9, and 3. DR5, but not DR4, was recruited to the TRAIL-induced Death-Inducing Signaling Complex (DISC) within HT-29 cells pre-sensitized with doxorubicin, suggesting a TRAIL/DR5 specific pathway in CRC. To maximize the therapeutic efficacy of the sensitizer in vivo, doxorubicin was encapsulated in tumor-homing hyaluronic acid nanoparticles (HAC/DOX). Confocal microscopy and HPLC analysis enabled us to observe the efficient uptake and biodistribution of HAC/DOX in tumor tissues from xenografted HT-29 cells. HAC/DOX effectively sensitized the xenograft tumor, bearing the highly TRAIL-resistant HT-29 cells to TRAIL-induced apoptosis through the upregulated expression of DR5 and activation of caspases. Our study suggests an innovative approach to overcome the inherent TRAIL-based therapeutic limitations by introducing long-acting TRAIL and a tumor-homing TRAIL sensitizer to induce cancer cell-specific apoptosis in TRAIL-resistant CRC, particularly in physiological conditions. Citation Format: Yumin Oh, Maggie Swierczewska, Seulki Lee. Strategy to overcome inherent TRAIL-based therapeutic limitations. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4395. doi:10.1158/1538-7445.AM2015-4395