Scaled Formulations of Succinate based Polymeric particles for Eventual Testing in Clinical Settings

Description

With an estimated 19.3 million cases and nearly 10 million deaths from cancer in a year worldwide, immunotherapies, which stimulate the immune system so that it can attack and kill cancer cells, are of interest. Tumors are produced from the

With an estimated 19.3 million cases and nearly 10 million deaths from cancer in a year worldwide, immunotherapies, which stimulate the immune system so that it can attack and kill cancer cells, are of interest. Tumors are produced from the uncontrolled and rapid proliferation of cells in the body. Cancer cells rely heavily on glutamine for proliferation due to its contribution of nitrogen for nucleotides and amino acids. Glutamine enters the tricarboxylic acid (TCA) cycle as α-ketoglutarate via glutaminolysis, in which glutamine is converted into glutamate by the enzyme glutaminase (GLS). Cancer cell proliferation may be limited by using glutaminase inhibitor CB-839. However, immune cells also rely on these metabolic pathways. Thus, a method for restarting the metabolic pathways in the presence of inhibitors is attractive. Succinate, a key metabolite in the TCA cycle, has been shown to stimulate the immune system despite the presence of metabolic inhibitors, such as CB-839. A delivery method of succinate is through microparticles (MPs) or nanoparticles (NPs) which may be coated in polyethylene glycol (PEG) for improved hydrophilicity. Polyethylene glycol succinate (PEGS) MPs were generated and tested in vivo and were shown to reduce tumor growth and prolong mouse survival. With the success in stimulating the immune system with MPs, NPs were investigated for an improved immune response due to their smaller size. These PES NPs were generated in this study. For clinical settings, it is necessary to scale-up the production of particles. Two methods of scale-up were proposed: (1) a combination of multiple small batches into a mixed batch, and (2) a singular, big batch. Size and release properties were compared to a small batch of PES NPs, and it was concluded that the big batch more closely resembled the small batch compared to the mixed batch. Thus, it was concluded that batch-to-batch variability plays a larger role than volume changes when scaling-up. In clinical settings, it is recommended to produce the particles in a big batch rather than a mixed batch.

Date Created
2023-05
Agent

Engineering the Immune System using Metabolite-based Polymers for Cancer Immunotherapy

171409-Thumbnail Image.png
Description
Drug delivery has made a significant contribution to cancer immunotherapy and can have a tremendous impact on modulating immunometabolism, thereby affecting cancer outcomes. Notably, the science of delivery of cancer vaccines and immunotherapeutics, modulating immune cell functions has inspired development

Drug delivery has made a significant contribution to cancer immunotherapy and can have a tremendous impact on modulating immunometabolism, thereby affecting cancer outcomes. Notably, the science of delivery of cancer vaccines and immunotherapeutics, modulating immune cell functions has inspired development of several successful companies and clinical products. For example, cancer vaccines require activation of dendritic cells (DCs) and tumour associated Mɸs (TAMs) through modulation of their energy metabolism (e.g., glycolysis, glutaminolysis, Krebs cycle). Similar to activated immune cells, cancer cells also upregulate glucose and glutamine transporters for proliferation and survival. Cancer cells having accelerated energy metabolism, which has been exploited as a target for various therapeutic studies. In the first strategy, an immunometabolism strategy based on sustained release of succinate from biomaterials, which incorporate succinate in the backbone of the polymer was developed. This study demonstrates that succinate-based polymeric microparticles act as alarmins by modulating the immunometabolism of DCs and Mɸs to generate robust pro-inflammatory responses for melanoma treatment in immunocompetent young as well as aging mice. In the second strategy, a biomaterial-based strategy was developed to deliver metabolites one-step downstream of the node where the glycolytic pathway is inhibited, to specifically rescue DCs from glycolysis inhibition. The study successfully demonstrated for the first time that the glycolysis of DCs can be rescued both in vitro and in vivo using a biomaterial strategy of delivering metabolites downstream of the inhibitory node. Overall, it is believed that advanced drug delivery strategies will play an important role in marrying the fields of immunometabolism and immunotherapy to generate translatable anti-cancer treatments.
Date Created
2022
Agent

Hydrogel Nanosensors for Colorimetric Detection and Dosimetry in Proton Beam Radiotherapy

156032-Thumbnail Image.png
Description
Proton beam therapy (PBT) is a state-of-the-art radiotherapy treatment approach that uses focused proton beams for tumor ablation. A key advantage of this approach over conventional photon radiotherapy (XRT) is the unique dose deposition characteristics of protons, resulting in superior

Proton beam therapy (PBT) is a state-of-the-art radiotherapy treatment approach that uses focused proton beams for tumor ablation. A key advantage of this approach over conventional photon radiotherapy (XRT) is the unique dose deposition characteristics of protons, resulting in superior healthy tissue sparing. This results in fewer unwanted side effects and improved outcomes for patients. Current available dosimeters are intrinsic, complex and expensive; hence cannot be used to determine the dose delivered to the tumor routinely. Here, we report a hydrogel based plasmonic nanosensor for measurements of clinical doses in ranges between 2-4 GyRBE. In this nanosensor, gold ions, encapsulated in a hydrogel, are reduced to gold nanoparticles following irradiation with proton beams. Formation of gold nanoparticles renders a color change to the originally colorless hydrogel. The intensity of the color can be used to calibrate the hydrogel nanosensor in order to quantify different radiation doses employed during treatment. The potential of this nanosensor for clinical translation was demonstrated using an anthropomorphic phantom mimicking a clinical radiotherapy session. The simplicity of fabrication, detection range in the fractionated radiotherapy regime and ease of detection with translational potential makes this a first-in-kind plasmonic colorimetric nanosensor for applications in clinical proton beam therapy.
Date Created
2017
Agent

Emerging Applications of Exosomes in Cancer Therapeutics and Diagnostics

128357-Thumbnail Image.png
Description

Exosomes are nanoscale extracellular vesicles that are shed from different cells in the body. Exosomes encapsulate several biomolecules including lipids, proteins, and nucleic acids, and can therefore play a key role in cellular communication. These vesicles can be isolated from

Exosomes are nanoscale extracellular vesicles that are shed from different cells in the body. Exosomes encapsulate several biomolecules including lipids, proteins, and nucleic acids, and can therefore play a key role in cellular communication. These vesicles can be isolated from different body fluids and their small sizes make them attractive in various biomedical applications. Here, we review state-of-the art approaches in exosome isolation and purification, and describe their potential use in cancer vaccines, drug delivery, and diagnostics.

Date Created
2017-03
Agent