[4][6][7][8] This is advantageous because lower, less frequent dosing will be needed to have the same therapeutic effect in the patient, which will limit the cytotoxicity of the delivery system.
Pegfilgrastim stimulates production and release of neutrophils in patients who experience bone marrow toxicity after receiving myelosuppressive anticancer drugs or radiation.
[6] Ciliary neurotrophic factor (CNTF) is a cytokine used to combat diabetes symptoms such as appetite reduction and weight loss.
A major problem caused by pegylation is that the cytokine may change its molecular conformation, activity, and bioavailability upon PEG binding.
Systemic administration of huBC1-IL12 eliminated experimental PC3 metastases and suppressed the growth of multiple human tumor lines in immunocompromised mice more effectively than IL-12 alone.
[1][4] Nanoparticles can be made of organic or inorganic agents and possess the ability to stabilize cytokines in vivo, enhance activity at the target site, improve aqueous solubility, and reduce systemic toxicity.
[4][6] Solvent, pH, temperature, charge, and size are many parameters that influence the encapsulation efficiency, nanoparticle toxicity, and cytokine stability.
Liposomes can easily cross lipid bilayers and cell membranes but usually get rapidly eliminated in vivo unless stabilized with PEG or another polymer.
[1] Formation of liposomes can also present issues, as toxic solvents, high temperatures, and low pH can decrease the biosafety of the nanoparticles or denature the cytokine being delivered.
[13] Advantages of this nanoparticle design include multiple drug compartments for sequential cargo release, the ability to tailor surface chemistry with polymer layers to affect targeting and biodistribution, and improved pharmacokinetics.
[13] These layer-by-layer lipid nanoparticles significantly reduced IL-12 toxicity and demonstrated antitumor activity against colorectal and ovarian tumors at doses that were not tolerated with free IL-12 delivery[13] Gold nanoparticles are becoming increasingly popular as they exhibit high surface-to-volume ratio, they can easily travel to target cells, and they support high drug load.
[1][6] Gold nanoparticles can elicit an immune response that hinders their efficacy, so it is important to evaluate cellular response such as cytokine production and reactive oxygen species production[1] Silica nanoparticles have also been evaluated for cytokine delivery due to their high colloidal stability, extensive surface functionalization, and possibility to control both structure and pore size.
[1] However, silica nanoparticles present limitations for cytokine delivery due to the low internalization efficiency for larger biomolecules.
A phase II trial examined the safety and activity of plasmid encoding IL-12 followed by electroporation to treat stage III/IV unresectable melanoma.
PEI protects DNA from degradation in vivo, promotes interaction with negatively charged cell membranes, and enhances release from lysosomes by acting as a proton sponge.
Upon interaction with PLA2, the DNA nanoparticles transformed into nanofibers to deliver TRAIL to death receptors on the cancer cell membrane.
Anti-viral antibodies could be produced against viral cytokine delivery systems leading to delayed-type hypersensitivity responses, which may prevent repeated dosing.
Small volumes of intratumoral injection of adenoviruses were shown to cause significant transgene expression in the liver, intestine, spleen, kidney, and brain.
This mutated TNF cytokine was shown to only target endothelial cells of the tumor vasculature, allowing for a safe and effective delivery system.
[3] The homing capacity and tumor tropism capabilities of mesenchymal stem/stromal cells (MSCs) make them ideal drug delivery vehicles.
[2] Similarly, subcutaneous injections of bone marrow MSC-IFN-α affected tumor growth in vivo and increased overall survival in a multiple myeloma mouse model.
Antitumor effects were attributed to increased apoptosis of tumor cells, decreased microvessel density, and ischemic necrosis.
MSCs engineered to overexpress TRAIL have shown promising antitumor effects in xenograft models through apoptotic pathways.