Tuning the properties of drug carries to improve life time and distribution in patient’s bodies

Updated: Mar 29

Changing the elasticity of nanogels that can be used as a carriers for the administration of various drugs in patients suffering from medical conditions like cancer improves their circulation time by evading immune cells.


March 23, 2022

Scientist at the Max Planck Institute for Medical Research in Heidelberg and their collaborators at the RWTH Aachen show the effects of tuning the mechanical properties of nanogels (NGs) on its overall distribution in the body. NGs are nanoscale soft gel particles that can be used as a carrier for the administration of various drugs in patients suffering from medical conditions like cancer. For delivery of the drug using a nanocarrier such as NGs, it is vital to design them in such a way that they become ‘invisible’ to the immune system and thus are prevented from being eliminated out of the blood circulation. The group demonstrates why and how small changes in the mechanical properties of the NGs prevent its uptake by the immune cells. PET/CT was used to show that by optimizing the NGs elasticity a significant enhancement in circulation half-life of the gel was achieved. Computer simulations affirmed the results and predicted the mechanism by which the NGs evaded the immune cells. Altogether, this work emphasizes the important role of mechanical properties such as the elasticity of the drug delivery carriers for better therapeutic efficacy. The findings were recently published in Angewandte Chemie.

Peptide receptor radionuclide therapy (PRRT) is used to treat solid tumors by delivering radiation that targets specific receptors highly expressed in the tumor cells compared to healthy cells. Although PRRT holds promising advancement in nuclear medicine, it suffers from limitations such as toxic side effects for the liver and kidneys, which restricts its applied dose. To improve the efficacy of PRRT, nanocarriers such as NGs can be used. They are nanoscale soft gel particles that can be used as a carrier for the administration of various drugs in patients suffering from medical conditions like cancer. Their use can prevent non-specific organ accumulation, improve the distribution within the body, and thus can enhance the therapeutic effects of the radionuclide. However, to do so the main challenge the nanocarriers encounter is the immune system.


Evading immune cells

In this work, the researchers synthesized highly hydrophilic PEG-based NGs with an elasticity of 37KPa, which resembles soft jelly candies, but on a nanoscale. They show that uptake of such soft NG was drastically reduced by the immune cells. The highly hydrophilic nature of these PEG-based NGs tends to have i) low adhesive interaction with the cell membrane and ii) due to the low elastic modulus of the NGs, its contact area with the cell membrane increases, leading to deformation and spreading of the NGs on the cell membrane of immune cells. This large deformability of soft NGs requires more energy for cellular engulfment and thus prevents its uptake. ‘Thus modulation of mechanical property can be used as a tool to design different types of nanocarriers for drug delivery application for better therapeutic outcome’ says Smriti Singh, Departmental Research Group Leader at the MPIMR.


Simulation snapshots of single A) hard and B) soft nanogels at lipid membranes at different simulation times. Smriti Singh, MPI for Medical Research

In vivo evaluation

The NGs were labeled with a radionuclide, Gallium-68 (68Ga) and visualized using PET/CT in a mouse model. The result demonstrated enhanced circulation time of the soft NGs compared to their stiffer counterparts. The researchers also observed the ability of soft NGs to squeeze through the splenic pores owing to its deformable nature resulting in fast renal clearance. ‘In a follow-up study, these NGs will be radiolabeled with Lutetium-177 (177Lu) to target the somatostatin receptor 2 (SStR2) expressed in neuroendocrine tumors and will be further investigated for kidney toxicity’ says Prachi Desai, the first author on the paper and PhD student working with Smriti Singh.


In vivo profiles of different radiolabeled nanogels. A) PET/CT images of radiolabeled NGs injected in vivo at 1h and B) 4h post injection (p.i.) showing an increased circulation of soft NGs. SUV: Standardised uptake value, HU: Hounsfield units. Smriti Singh, MPI for Medical Research


The group strongly believes that modulating the stiffness of nanocarriers will potentially improve the delivery of drugs and minimize the side effects, especially in cancer treatments where chemotherapy and endogeneous radiotherapy are used.


Publication

Desai, P., Rimal, R., Florea, A., Gumerov, R..A., Santi, M., Sorokina, A..S., Sahnoun, S..E.M., Fischer, T., Mottaghy, F..M., Morgenroth, A., Mourran, A., Potemkin, I..I., Möller, M. and Singh, S. (2022) Tuning the Elasticity of Nanogels Improves their Circulation Time by Evading Immune Cells. Angew. Chem. Int. Ed.. Accepted Author Manuscript.

https://doi.org/10.1002/anie.202116653


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