<p>Thiol-Reactive Star Polymers Functionalized with Short Ethoxy-Containing Moieties Exhibit Enhanced Uptake in Acute Lymphoblastic Leukemia Cells</p>

Abstract

Directing nanoparticles to cancer cells without using antibodies is of great interest. Subtle changes to the surface chemistry of nanoparticles can significantly affect their biological fate, including their propensity to associate with different cell populations. For instance, nanoparticles functionalized with thiol-reactive groups can potentially enhance association with cells that over-express cell-surface thiol groups. The potential of such an approach for enhancing drug delivery for childhood acute lymphoblastic leukemia (ALL) cells has not been investigated. Herein, we investigate the impact of thiol-reactive star polymers on the cellular association and the mechanisms of uptake of the nanoparticles. Methods: We prepared fluorescently labeled star polymers functionalized with an mPEG brush corona and pyridyl disulfide to examine how reactivity to exofacial thiols impacts cellular association with ALL cells. We also studied how variations to the mPEG brush composition could potentially be used as a secondary method for controlling the extent of cell association. Specifically, we examined how the inclusion of shorter diethylene glycol brush moieties into the nanoparticle corona could be used to further influence cell association. Results: Star polymers incorporating both thiol-reactive and diethylene glycol brush moieties exhibited the highest cellular association, followed by those functionalized solely with thiol reactive groups compared to control nanoparticles in T and B pediatric ALL patient-derived xenografts harvested from the spleens and bone marrow of immunodeficient mice. Transfection of cells with an early endosomal marker and imaging with correlative light and electron microscopy confirmed cellular uptake. Endocytosis inhibitors revealed dynamindependent clathrin-mediated endocytosis as the main uptake pathway for all the star polymers. Conclusion: Thiol-reactive star polymers having an mPEG brush corona that includes a proportion of diethylene glycol brush moieties represent a potential strategy for improved leukemia cell delivery.

Thiolated-Polymer-Based Nanoparticles as an Avant-Garde Approach for Anticancer Therapies—Reviewing Thiomers from Chitosan and Hyaluronic Acid

“…It is also interesting to mention that Bayat et al explored how the functionalization of thiolated nanoparticles can affect drug delivery for childhood acute lymphoblastic leukemia (ALL), a study that had not been conducted before, even though ALL is the most common infant malignancy [163]. So far, most of the investigations regarding the use of nanoparticles for anticancer therapy have focused on treating solid tumors, so the fact that this group has developed an approach for hematological cancer is, by itself, worth mentioning.…”

“…So far, most of the investigations regarding the use of nanoparticles for anticancer therapy have focused on treating solid tumors, so the fact that this group has developed an approach for hematological cancer is, by itself, worth mentioning. In this case, Bayat and coworkers demonstrate that NPs based on star polymers made out of poly(oligoethylene glycol methyl ether acrylate) (POEGA), or POEGA and poly(diethylene glycol ethyl ether acrylate) (PDEGA), can be efficiently used for the objective previously stated, with the latter being more successful [163]. These star polymers were also thiolated and functionalized with several very short ethoxy repeating units in the outermost part.…”

“…Overall, it was demonstrated that thiolated and functionalized star polymers can be used to safely improve cellular association and uptake of diverse APIs in childhood ALL, opening a broad range of new opportunities for boosting thiomers' relevance in the treatment of blood cancers. In fact, some variants of these materials have already been developed for the delivery of siRNA and other chemical compounds involved in anticancer therapy (such as doxorubicin), as well as for magnetic resonance imaging contrast agents [163].…”

Nanoparticle Delivery Platforms for RNAi Therapeutics Targeting COVID-19 Disease in the Respiratory Tract

“…Subsequently, in the BALB/c nude mice model of pancreatic cancer in situ, the use of star polymer loaded with TUBB3 (βIII-tubulin) siRNA for treatment can silence the expression of βIII-tubulin and inhibit the growth and metastasis of pancreatic tumors [ 183 ]. In addition, star polymer–siRNA can also be used to enhance the drug delivery potential in acute lymphoblastic leukemia (ALL) cells [ 184 ].…”

Star Polymer Nanomedicines─Challenges and Future Perspectives

“…Nevertheless, further studies are warranted to confirm that this unique method is advantageous after conjugation with a drug and under in vivo conditions. 15 In an additional study by Somers et al, the utility of star polymers was explored for the delivery of siRNA to silence gene expression of hypoxia-inducible factor 1-alpha (HIF1α). In this study, star polymer-siRNA mediated gene silencing of HIF1α sensitized MLL-rearranged leukemia cells to inhibitor CCI-006.…”