Abstract
Liposomal spherical nucleic acids (L-SNAs) show significant promise as cancer immunotherapeutics. L-SNAs are highly modular nanoscale assemblies defined by a dense, upright radial arrangement of oligonucleotides around a liposomal core. Herein, we establish a set of L-SNA design rules by studying the biological and immunological properties of L-SNAs as a function of liposome composition. To achieve this, we synthesized liposomes where the lipid phosphatidylcholine headgroup was held constant, while the diacyl lipid tail chain length and degree of saturation were varied, using either 1,2-dioleylphosphatidylcholine (DOPC), 1,2-dimyristoyl-phosphatidylcholine (DMPC), 1,2-dipalmitoylphosphatidylcholine (DPPC), or 1,2-distearoyl-phosphatidylcholine (DSPC). These studies show that the identity of the constituent lipid dictates the DNA loading, cellular uptake, serum stability, in vitro immunostimulatory activity, and in vivo lymph node accumulation of the L-SNA. Furthermore, in the 4T1 mouse model of triple-negative breast cancer (TNBC), the subcutaneous administration of immunostimulatory L-SNAs synthesized with DPPC significantly decreases the production of lung metastases and delays tumor growth as compared to L-SNAs synthesized using DOPC, due to the enhanced stability of L-SNAs synthesized with DPPC over those synthesized with DOPC. Moreover, the inclusion of cell lysates derived from Py8119 TNBC cells as antigen sources in L-SNAs leads to a significant increase in antitumor efficacy in the Py8119 model when lysates are encapsulated in the cores of L-SNAs synthesized with DPPC rather than DOPC, presumably due to increased codelivery of adjuvant and antigen to dendritic cells in vivo. This difference is further amplified when using lysates from oxidized Py8119 cells as a more potent antigen source, revealing synergy between the lysate preparation method and liposome composition in synthesizing immunotherapeutic L-SNAs. Together, this work shows that the biological properties and immunomodulatory activity of L-SNAs can be modulated by exchanging liposome components, providing another handle for the rational design of nanoscale immunotherapeutics.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 892-899 |
| Number of pages | 8 |
| Journal | ACS Central Science |
| Volume | 7 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 26 2021 |
Funding
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health Award U54CA199091. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The project was also supported by the Prostate Cancer Foundation and the Movember Foundation award 17CHAL08, the Polsky Urologic Cancer Institute of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University at Northwestern Memorial Hospital, and the Air Force Research Laboratory agreement FA8650-15-2-5518. The U.S. Government is authorized to reproduce and distribute reprints for Governmental purposes notwithstanding any copyright notation thereon. The views and conclusions contained herein are those of the authors and should not be interpreted as necessarily representing the official policies or endorsements, either expressed or implied, of Air Force Research Laboratory or the U.S. Government. C.E.C. was supported by a Postdoctoral Fellowship, PF-20-046-01 - LIB, from the American Cancer Society, as well as the Eden and Steven Romick Postdoctoral Fellowship through the American Committee for the Weizmann Institute of Science. J.W.D. acknowledges support by the Chemistry of Life Processes Predoctoral Training Program at Northwestern University. L.B. acknowledges support from Northwestern URG award 923ACADYR1916683. The content is solely the responsibility of the authors and does not necessarily represent the official views of Northwestern University.
ASJC Scopus subject areas
- General Chemical Engineering
- General Chemistry
