Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that has no therapeutic targets, relies on chemotherapeutics for treatment, and is in dire need of novel therapeutic approaches for improved patient outcomes. Extracellular vesicles (EVs) serve as intercellular communicators and have been proposed as ideal drug delivery vehicles. Here, EVs were engineered with RNA nanotechnology to develop TNBC tumor inhibitors. Using super resolved-structured illumination microscopy, EVs were optimized for precise Survivin small interfering RNA (siRNA) conjugated to chemotherapeutics loading and CD44 aptamer ligand decoration, thereby enhancing specificity toward TNBC cells. Conventional treatments typically employ chemotherapy drugs gemcitabine (GEM) and paclitaxel (PTX) at dosages on the order of mg/kg respectively, per injection (intravenous) in mice. In contrast, engineered EVs encapsulating these drugs saw functional tumor growth inhibition at significantly reduced concentrations: 2.2 μg/kg for GEM or 5.6 μg/kg for PTX, in combination with 21.5 μg/kg survivin-siRNA in mice. The result is a substantial decrease in the chemotherapeutic dose required, by orders of magnitude, compared with standard regimens. In vivo and in vitro evaluations in a TNBC orthotopic xenograft mouse model demonstrated the efficacy of this decreased dosage strategy, indicating the potential for decreased chemotherapy-associated toxicity.
| Original language | English |
|---|---|
| Pages (from-to) | 4467-4481 |
| Number of pages | 15 |
| Journal | Molecular Therapy |
| Volume | 32 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 4 2024 |
Bibliographical note
Publisher Copyright:© 2024 The American Society of Gene and Cell Therapy
Funding
P.G.\u2019s Sylvan Frank Endowed Chair in Pharmaceutics and Drug Delivery position is supported by the Chen\u2019s Foundation. P.G. is the consultant, licensor, and grantee of Oxford Nanopore Technologies. P.G. also has a patent EP3440090B1 RNA ligand-displaying exosomes for specific delivery of therapeutics to cell by RNA nanotechnology. This work was supported by the National Cancer Institute (NCI) grants R01CA257961 to D.S. and D.W.B. and U01CA207946 to P.G. Confocal, TEM, and SR-SIM images presented in this report were generated with the instruments and services at the Campus Microscopy and Imaging Facility (CMIF) (RRID: SCR_025078), The Ohio State University. This facility is supported in part by P30CA016058 also from the NCI with the Nikon N-SIM system acquired with support of NIH S10OD025008 grant. The authors thank Preeti (Pieter) Grewal for processing the unloaded and undecorated EV image. We would like to thank the Schwartz Lab at The Ohio State University Department of Chemistry for use of the NTA. We also thank Dr. Jeff Tonniges for acquiring the TEM images of the EVs. Dr. Stephani Amici and Dr. Anthony Vetter also provided significant assistance for imaging on the Nikon Ti-2 and AXR. This work was supported by the National Cancer Institute (NCI) grants R01CA257961 to D.S. and D.W.B. and U01CA207946 to P.G. Confocal, TEM, and SR-SIM images presented in this report were generated with the instruments and services at the Campus Microscopy and Imaging Facility (CMIF) (RRID: SCR_025078), The Ohio State University. This facility is supported in part by P30CA016058 also from the NCI with the Nikon N-SIM system acquired with support of NIH S10OD025008 grant. The authors thank Preeti (Pieter) Grewal for processing the unloaded and undecorated EV image. We would like to thank the Schwartz Lab at The Ohio State University Department of Chemistry for use of the NTA. We also thank Dr. Jeff Tonniges for acquiring the TEM images of the EVs. Dr. Stephani Amici and Dr. Anthony Vetter also provided significant assistance for imaging on the Nikon Ti-2 and AXR. We would like to acknowledge Dr. Emanuele Coccuci, and Dr. Comert Kurel for their invaluable insights on interpreting and confirming the SIM data.
| Funders | Funder number |
|---|---|
| Chen’s Foundation | |
| Schwartz Lab | |
| Ohio Water Resources Center, Ohio State University | P30CA016058 |
| Ohio Water Resources Center, Ohio State University | |
| National Childhood Cancer Registry – National Cancer Institute | SCR_025078, U01CA207946, R01CA257961 |
| National Childhood Cancer Registry – National Cancer Institute | |
| National Institutes of Health (NIH) | S10OD025008 |
| National Institutes of Health (NIH) |
Keywords
- CD44
- RNA nanotechnology
- TNBC
- cancer therapy
- extracellular vesicles
- survivin siRNA
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Genetics
- Pharmacology
- Drug Discovery
