An Aptamer That Rapidly Internalizes into Cancer Cells Utilizes the Transferrin Receptor Pathway
Strategies to direct drugs specifically to cancer cells have been increasingly explored, and significant progress has been made toward such targeted therapy. For example, drugs have been conjugated into tumor-targeting antibodies to enable delivery directly to tumor cells. Aptamers are an attractive...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-04-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/15/8/2301 |
| _version_ | 1811153801911992320 |
|---|---|
| author | Xirui Song Haixiang Yu Cynthia Sullenger Bethany Powell Gray Amy Yan Linsley Kelly Bruce Sullenger |
| author_facet | Xirui Song Haixiang Yu Cynthia Sullenger Bethany Powell Gray Amy Yan Linsley Kelly Bruce Sullenger |
| author_sort | Xirui Song |
| collection | DOAJ |
| description | Strategies to direct drugs specifically to cancer cells have been increasingly explored, and significant progress has been made toward such targeted therapy. For example, drugs have been conjugated into tumor-targeting antibodies to enable delivery directly to tumor cells. Aptamers are an attractive class of molecules for this type of drug targeting as they are high-affinity/high-specificity ligands, relatively small in size, GMP manufacturable at a large-scale, amenable to chemical conjugation, and not immunogenic. Previous work from our group revealed that an aptamer selected to internalize into human prostate cancer cells, called E3, can also target a broad range of human cancers but not normal control cells. Moreover, this E3 aptamer can deliver highly cytotoxic drugs to cancer cells as Aptamer-highly Toxic Drug Conjugates (ApTDCs) and inhibit tumor growth in vivo. Here, we evaluate its targeting mechanism and report that E3 selectively internalizes into cancer cells utilizing a pathway that involves transferrin receptor 1 (TfR 1). E3 binds to recombinant human TfR 1 with high affinity and competes with transferrin (Tf) for binding to TfR1. In addition, knockdown or knockin of human TfR1 results in a decrease or increase in E3 cell binding. Here, we reported a molecular model of E3 binding to the transferrin receptor that summarizes our findings. |
| first_indexed | 2024-03-11T05:10:13Z |
| format | Article |
| id | doaj.art-8efa3219aefc43a2b0a42d367dc99650 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T05:10:13Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-8efa3219aefc43a2b0a42d367dc996502023-11-17T18:39:04ZengMDPI AGCancers2072-66942023-04-01158230110.3390/cancers15082301An Aptamer That Rapidly Internalizes into Cancer Cells Utilizes the Transferrin Receptor PathwayXirui Song0Haixiang Yu1Cynthia Sullenger2Bethany Powell Gray3Amy Yan4Linsley Kelly5Bruce Sullenger6Department of Surgery, Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USADepartment of Surgery, Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USADepartment of Biology, Duke University, Durham, NC 27710, USADepartment of Surgery, Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USADepartment of Surgery, Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USADepartment of Surgery, Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USADepartment of Surgery, Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USAStrategies to direct drugs specifically to cancer cells have been increasingly explored, and significant progress has been made toward such targeted therapy. For example, drugs have been conjugated into tumor-targeting antibodies to enable delivery directly to tumor cells. Aptamers are an attractive class of molecules for this type of drug targeting as they are high-affinity/high-specificity ligands, relatively small in size, GMP manufacturable at a large-scale, amenable to chemical conjugation, and not immunogenic. Previous work from our group revealed that an aptamer selected to internalize into human prostate cancer cells, called E3, can also target a broad range of human cancers but not normal control cells. Moreover, this E3 aptamer can deliver highly cytotoxic drugs to cancer cells as Aptamer-highly Toxic Drug Conjugates (ApTDCs) and inhibit tumor growth in vivo. Here, we evaluate its targeting mechanism and report that E3 selectively internalizes into cancer cells utilizing a pathway that involves transferrin receptor 1 (TfR 1). E3 binds to recombinant human TfR 1 with high affinity and competes with transferrin (Tf) for binding to TfR1. In addition, knockdown or knockin of human TfR1 results in a decrease or increase in E3 cell binding. Here, we reported a molecular model of E3 binding to the transferrin receptor that summarizes our findings.https://www.mdpi.com/2072-6694/15/8/2301aptamertransferrin receptordrug targetingcancercanine cancer |
| spellingShingle | Xirui Song Haixiang Yu Cynthia Sullenger Bethany Powell Gray Amy Yan Linsley Kelly Bruce Sullenger An Aptamer That Rapidly Internalizes into Cancer Cells Utilizes the Transferrin Receptor Pathway Cancers aptamer transferrin receptor drug targeting cancer canine cancer |
| title | An Aptamer That Rapidly Internalizes into Cancer Cells Utilizes the Transferrin Receptor Pathway |
| title_full | An Aptamer That Rapidly Internalizes into Cancer Cells Utilizes the Transferrin Receptor Pathway |
| title_fullStr | An Aptamer That Rapidly Internalizes into Cancer Cells Utilizes the Transferrin Receptor Pathway |
| title_full_unstemmed | An Aptamer That Rapidly Internalizes into Cancer Cells Utilizes the Transferrin Receptor Pathway |
| title_short | An Aptamer That Rapidly Internalizes into Cancer Cells Utilizes the Transferrin Receptor Pathway |
| title_sort | aptamer that rapidly internalizes into cancer cells utilizes the transferrin receptor pathway |
| topic | aptamer transferrin receptor drug targeting cancer canine cancer |
| url | https://www.mdpi.com/2072-6694/15/8/2301 |
| work_keys_str_mv | AT xiruisong anaptamerthatrapidlyinternalizesintocancercellsutilizesthetransferrinreceptorpathway AT haixiangyu anaptamerthatrapidlyinternalizesintocancercellsutilizesthetransferrinreceptorpathway AT cynthiasullenger anaptamerthatrapidlyinternalizesintocancercellsutilizesthetransferrinreceptorpathway AT bethanypowellgray anaptamerthatrapidlyinternalizesintocancercellsutilizesthetransferrinreceptorpathway AT amyyan anaptamerthatrapidlyinternalizesintocancercellsutilizesthetransferrinreceptorpathway AT linsleykelly anaptamerthatrapidlyinternalizesintocancercellsutilizesthetransferrinreceptorpathway AT brucesullenger anaptamerthatrapidlyinternalizesintocancercellsutilizesthetransferrinreceptorpathway AT xiruisong aptamerthatrapidlyinternalizesintocancercellsutilizesthetransferrinreceptorpathway AT haixiangyu aptamerthatrapidlyinternalizesintocancercellsutilizesthetransferrinreceptorpathway AT cynthiasullenger aptamerthatrapidlyinternalizesintocancercellsutilizesthetransferrinreceptorpathway AT bethanypowellgray aptamerthatrapidlyinternalizesintocancercellsutilizesthetransferrinreceptorpathway AT amyyan aptamerthatrapidlyinternalizesintocancercellsutilizesthetransferrinreceptorpathway AT linsleykelly aptamerthatrapidlyinternalizesintocancercellsutilizesthetransferrinreceptorpathway AT brucesullenger aptamerthatrapidlyinternalizesintocancercellsutilizesthetransferrinreceptorpathway |