期刊
EJNMMI RADIOPHARMACY AND CHEMISTRY
卷 5, 期 1, 页码 -出版社
SPRINGERNATURE
DOI: 10.1186/s41181-020-00111-y
关键词
EGFR; Panitumumab; Pancreatic cancer; In-111; Lu-177
类别
资金
- Canadian Cancer Society
- Natural Sciences and Engineering Research Council (NSERC)
- Ontario Graduate Scholarship
- Terry Fox Foundation Strategic Initiative for Excellence in Radiation Research for the twenty-first Century (STARS21)
- Centre for Pharmaceutical Oncology (CPO) at the University of Toronto
- NSERC Polymer Nanoparticles in Drug Delivery (POND) CREATE program
Background: Epidermal growth factor receptors (EGFR) are overexpressed on >90% of pancreatic cancers (PnCa) and represent an attractive target for the development of novel therapies, including radioimmunotherapy (RIT). Our aim was to study RIT of subcutaneous (s.c.) PANC-1 human PnCa xenografts in mice using the anti-EGFR monoclonal antibody, panitumumab labeled with Auger electron (AE)-emitting, In-111 or beta-particle emitting, Lu-177 at amounts that were non-toxic to normal tissues. Results: Panitumumab was conjugated to DOTA chelators for complexing In-111 or Lu-177 (panitumumab-DOTA-[In-111]In and panitumumab-DOTA-[Lu-177]Lu) or to a metal-chelating polymer (MCP) with multiple DOTA to bind In-111 (panitumumab-MCP-[In-111]In). Panitumumab-DOTA-[Lu-177]Lu was more effective per MBq exposure at reducing the clonogenic survival in vitro of PANC-1 cells than panitumumab-DOTA-[In-111]In or panitumumab-MCP-[In-111]In. Panitumumab-DOTA-[Lu-177]Lu caused the greatest density of DNA double-strand breaks (DSBs) in the nucleus measured by immunofluorescence for gamma-H2AX. The absorbed dose in the nucleus was 3.9-fold higher for panitumumab-DOTA-[Lu-177]Lu than panitumumab-DOTA-[In-111]In and 7.7-fold greater than panitumumab-MCP-[In-111]In. No normal tissue toxicity was observed in NOD/SCID mice injected intravenously (i.v.) with 10.0MBq (10 mu g; 0.07 nmoles) of panitumumab-DOTA-[In-111]In or panitumumab-MCP-[In-111]In or in NRG mice injected i.v. with 6.0MBq (10 mu g; similar to 0.07 nmoles) of panitumumab-DOTA-[Lu-177]Lu. There was no decrease in complete blood cell counts (CBC) or increased serum alanine aminotransferase (ALT) or creatinine (Cr) or decreased body weight. RIT inhibited the growth of PANC-1 tumours but a 5-fold greater total amount of panitumumab-DOTA-[In-111]In or panitumumab-MCP-[In-111]In (30MBq; 30 mu g; similar to 0.21 nmoles) administered in three fractionated amounts every three weeks was required to achieve greater or equivalent tumour growth inhibition, respectively, compared to a single amount of panitumumab-DOTA-[Lu-177]Lu (6MBq; 10 mu g; similar to 0.07 nmoles). The tumour doubling time (TDT) for NOD/SCID mice with s.c. PANC-1 tumours treated with panitumumab-DOTA-[In-111]In or panitumumab-MCP-[In-111]In was 51.8days and 28.1days, respectively. Panitumumab was ineffective yielding a TDT of 15.3days vs. 15.6days for normal saline treated mice. RIT of NRG mice with s.c. PANC-1 tumours with 6.0MBq (10 mu g; similar to 0.07 nmoles) of panitumumab-DOTA-[Lu-177]Lu increased the TDT to 20.9days vs. 11.5days for panitumumab and 9.1days for normal saline. The absorbed doses in PANC-1 tumours were 8.83.0Gy and 2.6 +/- 0.3Gy for panitumumab-DOTA-[In-111]In and panitumumab-MCP-[In-111]In, respectively, and 11.6 +/- 4.9Gy for panitumumab-DOTA-[Lu-177]Lu. Conclusion: RIT with panitumumab labeled with Auger electron-emitting, In-111 or beta-particle-emitting, Lu-177 inhibited the growth of s.c. PANC-1 tumours in NOD/SCID or NRG mice, at administered amounts that caused no normal tissue toxicity. We conclude that EGFR-targeted RIT is a promising approach to treatment of PnCa.
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