Pharmacotechnical development of a freeze dried kit for 68Ga labeling and preclinical evaluation

Author(s)

Maria Renata Valente Brandão Freire

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Pesquisas Energéticas e Nucleares (IPEN/BT)
• Defense date: 2024-03-14

Examining board members

Elaine Bortoleti de Araújo; Ana Cláudia Camargo Miranda; Camila Motta Venchiarutti Moniz

• Advisor: Elaine Bortoleti de Araújo

Abstract

Currently, in the detection of metastatic prostate cancer, the target molecules of the type II transmembrane receptor, called \"PSMA,\" due to the receptor they bind to, have been shown to be a superior alternative to other conventional imaging modalities, as well as to other PET imaging agents such as FDG18F or Choline18F. PSMA-11- 68Ga was approved by the Food and Drug Administration (FDA) in the United States as the first 68Ga-labeled radiopharmaceutical for PET imaging of PSMA-positive prostate cancer in 2020. This radiopharmaceutical is considered the most promising for detecting micro and oligometastases in advanced prostate cancer, being used for therapeutic planning as well as for treatment response evaluation. This work aimed to develop a lyophilized kit of receptor-specific peptide for direct labeling with 68Ga to solve the problem of distribution limitation due to distance. The conditions for direct radiolabeling of receptor-specific peptides with 68Ga were evaluated and standardized using eluate from 68Ge/68Ga generators from two different manufacturers. Radiolabeling parameters were studied, including variations in pH, concentration of sodium acetate buffer, temperature, and the use of mannitol, to define the formulation of a ready-to-use labeling kit. The lyophilization process of the PSMA-11 formulation was studied. The radiochemical purity of the labels was evaluated by CCD and HPLC. Biological evaluation was performed with lyophilized PSMA-11 to demonstrate the integrity of the peptide and preservation of biological activity after the lyophilization process. It was demonstrated that PSMA-11- 68Ga can be obtained with a radiochemical purity (%RP) > 95% using directly the 68Ga eluate from the 68Ge/68Ga generators from ITG or Eckert & Ziegler and with a final formulation pH between 4.0 and 4.5. It was also shown that PSMA-11- 68Ga can be obtained with satisfactory %RP using heating or at room temperature conditions and without the need for final purification. Regarding the lyophilized formulation of the PSMA-11 peptide, it was concluded that the peptide should be lyophilized without the presence of the labeling buffer. The results obtained from the in vitro and in vivo competitive biological studies confirmed the preservation of PSMA-11\'s affinity for the receptor after lyophilization. A lyophilized formulation (Kit) of PSMA-11 was successfully obtained, preserving the integrity and biological activity of the peptide and ensuring labeling efficiency. (AU)

• FAPESP's process: 19/04172-7 - Pharmacotechnical development of DOTATATO lyophilized kit for 68Ga labeling and preclinical evaluation
• Grantee: Maria Renata Valente Brandão Freire
• Support Opportunities: Scholarships in Brazil - Doctorate