PET imaging of PTX/ POEG-b-PVBA-b-PFTS for an imaging guided cancer therapy

Objectives: PTX/ POEG-b-PVBA-b-PFTS nanosized micelles possessed excellent anti-proliferative activity, demonstrating its potential clinical applications for the cancer treatment. However, in vivo distribution of this type of micelles remained unclear, which was important for predicting its therapeutic outcomes. Therefore, an imaging guided therapy strategy is highly desired. Herein, we have PTX/ POEG-b-PVBA-b-PFTS micelles labeled with radioisotopes for tracking their in vivo distribution via the PET imaging so as to evaluate the drug delivery efficiency of this nanocarrier.

Methods: Cumulative release of PTX from the micelle in vitro was monitored up to 60 hours. Micelles were then labeled with either Cu64 or Zr89 via the post labeling conjugation with DBCO-LNETA (Cu64) or DBCO-DFO (Zr89) respectively at room temperature. Nude mice bearing the breast cancer 4T1.2 xenograft were administrated with either Cu64 labeled micelles or Zr89-labeled micelles at a dose of 100µCi/mice for monitoring their in vivo distribution at short time points (1h, 4h, 8h & 24h) or long time points (48h, 72h & 96h) respectively. Cu64 based serum stability test was also conducted for evaluating the potential in vivo stability of this type of micelles.

Results: Based on the in vitro cumulative release study, less than 20% of loaded PTX was released in the first 4 h while a slower release was observed for an extended time period of up to 60 hours. Micelles were successfully labeled with either Cu64 or Zr89 via the post labeling conjugation with a specific activity of 100µCi/mg. According to the PET imaging result, micelles started to accumulate in tumor since 1 h post injection. Decent tumor accumulation (6.5%ID/g) was observed at 4 h while the maximal tumor accumulation (8.7%ID/g) was achieved at 8 h, which maintained until 72 h. Taking into account both the release curve and PET images, most PTX remained in micelles at the time when significant accumulation of micelles in tumor was observed, indicating a high drug delivery efficiency. In Cu64 based serum stability test, micelles showed great serum stability with less than 5% Cu64 disassociation after being incubated with serum over 24 h at 37 °C.

Conclusion: PTX loaded micelles successively delivered PTX to the tumor for around 3 days thus greatly enhance the tumor bioavailability compared to injecting the same amount of free PTX. Therefore, promising therapeutic outcomes could be expected for the following cancer therapy study. Currently, optimization of the POEG-b-PVBA-b-PFTS nanocarrier is going to reduce the potential liver and kidney toxicity. Research Support: This research was supported by NIH R21-EB020737.