PLGA Nanoparticles for Peptide Receptor Radionuclide Therapy of Neuroendocrine Tumors: A Novel Approach towards Reduction of Renal Radiation Dose

Background: Peptide receptor radionuclide therapy (PRRT), employed for treatment of neuroendocrine tumors (NETs) is based on over-expression of Somatostatin Receptors (SSTRs) on NETs. It is, however, limited by high uptake and retention of radiolabeled peptide in kidneys resulting in unnecessary radiation exposure thus causing nephrotoxicity. Employing a nanocarrier to deliver PRRT drugs specifically to the tumor can reduce the associated nephrotoxicity. Based on this, Lu-177-DOTATATE loaded PLGA nanoparticles (NPs) were formulated in the present study, as a potential therapeutic model for NETs. Methodology and Findings: DOTATATE was labeled with Lutetium-177 (Lu-177) (labeling efficiency 98%; R-f similar to 0.8). Polyethylene Glycol (PEG) coated Lu-177-DOTATATE-PLGA NPs (50: 50 and 75: 25) formulated, were spherical with mean size of 304.5 +/- 80.8 and 733.4 +/- 101.3 nm (uncoated) and 303.8 +/- 67.2 and 494.3 +/- 71.8 nm (coated) for PLGA(50: 50) and PLGA(75: 25) respectively. Encapsulation efficiency (EE) and In-vitro release kinetics for uncoated and coated NPs of PLGA (50: 50 & 75: 25) were assessed and compared. Mean EE was 77.375 +/- 4.98% & 67.885 +/- 5.12% (uncoated) and 65.385 +/- 5.67% & 58.495 +/- 5.35% (coated). NPs showed initial burst release between 16.64-21.65% with total 42.83-44.79% over 21days. The release increased with coating to 20.4-23.95% initially and 60.97-69.12% over 21days. In-vivo studies were done in rats injected with Lu-177-DOTATATE and Lu-177-DOTATATE-NP (uncoated and PEG-coated) by imaging and organ counting after sacrificing rats at different time points over 24 hr post-injection. With Lu-177-DOTATATE, renal uptake of 37.89 +/- 10.2% ID/g was observed, which reduced to 4.6 +/- 1.97% and 5.27 +/- 1.66% ID/g with uncoated and coated Lu-177-DOTATATE-NP. The high liver uptake with uncoated Lu-177-DOTATATE-NP (13.68 +/- 3.08% ID/g), reduced to 7.20 +/- 2.04% ID/g (p = 0.02) with PEG coating. Conclusion: PLGA NPs were easily formulated and modified for desired release properties. PLGA 50: 50 NPs were a more suitable delivery vehicle for Lu-177-DOTATATE than PLGA 75: 25 because of higher EE and slower release rate. Reduced renal retention of Lu-177-DOTATATE and reduced opsonisation strongly advocate the potential of Lu-177-DOTATATE-PLGA-PEG NPs to reduce radiation dose in PRRT.