Formulation of radioactive nanoparticles for therapy of neuroendocrine tumors: Encapsulation and in-vitro release kinetics

Objectives Various biodegradable Lu-177 DOTATATE loaded nanoparticles (NPs) are formulated to reduce renal toxicity and enhance therapeutic efficacy for Neuroendocrine Tumors (NETs). Encapsulation and in-vitro release kinetics have been evaluated and compared.

Methods Blank NPs of PLGA (50:50; 75:25), Alginate (Alg-2%, 5% & 10%), Alginate-Chitosan and Chitosan (Chi) were formulated. To reduce opsonisation, NPs were coated with Polyethylene Glycol (PEG). Particle shape and size were evaluated by electron microscopy (EM) and particle size analyzer. Stability of NPs was checked at pH 2, 7.4, and 9. DOTATATE was labeled with Lu-177 and labeling efficiency and stability was checked by ITLC upto 6 days post labeling. Lu-177 DOTATATE was encapsulated in blank NPs by incubating with Lu-177 DOTATATE overnight (4mg/ml) at 37°C and centrifuged. % encapsulation was calculated by counting unencapsulated activity in supernatant. In-vitro release kinetics was assessed in PBS (pH 7.4) at 37°C by counting activity in supernatant at regular intervals. Experiments were done in triplicates.

Results Particle size range was between 92.59 - 408.9nm. PLGA & Alg NPs were spherical while others were irregularly shaped. Labeling efficiency of Lu-177 DOTATATE was 98% (Rf ~ 0.8) and stable upto 6 days (95.4%). PLGA and Chi were most stable NPs at pH-7.4. Encapsulation of drug ranged from 66-99%. NPs showed initial burst release between 17-28%. PLGA NPs showed lowest initial burst with minimal cumulative release, Alg showed 52-62%, Alg-Chi 48% and Chi 40% upto 7 days. Alg showed highest encapsulation but 40-50% of activity was released in first 4hr which does not favour reduction of renal toxicity.

Conclusions PLGA NPs are most suitable delivery vehicle for Lu-177 DOTATATE delivery. Further In-vitro and in-vivo studies are being done for developing an effective drug delivery device for NETs.

Research Support Department of Science and Technology, Government of Indi