Evaluation of theranostic dendrimers for radiotherapy and MRI of gliomas

Aim: A new oncologic strategy, based on the integration of nanovectorized radiotherapy and locoregional delivery was evaluated for the treatment of gliomas. Our focus was the synthesis of heterofunctional dendrimers to... [ view full abstract ]

Aim: A new oncologic strategy, based on the integration of nanovectorized radiotherapy and locoregional delivery was evaluated for the treatment of gliomas. Our focus was the synthesis of heterofunctional dendrimers to facilitate personalized management of the most common and lethal type of primary brain tumors. Gallic acid-triethylene glycol (GATG) dendrimers, fully functionalized with DTPA derivatives, were the nanovectors of choice to deliver the radiotherapeutic 188-Re and paramagnetic nuclei Gd(III), targeting the radiotherapeutic dose to the tumor site with a minimally invasive stereotactic surgery, in an F98 rat glioma model. Intravenous injection was used to further investigate the pharmacokinetics, throughout body distribution and clearance profiles of these dendrimers.

Methods: F98 tumor cells were implanted intracerebrally in syngeneic Fischer rats (n=15). A comparison of brain retention and tissue biodistribution between 188Re-perrhenate (n=6) and (188Re+Gd)-2[G3]-DTPA dendrimers (n=6) was done following CED (3.7 MBq/injection) at Day 20 post-tumor implantation, using an osmotic pump (0.5µL/min for 20 minutes). Brain retention of Gd-2[G3]-DTPA dendrimers in F98 glioma rats, was also evaluated by MRI, at 24h post-CED (n=3). Intravenous injection was used to mimic the behavior of dendrimers in the bloodstream, following their brain clearance. To investigate if the generation sizes of dendrimers influenced any differences in their pharmacokinetics, throughout body distribution and clearance profiles, three highest generations (2[G2]-2[G4]) of GATG dendrimers were synthesised and radiolabeled with technetium. Rats (n=36) were intravenously injected with 3.7 MBq of 99mTc-2[G2]-DTPA, 99mTc-2[G3]-DTPA, and 99mTc-2[G4]-DTPA dendrimers, and put in individual metabolic cages. They were sacrificed at 1, 6, 24 and 48 hours post-injection (n=9 per each time interval; 3 rats per generation of dendrimers). The content activity of urine, feces and each organ was determined using a gamma counter and expressed as percentage of injected dose/organ (%ID).

Conclusion: The use of dendrimers as nanovectors prevented the fast brain clearance of the radionuclide on its own, and prolonged the confinement of the internal radiation at the tumor site. Molecular weight and architecture of dendrimers had an important role on the in vivo behavior of these nanovectors. The easy dual labeling procedure opens the perspective of multimodality in therapy and imaging of gliomas.