Characterization of Intrinsically Radiolabeled Poly(lactic-co-glycolic acid) Nanoparticles for ex Vivo Autologous Cell Labeling and in Vivo Tracking

Abstract

With the advent of novel immunotherapies, interest in ex vivo autologous cell labeling for in vivo cell tracking has revived. However, current clinically available labeling strategies have several drawbacks, such as release of radiolabel over time and cytotoxicity. Poly(lactic- co -glycolic acid) nanoparticles (PLGA NPs) are clinically used biodegradable carriers of contrast agents, with high loading capacity for multimodal imaging agents. Here we show the development of PLGA-based NPs for ex vivo cell labeling and in vivo cell tracking with SPECT. We used primary amine-modified PLGA polymers (PLGA-NH 2 ) to construct NPs similar to unmodified PLGA NPs. PLGA-NH 2 NPs were efficiently radiolabeled without chelator and retained the radionuclide for 2 weeks. Monocyte-derived dendritic cells labeled with [ 111 In]In-PLGA-NH 2 showed higher specific activity than those labeled with [ 111 In]In-oxine, with no negative effect on cell viability. SPECT/CT imaging showed that radiolabeled THP-1 cells accumulated at the Staphylococcus aureus infection site in mice. In conclusion, PLGA-NH 2 NPs are able to retain 111 In, independent of chelator presence. Furthermore, [ 111 In]In-PLGA-NH 2 allows cell labeling with high specific activity and no loss of activity over prolonged time intervals. Finally, in vivo tracking of ex vivo labeled THP-1 cells was demonstrated in an infection model using SPECT/CT imaging.

In Vivo PET Imaging of Monocytes Labeled with [89Zr]Zr-PLGA-NH2 Nanoparticles in Tumor and Staphylococcus aureus Infection Models

“…In our previous work, we have shown that poly(lactic-co-glycolic acid) NPs with amine groups (PLGA-NH 2 NPs) can be used to radiolabel cells and demonstrates improved radiolabel retention compared with the oxine labeling method [31]. Here, we report the intrinsic labeling capacity of these NPs with [ 89 Zr]ZrCl 4 under various conditions.…”

“…The same preparation protocol was used as described before [31]. Briefly, 100 mg of poly(lactic-co-glycolic acid) diamine endcap copolymer (PLGA-NH 2 , Mn = 5000, Sigma-Aldrich, Merck, Saint Louis, MO, USA), 200 µL of poly(propylene glycol) (PPO, 50 mg/mL stock, Sigma-Aldrich, average Mn 2700) and 900 µL perfluoro-15-crown-5-ether (PFCE, Exfluor Inc., Round Rock, TX, USA) were dissolved in 3 mL dichloromethane (DCM, Merck, Darmstadt, Germany).…”

“…PLGA-NH 2 NPs were analyzed for size, polydispersity index (PDI) and zeta potential, in the same way as in our previous study [31]. The NPs were dissolved at 0.1 mg/mL in MilliQ, and both size and PDI were measured by using a NANO-flex (Microtrac, Inc., Duesseldorf, Germany), and the data were analyzed by using Microtrac software (Microtrac FLEX 11.1.0.2, Duesseldorf, Germany).…”

“…Finally, the 89 Zr-label was eluted with 1 mL HCl (0.1 M) in 100 µL aliquots. This experiment was performed in the same manner as described in our previous study [31]. For intrinsic labeling, 1 mg NPs were dissolved in 0.5 M NH 4 Ac and incubated with 1-5 MBq [ 89 Zr]ZrCl 4 , at 37 • C, for 30 min.…”

“…The immortalized human monocyte cell line THP-1 (ATCC ® TIB-202 TM , VA, Gaithersburg, MD, USA) was used for cell labeling (passage of <20). The cells were maintained in culture as described previously [31].…”