The use of exosomes as a drug delivery vehicle has gained considerable interest. To establish if exosomes could be utilized effectively for drug delivery, a better understanding of their in vivo fate must be established. Through comparisons to liposomal formulations, which have been studied extensively for the last thirty years, we were able to make some comprehensive conclusions about the fate of unmodified tumor-derived exosomes in vivo. We observed a comparable rapid clearance and minimal tumor accumulation of intravenously-injected exosomes, PC:Chol liposomes, and liposomes formulated with the lipid extract of exosomes, suggesting the unique protein and lipid composition of exosomes does not appreciably impact exosomes’ rate of clearance and biodistribution. This rapid clearance along with minimal tumor accumulation of unmodified exosomes limits their use as an anti-cancer drug delivery vehicle; however, when delivered intratumorally, exosomes remained associated with tumor tissue to a significantly greater extent than PC:Chol liposomes. Furthermore, experiments utilizing mice with impaired adaptive or innate immune systems, revealed the significance of the innate immune system along with the complement protein C5 on exosomes’ rate of clearance.
In peptide receptor radionuclide therapy with 90 Y-labeled DOTATATE, the kidney absorbed dose limits the maximum amount of total activity that can be safely administered in many patients. A higher tumor-to-kidney absorbed dose ratio might be achieved by optimizing the amount of injected peptide and activity, as recent studies have shown different degrees of receptor saturation for normal tissue and tumor. The aim of this work was to develop and implement a modeling method for treatment planning to determine the optimal combination of peptide amount and pertaining therapeutic activity for each patient. Methods: A whole-body physiologically based pharmacokinetic (PBPK) model was developed. General physiologic parameters were taken from the literature. Individual model parameters were fitted to a series (n 5 12) of planar γ-camera and serum measurements ( 111 In-DOTATATE) of patients with meningioma or neuroendocrine tumors (NETs). Using the PBPK model and the individually estimated parameters, we determined the tumor, liver, spleen, and red marrow biologically effective doses (BEDs) for a maximal kidney BED (20 Gy 2.5 ) for different peptide amounts and activities. The optimal combination of peptide amount and activity for maximal tumor BED, considering the additional constraint of a red marrow BED less than 1 Gy 15 , was individually quantified. Results: The PBPK model describes the biokinetic data well considering the criteria of visual inspection, the coefficients of determination, the relative standard errors (,50%), and the correlation of the parameters (,0.8). All fitted parameters were in a physiologically reasonable range but varied considerably between patients, especially tumor perfusion (meningioma, 0.1-1 mLÁg −1 Ámin −1 , and NETs, 0.02-1 mLÁg −1 Ámin −1 ) and receptor density (meningioma, 5-34 nmolÁL −1 , and NETs, 7-35 nmolÁL −1 ). Using the proposed method, we identified the optimal amount and pertaining activity to be 76 ± 46 nmol (118 ± 71 μg) and 4.2 ± 1.8 GBq for meningioma and 87 ± 50 nmol (135 ± 78 μg) and 5.1 ± 2.8 GBq for NET patients. Conclusion: The presented work suggests that to achieve higher efficacy and safety for 90 Y-DOATATE therapy, both the administered amount of peptide and the activity should be optimized in treatment planning using the proposed method. This approach could also be adapted for therapy with other peptides.
An efficient and one-pot method for the radiosynthesis of [Al(18)F]PSMA-HBED was developed (0.26 μmol of precursor at 35 °C). In cell culture studies, the K D suggests [Al(18)F]PSMA-HBED as a potential PSMA ligand for future investigations in vivo and clinical applications afterwards.
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