Using Human Serum Albumin Binding Affinities as a Proactive Strategy to Affect the Pharmacodynamics and Pharmacokinetics of Preclinical Drug Candidates

Fan, Jianwei; Gilmartin, Katherine; Octaviano, Steven; Villar, Francisca; Remache, Brianna; Regan, J.T.

doi:10.1021/acsptsci.2c00115

Cited by 18 publications

(7 citation statements)

References 34 publications

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“…As context for the present effort, we note that following successful exploitation of albumin binding mechanism for pharmaceuticals to enhance the therapeutic index (Lee and Wu 2015 ; Fan et al. 2022 ), there has been an increased motivation in the nuclear medicine community to study the effect of albumin binding in radiopharmaceuticals (Boinapally et al. 2023 ; Szücs et al.…”

Section: Discussionmentioning

confidence: 99%

Physiologically based radiopharmacokinetic (PBRPK) modeling to simulate and analyze radiopharmaceutical therapies: studies of non-linearities, multi-bolus injections, and albumin binding

Fele-Paranj,

Saboury,

Uribe

et al. 2024

EJNMMI radiopharm. chem.

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Background We aimed to develop a publicly shared computational physiologically based pharmacokinetic (PBPK) model to reliably simulate and analyze radiopharmaceutical therapies (RPTs), including probing of hot-cold ligand competitions as well as alternative injection scenarios and drug designs, towards optimal therapies. Results To handle the complexity of PBPK models (over 150 differential equations), a scalable modeling notation called the “reaction graph” is introduced, enabling easy inclusion of various interactions. We refer to this as physiologically based radiopharmacokinetic (PBRPK) modeling, fine-tuned specifically for radiopharmaceuticals. As three important applications, we used our PBRPK model to (1) study the effect of competition between hot and cold species on delivered doses to tumors and organs at risk. In addition, (2) we evaluated an alternative paradigm of utilizing multi-bolus injections in RPTs instead of prevalent single injections. Finally, (3) we used PBRPK modeling to study the impact of varying albumin-binding affinities by ligands, and the implications for RPTs. We found that competition between labeled and unlabeled ligands can lead to non-linear relations between injected activity and the delivered dose to a particular organ, in the sense that doubling the injected activity does not necessarily result in a doubled dose delivered to a particular organ (a false intuition from external beam radiotherapy). In addition, we observed that fractionating injections can lead to a higher payload of dose delivery to organs, though not a differential dose delivery to the tumor. By contrast, we found out that increased albumin-binding affinities of the injected ligands can lead to such a differential effect in delivering more doses to tumors, and this can be attributed to several factors that PBRPK modeling allows us to probe. Conclusions Advanced computational PBRPK modeling enables simulation and analysis of a variety of intervention and drug design scenarios, towards more optimal delivery of RPTs.

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Section: Discussionmentioning

confidence: 99%

Physiologically based radiopharmacokinetic (PBRPK) modeling to simulate and analyze radiopharmaceutical therapies: studies of non-linearities, multi-bolus injections, and albumin binding

Fele-Paranj,

Saboury,

Uribe

et al. 2024

EJNMMI radiopharm. chem.

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“…Hence, endogenous HSA can serve as a valuable carrier for targeted drug delivery to tumors by utilizing albumin-binding moieties, enabling the biomimetic delivery of drugs to tumor cells ( Zhang et al, 2017 ; Rapozzi et al, 2022 ). Several studies have shown that the attachment of drugs or molecular conjugates to HSA significantly prolongs their circulation time and decreases their clearance from the reticuloendothelial system, thus promoting accumulation and retention at the tumor site ( Spada et al, 2021 ; Fan et al, 2022 ; Ullah et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

HSA-nanobinders crafted from bioresponsive prodrugs for combined cancer chemoimmunotherapy–an in vitro exploration

Tubertini,

Menilli,

Milani

et al. 2024

Front. Chem.

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Introduction: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer still lacking effective treatment options. Chemotherapy in combination with immunotherapy can restrict tumor progression and repolarize the tumor microenvironment towards an anti-tumor milieu, improving clinical outcome in TNBC patients. The chemotherapeutic drug paclitaxel has been shown to induce immunogenic cell death (ICD), whereas inhibitors of the indoleamine 2,3- dioxygenase 1 (IDO1) enzyme, whose expression is shared in immune regulatory and tumor cells, have been revealed to enhance the anti-tumor immune response. However, poor bioavailability and pharmacokinetics, off-target effects and hurdles in achieving therapeutic drug concentrations at the target tissue often limit the effectiveness of combination therapies.Methods: This work describes the development of novel biomimetic and carrier-free nanobinders (NBs) loaded with both paclitaxel and the IDO1 inhibitor NLG919 in the form of bioresponsive and biomimetic prodrugs. A fine tuning of the preparation conditions allowed to identify NB@5 as the most suitable nanoformulation in terms of reproducibility, stability and in vitro effectiveness.Results and discussion: Our data show that NB@5 effectively binds to HSA in cell-free experiments, demonstrating its protective role in the controlled release of drugs and suggesting the potential to exploit the protein as the endogenous vehicle for targeted delivery to the tumor site. Our study successfully proves that the drugs encapsulated within the NBs are preferentially released under the altered redox conditions commonly found in the tumor microenvironment, thereby inducing cell death, promoting ICD, and inhibiting IDO1.

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“…Furthermore, albumin helps maintain proper oncotic pressure, preventing fluid extravasation that could impede urine flow and heighten the risk of UTIs ( 29 ). Albumin also impacts pharmacokinetics by binding drugs and affecting their distribution and elimination ( 30 ). Hypoalbuminemia may increase the unbound antibiotic fraction, reducing therapeutic efficacy against urinary pathogens.…”

Section: Discussionmentioning

confidence: 99%

Common hematological and biochemical parameters for predicting urinary tract infections in geriatric patients with hip fractures

Tang,

Yao,

Wang

et al. 2024

Front. Med.

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BackgroundThis study aims to discern the significance of common hematological and biochemical parameters for predicting urinary tract infections in geriatric patients with hip fractures.MethodsMultivariable logistic regression and propensity score-matched analyses were conducted to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for UTIs. The abilities of these parameters to predict UTIs were evaluated by receiver operating characteristic (ROC) curves. Dose–response relationships were assessed by categorizing hematological and biochemical parameters into quartiles. Subgroup analyses were further explored to investigate the relationship between these parameters and urinary tract infections.ResultsOut of the 1,231 participants, 23.2% were diagnosed with UTIs. Hyperglycemia, hypoproteinemia and hyperglobulinemia were risk factors for UTIs in multivariate analysis. After propensity score matching, hyperglycemia (OR 2.14, 95% CI 1.50–3.05, p < 0.001), hypoproteinemia (OR 1.75, 95% CI 1.18–2.63, p = 0.006), and hyperglobulinemia (OR 1.38, 95% CI 0.97–1.97, p = 0.074) remained significantly associated with increased odds of urinary tract infections. ROC curve analyses showed moderate predictive accuracy of blood glucose, albumin and globulin for UTIs, with areas under the curves of 0.714, 0.633, and 0.596, respectively. Significant dose–response relationships were observed between these parameters and UTIs. The associations were consistent in subgroup analyses.ConclusionBlood glucose, albumin and globulin levels can facilitate early identification of geriatric hip fracture patients at high risk of UTIs. These easily obtainable hematological and biochemical parameters provide a practical clinical prediction tool for individualized UTI prevention in this population.

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Using Human Serum Albumin Binding Affinities as a Proactive Strategy to Affect the Pharmacodynamics and Pharmacokinetics of Preclinical Drug Candidates

Cited by 18 publications

References 34 publications

Physiologically based radiopharmacokinetic (PBRPK) modeling to simulate and analyze radiopharmaceutical therapies: studies of non-linearities, multi-bolus injections, and albumin binding

Physiologically based radiopharmacokinetic (PBRPK) modeling to simulate and analyze radiopharmaceutical therapies: studies of non-linearities, multi-bolus injections, and albumin binding

HSA-nanobinders crafted from bioresponsive prodrugs for combined cancer chemoimmunotherapy–an in vitro exploration

Common hematological and biochemical parameters for predicting urinary tract infections in geriatric patients with hip fractures

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