Special Issue "Advances in Drug and Drug-Conjugate Design for Improved Pharmacokinetics and Targeting"

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 1 December 2021.

Special Issue Editor

Prof. Dr. Sophie Hernot
E-Mail Website
Guest Editor
Vrije Universiteit Brussel, In Vivo Cellular and Molecular Imaging Laboratory (ICMI), Laarbeeklaan 103, 1090, Brussels, Belgium
Interests: molecular imaging and therapy; fluorescence-guided surgery; in vivo biodistribution; nanobody; tracer design
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Special Issue Information

Dear Colleagues,

Targeting moieties that specifically interact with molecules expressed or involved in pathophysiological conditions are increasingly being exploited in precision medicine for diagnostic and therapeutic purposes. Targeted drugs and drug-conjugates based on antibodies, peptides, or small molecules can significantly improve treatment efficacy, while unwanted side-effects are reduced. Analogously, molecular targeted contrast agents are gaining in popularity for patient stratification as companion diagnostics or for image-guided surgery.

Nevertheless, careful considerations on all aspects of drug and drug-conjugate design (e.g., type of targeting vehicle, size, and physicochemical properties of all components; linking or loading strategy, binding characteristics, or selected target) are key to assuring a proper pharmacokinetic profile complying with the intended application. This Special Issue focuses on the latest findings and advances in targeted drug and drug-conjugate design resulting in improved pharmacokinetics and eventually in better therapeutic and diagnostics applications.

Prof. Dr. Sophie Hernot
Guest Editor

Manuscript Submission Information

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Keywords

  • targeted imaging and therapy
  • in vivo biodistribution
  • improved pharmacokinetics
  • drug design
  • targeted drugs
  • drug conjugates

Published Papers (2 papers)

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Research

Article
Site-Specific Radiolabeling of a Human PD-L1 Nanobody via Maleimide–Cysteine Chemistry
Pharmaceuticals 2021, 14(6), 550; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060550 - 08 Jun 2021
Cited by 1 | Viewed by 1069
Abstract
Immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1) and its ligand PD-L1 have proven to be efficient cancer therapies in a subset of patients. From all the patients with various cancer types, only 20% have a positive response. Being able to distinguish [...] Read more.
Immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1) and its ligand PD-L1 have proven to be efficient cancer therapies in a subset of patients. From all the patients with various cancer types, only 20% have a positive response. Being able to distinguish patients that do express PD-1/PD-L1 from patients that do not allows patients to benefit from a more personalized and efficient treatment of tumor lesion(s). Expression of PD-1 and PD-L1 is typically assessed via immunohistochemical detection in a tumor biopsy. However, this method does not take in account the expression heterogeneity within the lesion, nor the possible metastasis. To visualize whole-body PD-L1 expression by PET imaging, we developed a nanobody-based radio-immunotracer targeting PD-L1 site-specifically labeled with gallium-68. The cysteine-tagged nanobody was site-specifically conjugated with a maleimide (mal)-NOTA chelator and radiolabeling was tested at different nanobody concentrations and temperatures. Affinity and specificity of the tracer, referred to as [68Ga]Ga-NOTA-mal-hPD-L1 Nb, were assayed by surface plasmon resonance and on PD-L1POS or PD-L1NEG 624-MEL cells. Xenografted athymic nude mice bearing 624-MEL PD-L1POS or PD-L1NEG tumors were injected with the tracer and ex vivo biodistribution was performed 1 h 20 min post-injection. Ideal 68Ga-labeling conditions were found at 50 °C for 15 min. [68Ga]Ga-NOTA-mal-hPD-L1 Nb was obtained in 80 ± 5% DC-RCY with a RCP > 99%, and was stable in injection buffer and human serum up to 3 h (>99% RCP). The in vitro characterization showed that the NOTA-functionalized Nb retained its affinity and specificity. Ex vivo biodistribution revealed a tracer uptake of 1.86 ± 0.67% IA/g in the positive tumors compared with 0.42 ± 0.04% IA/g in the negative tumors. Low background uptake was measured in the other organs and tissues, except for the kidneys and bladder, due to the expected excretion route of Nbs. The data obtained show that the site-specific 68Ga-labeled NOTA-mal-hPD-L1 Nb is a promising PET radio-immunotracer due to its ease of production, stability and specificity for PD-L1. Full article
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Article
Decorating sdAbs with Chelators: Effect of Conjugation on Biodistribution and Functionality
Pharmaceuticals 2021, 14(5), 407; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14050407 - 25 Apr 2021
Viewed by 868
Abstract
Single domain antibodies (sdAbs) have proven to be valuable probes for molecular imaging. In order to produce such probes, one strategy is the functionalization of the reactive amine side chain of lysines with a chelator, resulting in a mixture of compounds with a [...] Read more.
Single domain antibodies (sdAbs) have proven to be valuable probes for molecular imaging. In order to produce such probes, one strategy is the functionalization of the reactive amine side chain of lysines with a chelator, resulting in a mixture of compounds with a different degree of conjugation. In this study, we implemented anion exchange chromatography (AEX) to separate the different compounds or fractions that were further characterized and evaluated to study the impact of the conjugation degree on pharmacokinetic properties and functionality. Anti-HER2 and anti-MMR sdAbs were functionalized with NOTA or DTPA chelator. Anion exchange chromatography was performed using 0.02 mol/L Tris pH 7.5 as the first solvent and 0.25 M or 0.4 M NaCl (in case of NOTA chelator or DTPA chelator, respectively) as the second solvent applied as a gradient. The fractions were characterized via mass spectrometry (MS), surface plasmon resonance (SPR), and isoelectric focusing gel electrophoresis (IEF), while in vivo studies were performed after radiolabeling with either 68Ga (NOTA) or 111In (DTPA) to assess the impact of the conjugation degree on pharmacokinetics. AEX could successfully be applied to separate fractions of (chelator)n-anti-HER2 and (chelator)n-anti-MMR sdAb constructs. MS confirmed the identity of different peaks obtained in the separation process. SPR measurement suggests a small loss of affinity for (chelator)3-anti-sdAb, while IEF revealed a correlated decrease in isoelectric point (pI) with the number of conjugated chelators. Interestingly, both the reduction in affinity and in pI was stronger with the DTPA chelator than with NOTA for both sdAbs. In vivo data showed no significant differences in organ uptake for any construct, except for (DTPA)n-anti-MMR, which showed a significantly higher liver uptake for (DTPA)1-anti-MMR compared to (DTPA)2-anti-MMR and (DTPA)3-anti-MMR. For all constructs in general, high kidney uptake was observed, due to the typical renal clearance of sdAb-based tracers. The kidney uptake showed significant differences between fractions of a same construct and indicates that a higher conjugation degree improves kidney clearance. AEX allows the separation of sdAbs with a different degree of conjugation and provides the opportunity to further characterize individual fractions. The conjugation of a chelator to sdAbs can alter some properties of the tracers, such as pI; however, the impact on the general biodistribution profile and tumor targeting was minimal. Full article
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