Theranostic Microbubbles with Homogeneous Ligand Distribution for Higher Binding Efficacy

Langeveld, Simone A. G.; Meijlink, Bram; Beekers, Inés; Olthof, Mark; Steen, Antonius F.W. van der; Jong, Nico de; Kooiman, Klazina

doi:10.3390/pharmaceutics14020311

Cited by 3 publications

(4 citation statements)

References 69 publications

(99 reference statements)

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“…It was confirmed that the dissociation of MBs from both charged and uncharged surfaces was less pronounced at wall shear stress values up to 0.5 Pa, but occurred more rapidly from 0.5 Pa to 1 Pa for all formulations ( Figure 3 ). Phospholipid-coated ανβ3-targeted MBs used in endothelial cell targeting by Langeveld et al remained attached to their target under flow up to shear stress values of approximately 0.2 Pa [ 59 ]. There was a significant reduction in the number of bound MBs from approximately 0.5 Pa, which is consistent with levels of attachment and loss of cationic MBs under flow in this work.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, Langeveld et al also compared how the homogeneity of the ligand distribution affected MB binding. They showed that MBs with a more homogenous ligand distribution had a higher binding efficacy than those with a heterogenous distribution [ 59 ]; future work in this area could investigate how the arrangement of lipids in a cationic MB may also affect MB binding efficacy. In our investigation, both RAMBs + and NOMBs + were able to remain in contact or continue accumulating on the negatively charged surface up to wall shear stress values of 0.2 Pa and 0.5 Pa, respectively.…”

Section: Discussionmentioning

confidence: 99%

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Cationic Microbubbles for Non-Selective Binding of Cavitation Nuclei to Bacterial Biofilms

LuTheryn

Choi

et al. 2023

Pharmaceutics

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The presence of multi-drug resistant biofilms in chronic, persistent infections is a major barrier to successful clinical outcomes of therapy. The production of an extracellular matrix is a characteristic of the biofilm phenotype, intrinsically linked to antimicrobial tolerance. The heterogeneity of the extracellular matrix makes it highly dynamic, with substantial differences in composition between biofilms, even in the same species. This variability poses a major challenge in targeting drug delivery systems to biofilms, as there are few elements both suitably conserved and widely expressed across multiple species. However, the presence of extracellular DNA within the extracellular matrix is ubiquitous across species, which alongside bacterial cell components, gives the biofilm its net negative charge. This research aims to develop a means of targeting biofilms to enhance drug delivery by developing a cationic gas-filled microbubble that non-selectively targets the negatively charged biofilm. Cationic and uncharged microbubbles loaded with different gases were formulated and tested to determine their stability, ability to bind to negatively charged artificial substrates, binding strength, and, subsequently, their ability to adhere to biofilms. It was shown that compared to their uncharged counterparts, cationic microbubbles facilitated a significant increase in the number of microbubbles that could both bind and sustain their interaction with biofilms. This work is the first to demonstrate the utility of charged microbubbles for the non-selective targeting of bacterial biofilms, which could be used to significantly enhance stimuli-mediated drug delivery to the bacterial biofilm.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cationic Microbubbles for Non-Selective Binding of Cavitation Nuclei to Bacterial Biofilms

LuTheryn

Choi

et al. 2023

Pharmaceutics

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“…For contrast-enhanced molecular imaging applications, labeling consistency of ligands on the surface of the MB shell is important for the optimal target-binding performance of targeted MBs. Furthermore, ligand labeling distribution can be enhanced upon preferential use of phospholipid formulations and specific lipid handling methods prior to MB production [22,23]. Microfluidic devices allow precise control over these production parameters to achieve standardized methodologies of targeted MB synthesis.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of Clinically Translatable Targeted Microbubbles Using a Microfluidic Device for In Vivo Ultrasound Molecular Imaging

Bam

Natarajan

Tabesh

et al. 2023

IJMS

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The main aim of this study is to synthesize contrast microbubbles (MB) functionalized with engineered protein ligands using a microfluidic device to target breast cancer specific vascular B7-H3 receptor in vivo for diagnostic ultrasound imaging. We used a high-affinity affibody (ABY) selected against human/mouse B7-H3 receptor for engineering targeted MBs (TMBs). We introduced a C-terminal cysteine residue to this ABY ligand for facilitating site-specific conjugation to DSPE-PEG-2K-maleimide (M. Wt = 2.9416 kDa) phospholipid for MB formulation. We optimized the reaction conditions of bioconjugations and applied it for microfluidic based synthesis of TMBs using DSPE-PEG-ABY and DPPC liposomes (5:95 mole %). The binding affinity of TMBs to B7-H3 (MBB7-H3) was tested in vitro in MS1 endothelial cells expressing human B7-H3 (MS1B7-H3) by flow chamber assay, and by ex vivo in the mammary tumors of a transgenic mouse model (FVB/N-Tg (MMTV-PyMT)634Mul/J), expressing murine B7-H3 in the vascular endothelial cells by immunostaining analyses. We successfully optimized the conditions needed for generating TMBs using a microfluidic system. The synthesized MBs showed higher affinity to MS1 cells engineered to express higher level of hB7-H3, and in the endothelial cells of mouse tumor tissue upon injecting TMBs in a live animal. The average number (mean ± SD) of MBB7-H3 binding to MS1B7-H3 cells was estimated to be 354.4 ± 52.3 per field of view (FOV) compared to wild-type control cells (MS1WT; 36.2 ± 7.5/FOV). The non-targeted MBs did not show any selective binding affinity to both the cells (37.7 ± 7.8/FOV for MS1B7-H3 and 28.3 ± 6.7/FOV for MS1WT cells). The fluorescently labeled MBB7-H3 upon systemic injection in vivo co-localized to tumor vessels, expressing B7-H3 receptor, as validated by ex vivo immunofluorescence analyses. We have successfully synthesized a novel MBB7-H3 via microfluidic device, which allows us to produce on demand TMBs for clinical applications. This clinically translatable MBB7-H3 showed significant binding affinity to vascular endothelial cells expressing B7-H3 both in vitro and in vivo, which shows its potential for clinical translation as a molecular ultrasound contrast agent for human applications.

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“…Pioneering works of MB shell stabilization with albumin by Feinstein and Keller led to the regulatory approval of Albunex (Molecular Biosystems Inc., San Diego, CA, USA) MBs are colloidal systems with a mean diameter of 1-7 µm, acting as real blood pool agents. Beyond imaging applications, MBs are actively investigated as drug delivery systems due to their shell drug loading capacities and gaseous core US stimuliresponsiveness [10,[13][14][15][16]]. An MB shell is mainly stabilized with lipids, proteins, or polymers [17][18][19][20][21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Microbubbles Stabilized by Protein Shell: From Pioneering Ultrasound Contrast Agents to Advanced Theranostic Systems

et al. 2022

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Ultrasound is a widely-used imaging modality in clinics as a low-cost, non-invasive, non-radiative procedure allowing therapists faster decision-making. Microbubbles have been used as ultrasound contrast agents for decades, while recent attention has been attracted to consider them as stimuli-responsive drug delivery systems. Pioneering microbubbles were Albunex with a protein shell composed of human serum albumin, which entered clinical practice in 1993. However, current research expanded the set of proteins for a microbubble shell beyond albumin and applications of protein microbubbles beyond ultrasound imaging. Hence, this review summarizes all-known protein microbubbles over decades with a critical evaluation of formulations and applications to optimize the safety (low toxicity and high biocompatibility) as well as imaging efficiency. We provide a comprehensive overview of (1) proteins involved in microbubble formulation, (2) peculiarities of preparation of protein stabilized microbubbles with consideration of large-scale production, (3) key chemical factors of stabilization and functionalization of protein-shelled microbubbles, and (4) biomedical applications beyond ultrasound imaging (multimodal imaging, drug/gene delivery with attention to anticancer treatment, antibacterial activity, biosensing). Presented critical evaluation of the current state-of-the-art for protein microbubbles should focus the field on relevant strategies in microbubble formulation and application for short-term clinical translation. Thus, a protein bubble-based platform is very perspective for theranostic application in clinics.

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Theranostic Microbubbles with Homogeneous Ligand Distribution for Higher Binding Efficacy

Cited by 3 publications

References 69 publications

Cationic Microbubbles for Non-Selective Binding of Cavitation Nuclei to Bacterial Biofilms

Cationic Microbubbles for Non-Selective Binding of Cavitation Nuclei to Bacterial Biofilms

Synthesis and Evaluation of Clinically Translatable Targeted Microbubbles Using a Microfluidic Device for In Vivo Ultrasound Molecular Imaging

Microbubbles Stabilized by Protein Shell: From Pioneering Ultrasound Contrast Agents to Advanced Theranostic Systems

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