Screening of chemical linkers for development of pullulan bioconjugates for intravitreal ocular applications

Balasso, Anna; Subrizi, Astrid; Salmaso, Stefano; Mastrotto, Francesca; Garofalo, Mariangela; Tang, Miao; Chen, Mei; Xu, Heping; Urtti, Arto; Caliceti, Paolo

doi:10.1016/j.ejps.2021.105785

Cited by 10 publications

(7 citation statements)

References 67 publications

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“…The chromatographic and ESI-TOF mass spectrometry analyses confirmed that the drug was released in its native form (SI-7, Figures S6 and S7). This result is in agreement with previously published data showing that in the case of hydrazone-linked bioconjugates, the cleavage of the hydrazone bond is the main degradation process [18]. However, the previous study showed also that additional chemical cleavages can contribute to the backbone degradation, while in vivo enzymes could participate in the overall polymer degradation.…”

Section: Dexamethasone Releasesupporting

confidence: 93%

“…The chemical procedure for drug conjugation to the polymer backbone is paramount to control the drug release rate. Recently, we showed that the release rate of conjugated drug from pullulan can be controlled by selecting proper cleavable linkers [18]. In particular, hydrazone linker was found to provide slow drug release under neutral conditions resembling the vitreous compartment, whereas previous studies show that hydrazone is rapidly cleaved under acidic conditions.…”

Section: Introductionmentioning

confidence: 99%

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Pullulan Based Bioconjugates for Ocular Dexamethasone Delivery

et al. 2021

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Posterior segment eye diseases are mostly related to retinal pathologies that require pharmacological treatments by invasive intravitreal injections. Reduction of frequent intravitreal administrations may be accomplished with delivery systems that provide sustained drug release. Pullulan-dexamethasone conjugates were developed to achieve prolonged intravitreal drug release. Accordingly, dexamethasone was conjugated to ~67 kDa pullulan through hydrazone bond, which was previously found to be slowly cleavable in the vitreous. Dynamic light scattering and transmission electron microscopy showed that the pullulan-dexamethasone containing 1:20 drug/glucose unit molar ratio (10% w/w dexamethasone) self-assembled into nanoparticles of 461 ± 30 nm and 402 ± 66 nm, respectively. The particles were fairly stable over 6 weeks in physiological buffer at 4, 25 and 37 °C, while in homogenized vitreous at 37 °C, the colloidal assemblies underwent size increase over time. The drug was released slowly in the vitreous and rapidly at pH 5.0 mimicking lysosomal conditions: 50% of the drug was released in about 2 weeks in the vitreous, and in 2 days at pH 5.0. In vitro studies with retinal pigment epithelial cell line (ARPE-19) showed no toxicity of the conjugates in the cells. Flow cytometry and confocal microscopy showed cellular association of the nanoparticles and intracellular endosomal localization. Overall, pullulan conjugates showed interesting features that may enable their successful use in intravitreal drug delivery.

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Section: Dexamethasone Releasesupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Pullulan Based Bioconjugates for Ocular Dexamethasone Delivery

et al. 2021

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“…Conjugation of drug molecules with different polymers through linkers with different stabilities (amide, hydrazone, or ester linkages) provides prolonged release by controlled hydrolysis of the formed chemical bonds [41]. We used a succinyl linker to introduce the carboxyl function to DEX for subsequent conjugation with CS amino groups [42].…”

Section: Synthesis and Characterization Of The Succinyl Chitosan-dexamethasone Conjugates (Succs-dex)mentioning

confidence: 99%

Synthesis and Characterization of Novel Succinyl Chitosan-Dexamethasone Conjugates for Potential Intravitreal Dexamethasone Delivery

Dubashynskaya

Bokatyi

Головкин

et al. 2021

IJMS

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The development of intravitreal glucocorticoid delivery systems is a current global challenge for the treatment of inflammatory diseases of the posterior segment of the eye. The main advantages of these systems are that they can overcome anatomical and physiological ophthalmic barriers and increase local bioavailability while prolonging and controlling drug release over several months to improve the safety and effectiveness of glucocorticoid therapy. One approach to the development of optimal delivery systems for intravitreal injections is the conjugation of low-molecular-weight drugs with natural polymers to prevent their rapid elimination and provide targeted and controlled release. This study focuses on the development of a procedure for a two-step synthesis of dexamethasone (DEX) conjugates based on the natural polysaccharide chitosan (CS). We first used carbodiimide chemistry to conjugate DEX to CS via a succinyl linker, and we then modified the obtained systems with succinic anhydride to impart a negative ζ-potential to the polymer particle surface. The resulting polysaccharide carriers had a degree of substitution with DEX moieties of 2–4%, a DEX content of 50–85 μg/mg, and a degree of succinylation of 64–68%. The size of the obtained particles was 400–1100 nm, and the z-potential was −30 to −33 mV. In vitro release studies at pH 7.4 showed slow hydrolysis of the amide and ester bonds in the synthesized systems, with a total release of 8–10% for both DEX and succinyl dexamethasone (SucDEX) after 1 month. The developed conjugates showed a significant anti-inflammatory effect in TNFα-induced and LPS-induced inflammation models, suppressing CD54 expression in THP-1 cells by 2- and 4-fold, respectively. Thus, these novel succinyl chitosan-dexamethasone (SucCS-DEX) conjugates are promising ophthalmic carriers for intravitreal delivery.

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“…Modified polysaccharides are promising candidates for the development of ocular drug delivery systems [13]. For example, pullulan [14], dextran [15], hyaluronic acid [16] and chitosan [17] have been investigated in this respect. Many polysaccharides can be chemically functionalized for optimized drug delivery [13,18] and they can be formulated as macroscopic implants [19,20], gels [21] and nanosized formulations [22].…”

Section: Introductionmentioning

confidence: 99%

“…Inexpensive and conveniently modified pullulan is considered to be a biocompatible polymer. Previously, pullulan has been used as a backbone in the synthesis of bioconjugates for drug delivery to the liver and pancreas [14,27,33,[35][36][37]. Conjugation of hydrophobic drugs to pullulan results in self-assembled colloids with drug molecules oriented to the core of the nanoparticles [27,28,33,35,36].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of Pullulan–Dexamethasone Conjugates in Retinal Drug Delivery

et al. 2021

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The treatment of retinal diseases by intravitreal injections requires frequent administration unless drug delivery systems with long retention and controlled release are used. In this work, we focused on pullulan (≈67 kDa) conjugates of dexamethasone as therapeutic systems for intravitreal administration. The pullulan–dexamethasone conjugates self-assemble into negatively charged nanoparticles (average size 326 ± 29 nm). Intravitreal injections of pullulan and pullulan–dexamethasone were safe in mouse, rat and rabbit eyes. Fluorescently labeled pullulan particles showed prolonged retention in the vitreous and they were almost completely eliminated via aqueous humor outflow. Pullulan conjugates also distributed to the retina via Müller glial cells when tested in ex vivo retina explants and in vivo. Pharmacokinetic simulations showed that pullulan–dexamethasone conjugates may release free and active dexamethasone in the vitreous humor for over 16 days, even though a large fraction of dexamethasone may be eliminated from the eye as bound pullulan–dexamethasone. We conclude that pullulan based drug conjugates are promising intravitreal drug delivery systems as they may reduce injection frequency and deliver drugs into the retinal cells.

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Screening of chemical linkers for development of pullulan bioconjugates for intravitreal ocular applications

Cited by 10 publications

References 67 publications

Pullulan Based Bioconjugates for Ocular Dexamethasone Delivery

Pullulan Based Bioconjugates for Ocular Dexamethasone Delivery

Synthesis and Characterization of Novel Succinyl Chitosan-Dexamethasone Conjugates for Potential Intravitreal Dexamethasone Delivery

Pharmacokinetics of Pullulan–Dexamethasone Conjugates in Retinal Drug Delivery

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