Leveraging Affinity Interactions to Prolong Drug Delivery of Protein Therapeutics

Dogan, Alan B.; Dabkowski, Katherine; Recum, Horst A. von

doi:10.3390/pharmaceutics14051088

Cited by 10 publications

(11 citation statements)

References 45 publications

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“…Because the paclitaxel drug is encapsulated, its efficacy is significantly enhanced, and it is continuously released from the capsule in the presence of HAase, thereby effectively killing breast cancer cells. To achieve highly efficient drug delivery and prolong drug delivery of protein therapeutics, , some anticancer drugs are modified with adamantyl groups. , Based on the strong binding affinity of adamantane and β-CD, the obtained drug–adamantane conjugates can be specifically complexed with HACD to target cancer cells and then release drugs in response to multiple stimuli. Therefore, we synthesized four HACDs for adamplatin prodrug delivery, in which the degrees of β-CD substitution were 5.6, 11.5, 16, and 17 (Figure a) .…”

Section: Ha-based Macrocyclic Supramolecular Assemblymentioning

confidence: 99%

Macrocyclic Supramolecular Assemblies Based on Hyaluronic Acid and Their Biological Applications

2022

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Metrics & MoreArticle Recommendations CONSPECTUS: Hyaluronic acid (HA), which contains multiple carboxyl, hydroxyl, and acetylamino groups and is an agent that targets tumors, has drawn great attention in supramolecular diagnosis and treatment research. It can not only assemble directly with macrocyclic host−guest complexes through hydrogen bonding and electrostatic interactions but also can be modified with macrocyclic compounds or functional guest molecules by an amidation reaction and used for further assembly. Macrocycles play a main role in the construction of supramolecular drug carriers, targeted imaging agents, and hydrogels, such as cyclodextrins and cucurbit[n]urils, which can encapsulate photosensitizers, drugs, or other functional guest molecules via host−guest interactions. Therefore, the formed supramolecular assemblies can respond to various stimuli, such as enzymes, light, electricity, and magnetism for controlled drug delivery, enhance the luminescence intensity of the assembly, and improve drug loading capacity. In addition, the nanosupramolecular assembly formed with HA can also improve the biocompatibility of drugs, reduce drug toxicity and side effects, and enhance cell permeability; thus, the assembly has extensive application value in biomedical research. This Account mainly focuses on macrocyclic supramolecular assemblies based on HA, especially their biological applications and progress in the field, and these assemblies include (i) guest-modified HA, such as pyridinium-, adamantane-, peptide-, and other functional-group-modified HA, along with their cyclodextrin and cucurbit[n]uril assemblies; (ii) macrocycle-modified HA, such as HA modified with cyclodextrins and cucurbit[n]uril derivatives and their assembly with various guests; (iii) direct assembly between unmodified HA and cyclodextrin-or cucurbit[n]uril-based host−guest complexes. Particularly, we discussed the important role of macrocyclic host−guest complexes in HA-based supramolecular assembly, and the roles included improving the water solubility and efficacy of hydrophobic drugs, enhancing the luminescent intensity of assemblies, inducing room temperature phosphorescence and providing energy transfer systems, constructing multi-stimulus-responsive supramolecular assemblies, and in situ formation of hydrogels. Additionally, we believe that obtaining in-depth knowledge of these HA-based macrocyclic supramolecular assemblies and their biological applications encompasses many challenges regarding drug carriers, targeted imaging agents, wound healing, and biomedical soft materials and would certainly contribute to the rapid development of supramolecular diagnosis and treatment.

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Section: Ha-based Macrocyclic Supramolecular Assemblymentioning

confidence: 99%

Macrocyclic Supramolecular Assemblies Based on Hyaluronic Acid and Their Biological Applications

2022

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“…The sustained local delivery of therapeutics is often desirable and may be accomplished through the use of specific supramolecular interactions between a material scaffold and small molecule ,, or biomolecular ,, cargo. Here, we specifically leverage the GH interaction between Ad and CD, where avidity of the guest-modified protein (controlled by the number of conjugated guests) controls release.…”

Section: Resultsmentioning

confidence: 99%

“…25 Molecular guests, including Ad, have been used as a linking moiety to enhance the retention of drug cargo, facilitating sustained release. 30,31 By engaging multiple GH interactions simultaneously, avidity (i.e., the effective interaction of multiple noncovalent bonds) can be leveraged to further improve bond strength, 32,33 which provides a unique opportunity for modulating therapeutic release through valency of the guest or host groups. Granular hydrogels have emerged as promising materials for tissue engineering that have the potential to be used for local drug delivery such as by harnessing the inclusion of GH complexes.…”

Section: ■ Introductionmentioning

confidence: 99%

Injectable Granular Hydrogels Enable Avidity-Controlled Biotherapeutic Delivery

D’Elia,

Jones,

Canziani

et al. 2024

ACS Biomater. Sci. Eng.

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Protein therapeutics represent a rapidly growing class of pharmaceutical agents that hold great promise for the treatment of various diseases such as cancer and autoimmune dysfunction. Conventional systemic delivery approaches, however, result in off-target drug exposure and a short therapeutic half-life, highlighting the need for more localized and controlled delivery. We have developed an affinity-based protein delivery system that uses guest−host complexation between β-cyclodextrin (CD, host) and adamantane (Ad, guest) to enable sustained localized biomolecule presentation. Hydrogels were formed by the copolymerization of methacrylated CD and methacrylated dextran. Extrusion fragmentation of bulk hydrogels yielded shear-thinning and self-healing granular hydrogels (particle diameter = 32.4 ± 16.4 μm) suitable for minimally invasive delivery and with a high host capacity for the retention of guest-modified proteins. Bovine serum albumin (BSA) was controllably conjugated to Ad via EDC chemistry without affecting the affinity of the Ad moiety for CD (K D = 12.0 ± 1.81 μM; isothermal titration calorimetry). The avidity of Ad−BSA conjugates was directly tunable through the number of guest groups attached, resulting in a fourfold increase in the complex half-life (t 1/2 = 5.07 ± 1.23 h, surface plasmon resonance) that enabled a fivefold reduction in protein release at 28 days. Furthermore, we demonstrated that the conjugation of Ad to immunomodulatory cytokines (IL-4, IL-10, and IFNγ) did not detrimentally affect cytokine bioactivity and enabled their sustained release. Our strategy of avidity-controlled delivery of proteinbased therapeutics is a promising approach for the sustained local presentation of protein therapeutics and can be applied to numerous biomedical applications.

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“…It is worth noticing that the asymptotic value for the membranes loaded with Dacarbazine, which have a higher affinity to the matrix, is generally lower than the one obtained for AuM1-loaded matrices. It is probably due to the higher matrix-filler interaction that leads to holding a higher quantity in the polymer matrix [ 39 ].…”

Section: Resultsmentioning

confidence: 99%

Bottom-Up Strategy to Forecast the Drug Location and Release Kinetics in Antitumoral Electrospun Drug Delivery Systems

Longo

Raimondo

Vertuccio

et al. 2023

IJMS

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Electrospun systems are becoming promising devices usable for topical treatments. They are eligible to deliver different therapies, from anti-inflammatory to antitumoral. In the current research, polycaprolactone electrospun membranes loaded with synthetic and commercial antitumoral active substances were produced, underlining how the matrix-filler affinity is a crucial parameter for designing drug delivery devices. Nanofibrous membranes loaded with different percentages of Dacarbazine (the drug of choice for melanoma) and a synthetic derivative of Dacarbazine were produced and compared to membranes loaded with AuM1, a highly active Au-complex with low affinity to the matrix. AFM morphologies showed that the surface profile of nanofibers loaded with affine substances is similar to one of the unloaded systems, thanks to the nature of the matrix-filler interaction. FTIR analyses proved the efficacy of the interaction between the amidic group of the Dacarbazine and the polycaprolactone. In AuM1-loaded membranes, because of the weak matrix-filler interaction, the complex is mainly aggregated in nanometric domains on the nanofiber surface, which manifests a nanometric roughness. Consequently, the release profiles follow a Fickian behavior for the Dacarbazine-based systems, whereas a two-step with a highly prominent burst effect was observed for AuM1 systems. The performed antitumoral tests evidence the high-cytotoxic activity of the electrospun systems against melanoma cell lines, proving that the synthetic substances are more active than the commercial dacarbazine.

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Leveraging Affinity Interactions to Prolong Drug Delivery of Protein Therapeutics

Cited by 10 publications

References 45 publications

Macrocyclic Supramolecular Assemblies Based on Hyaluronic Acid and Their Biological Applications

Macrocyclic Supramolecular Assemblies Based on Hyaluronic Acid and Their Biological Applications

Injectable Granular Hydrogels Enable Avidity-Controlled Biotherapeutic Delivery

Bottom-Up Strategy to Forecast the Drug Location and Release Kinetics in Antitumoral Electrospun Drug Delivery Systems

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