Linker-determined drug release mechanism of free camptothecin from self-assembling drug amphiphiles

Cheetham, Andrew G.; Ou, Yu‐Chuan; Zhang, Pengcheng; Cui, Honggang

doi:10.1039/c3cc49453e

Cited by 97 publications

(77 citation statements)

References 26 publications

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“…For example, one can use tethered drugs as cross-links in a hydrogel, with the network degradation itself facilitating the drug release. This approach can also minimize the use of excipients like cross-linkers and thus increase the drug loading 170 . A hetero-bifunctional PEG chain was tethered via the primary amines on BSA, forming a macromer cross-linked PEG hydrogel; by tuning the hydrolysis rate of ester bonds in the network via adjacent charged amino acids, the BSA was released over weeks 171 .…”

Section: Designing Across Length Scalesmentioning

confidence: 99%

Designing hydrogels for controlled drug delivery

2016

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Hydrogel delivery systems can leverage therapeutically beneficial outcomes of drug delivery and have found clinical use. Hydrogels can provide spatial and temporal control over the release of various therapeutic agents, including small-molecule drugs, macromolecular drugs and cells. Owing to their tunable physical properties, controllable degradability and capability to protect labile drugs from degradation, hydrogels serve as a platform in which various physiochemical interactions with the encapsulated drugs control their release. In this Review, we cover multiscale mechanisms underlying the design of hydrogel drug delivery systems, focusing on physical and chemical properties of the hydrogel network and the hydrogel–drug interactions across the network, mesh, and molecular (or atomistic) scales. We discuss how different mechanisms interact and can be integrated to exert fine control in time and space over the drug presentation. We also collect experimental release data from the literature, review clinical translation to date of these systems, and present quantitative comparisons between different systems to provide guidelines for the rational design of hydrogel delivery systems.

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Section: Designing Across Length Scalesmentioning

confidence: 99%

Designing hydrogels for controlled drug delivery

2016

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“…33–35 DAs possess one hundred percent loading capacity, as well as the ability to optimize the delivery of the drug via a biodegradable linker. 36 This biodegradation is one of the key factors in the stability of the drug delivery vehicle, and resulting dissociation and delivery.…”

Section: Introductionmentioning

confidence: 99%

Coarse-grained molecular dynamics studies of the structure and stability of peptide-based drug amphiphile filaments

2017

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Peptide-based supramolecular filaments, in particular filaments self-assembled by drug amphiphiles (DAs), possess great potential in the field of drug delivery. These filaments possess one hundred percent drug loading, with a release mechanism that can be tuned based on the dissociation of the supramolecular filaments and the degradation of the DAs [Cheetham et al., J. Am. Chem. Soc. 135 (8), 2907 (2013)]. Recently, much attention has been drawn to the competing intermolecular interactions that drive the self-assembly of peptide-based amphiphiles into supramolecular filaments. Recently, we reported on long-time atomistic molecular dynamics simulations to characterize the structure and growth of chiral filaments by the self-assembly of a DA containing the aromatic anti-cancer drug camptothecin [Kang et al., Macromolecules 49 (3), 994 (2016)]. We found that the π–π stacking of the aromatic drug governs the early stages of the self-assembly process, while also contributing towards the chirality of the self-assembled filament. Based on these all-atomistic simulations, we now build a chemically accurate coarse-grained model that can capture the structure and stability of these supramolecular filaments at long time-scales (microseconds). These coarse-grained models successfully recapitulate the growth of the molecular clusters (and their elongation trends) compared with previously reported atomistic simulations. Furthermore, the interfacial structure and the helicity of the filaments are conserved. Next, we focus on characterization of the disassembly process of a 0.675 μm DA filament at microsecond time-scales. These results provide very useful tools for the rational design of functional supramolecular filaments, in particular supramolecular filaments for drug delivery applications.

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“…182 Taking this into consideration, Cui and co-workers investigated the drug release mechanism from their DA platform using two disulphide linkers—buSS and a disulfanyl-ethyl carbonate etcSS linker. 188 Results indicated that CPT-etcSS-Tau exhibited a faster release of free drug upon contact with GSH due to a more effective self-immolation mechanism upon reduction. This was reflected in the cytotoxic nature of the molecule as the CPT-etcSS-Tau demonstrated a much lower IC 50 value than the CPT-buSS-Tau, one much closer to free CPT.…”

Section: Small Molecule Sapdsmentioning

confidence: 96%

Self-assembling prodrugs

et al. 2017

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Covalent modification of therapeutic compounds is a clinically proven strategy to devise prodrugs with enhanced treatment efficacies. This prodrug strategy relies on modified drugs that possess advantageous pharmacokinetic properties and administration routes over their parent drug. Self-assembling prodrugs represent an emerging class of therapeutic agents capable of spontaneously associating into well-defined supramolecular nanostructures in aqueous solutions. The self-assembly of prodrugs expands the functional space of conventional prodrug design, providing a possible pathway to more effective therapies as the assembled nanostructure possesses distinct physicochemical properties that can be tailored to specific administration routes and disease treatment. In this review, we will discuss the various types of self-assembling prodrugs in development, providing an overview of the methods used to control their structure and function and, ultimately, our perspective on their current and future potential.

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Linker-determined drug release mechanism of free camptothecin from self-assembling drug amphiphiles

Cited by 97 publications

References 26 publications

Designing hydrogels for controlled drug delivery

Designing hydrogels for controlled drug delivery

Coarse-grained molecular dynamics studies of the structure and stability of peptide-based drug amphiphile filaments

Self-assembling prodrugs

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