The Global Characterisation of a Drug-Dendrimer Conjugate - PEGylated poly-lysine Dendrimer

Akhtar, Nadim; Beer, Louisa; Bowes, Alex; Bristow, Tony; Broo, Anders; Buttar, David; Coombes, Stephen; Cross, Rebecca; Eriksson, Emma S. E.; Guilbaud, Jean‐Baptiste; Holman, Stephen W.; Hughes, Leslie P.; Jackman, Mark; Lawrence, M. Jayne; Lee, Jessica; Liu, Weimin; Linke, Rebecca; Mahmoudi, Najet; McCormick, Marc; MacMillan, Bryce; Newling, Benedict; Ngeny, Maryann; Patterson, Claire; Poulton, Andy; Ray, Andrew; Sanderson, Natalie; Sonzini, Silvia; Tang, Yayan; Treacher, Kevin; Whittaker, Dave; Wren, Stephen

doi:10.1016/j.xphs.2022.11.005

Cited by 6 publications

(5 citation statements)

References 46 publications

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“…The characterizations were performed both at AZ and in the EUNCL laboratories. The drug-dendrimer conjugate as a molecular entity (drug substance) was additionally analysed by several techniques, including nuclear magnetic resonance, mass spectrometry and reverse phase, size exclusion and supercritical fluid chromatography( Akhtar, 2022 ). Nevertheless, the aim of this partnership was to focus on drug product CQAs and thus drug substance characterizations are not reported herein.…”

Section: Methodssupporting

confidence: 86%

“…To note, AZD0466 C1d was an early small scale discovery batch whilst AZD0466 C2a was manufactured under good manufacturing practice (GMP) at significantly larger scale using a markedly different synthetic route. The structural characterization of AZD0466 is published elsewhere and not focus of this investigation ( Akhtar, 2022 ).…”

Section: Introductionsupporting

confidence: 86%

“…This hypothesis was confirmed by independent MD-SEC analyses in organic solvent which demonstrated that the drug substance is mainly monomeric in nature (>90% monomer vs . higher order species) with molecular weight between 100 and 105 kDa ( Akhtar, 2022 ). Interestingly, whilst the profiles of the AZD0466 drug product samples ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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In depth characterization of physicochemical critical quality attributes of a clinical drug-dendrimer conjugate

Sonzini

Caputo

Méhn

et al. 2023

International Journal of Pharmaceutics

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Section: Methodssupporting

confidence: 86%

Section: Introductionsupporting

confidence: 86%

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In depth characterization of physicochemical critical quality attributes of a clinical drug-dendrimer conjugate

Sonzini

Caputo

Méhn

et al. 2023

International Journal of Pharmaceutics

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“…Poly-l-lysine (PLL) dendrimers are amphiphilic dendrimers obtained by functionalizing positively charged basic amino acids such as lysine or 𝛽-amino-alanine. [34,35] Cationic polymers can absorb nucleic acids, including small nucleic acids (such as siRNA and miRNA) and large nucleic acids (such as pDNA and mRNA), to form complexes, which can protect nucleic acids from degradation and enhance absorption induced endocytosis. [36] As we all know, adjusting the conformation of the molecules can significantly improve the properties of the polymers, but PLL, which carries positive charges under physiological conditions, shows nonnegligible toxicity in both in vitro and in vivo.…”

Section: Poly-lysinementioning

confidence: 99%

Research Status of Dendrimer Micelles in Tumor Therapy for Drug Delivery

Wang,

Zhang,

et al. 2023

Small

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Dendrimers are a family of polymers with highly branched structure, well‐defined composition, and extensive functional groups, which have attracted great attention in biomedical applications. Micelles formed by dendrimers are ideal nanocarriers for delivering anticancer agents due to the explicit study of their characteristics of particle size, charge, and biological properties such as toxicity, blood circulation time, biodistribution, and cellular internalization. Here, the classification, preparation, and structure of dendrimer micelles are reviewed, and the specific functional groups modified on the surface of dendrimers for tumor active targeting, stimuli‐responsive drug release, reduced toxicity, and prolonged blood circulation time are discussed. In addition, their applications are summarized as various platforms for biomedical applications related to cancer therapy including drug delivery, gene transfection, nano‐contrast for imaging, and combined therapy. Other applications such as tissue engineering and biosensor are also involved. Finally, the possible challenges and perspectives of dendrimer micelles for their further applications are discussed.

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“…This is a fifth generation poly-L-lysine dendrimer, a highly optimized molecule containing the anti-cancer drug AZD4320, and a PEGylated poly-L-lysine dendrimer. AZD0466 belongs to a new class of oncology drugs that provide efficient delivery of a dual Bcl-2/xL inhibitor with an optimized release profile that is designed to reduce the potential for toxicity associated with dual Bcl-2/xL inhibition [119][120][121][122]. The AZD0466 construct is currently undergoing simultaneous phase1/phase 2 clinical trials in patients with advanced hematologic malignancies as monotherapy or in combination with certain combination therapies, such as antifungals.…”

Section: Validation Of Dendrimers In Clinical Trialsmentioning

confidence: 99%

Dendrimer-Mediated Delivery of DNA and RNA Vaccines

et al. 2023

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DNA and RNA vaccines (nucleic acid-based vaccines) are a promising platform for vaccine development. The first mRNA vaccines (Moderna and Pfizer/BioNTech) were approved in 2020, and a DNA vaccine (Zydus Cadila, India), in 2021. They display unique benefits in the current COVID-19 pandemic. Nucleic acid-based vaccines have a number of advantages, such as safety, efficacy, and low cost. They are potentially faster to develop, cheaper to produce, and easier to store and transport. A crucial step in the technology of DNA or RNA vaccines is choosing an efficient delivery method. Nucleic acid delivery using liposomes is the most popular approach today, but this method has certain disadvantages. Therefore, studies are actively underway to develop various alternative delivery methods, among which synthetic cationic polymers such as dendrimers are very attractive. Dendrimers are three-dimensional nanostructures with a high degree of molecular homogeneity, adjustable size, multivalence, high surface functionality, and high aqueous solubility. The biosafety of some dendrimers has been evaluated in several clinical trials presented in this review. Due to these important and attractive properties, dendrimers are already being used to deliver a number of drugs and are being explored as promising carriers for nucleic acid-based vaccines. This review summarizes the literature data on the development of dendrimer-based delivery systems for DNA and mRNA vaccines.

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The Global Characterisation of a Drug-Dendrimer Conjugate - PEGylated poly-lysine Dendrimer

Cited by 6 publications

References 46 publications

In depth characterization of physicochemical critical quality attributes of a clinical drug-dendrimer conjugate

In depth characterization of physicochemical critical quality attributes of a clinical drug-dendrimer conjugate

Research Status of Dendrimer Micelles in Tumor Therapy for Drug Delivery

Dendrimer-Mediated Delivery of DNA and RNA Vaccines

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