Multicomponent Organic Nanoparticles for Fluorescence Studies in Biological Systems

McDonald, Tom O.; Martin, Philip; Patterson, Joseph P.; Smith, Darren; Giardiello, Marco; Marcello, Marco; Sée, Violaine; O’Reilly, Rachel K.; Owen, Andrew; Rannard, Steve P.

doi:10.1002/adfm.201103059

Cited by 56 publications

(49 citation statements)

References 42 publications

(41 reference statements)

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“…The identification of single vehicles capable of dissolving multiple drugs for solution-based LA injections provides a number of hurdles, especially when attempting to overlay various partition coefficients to maintain the dose ratios over extended periods. Recent reports of bottom-up formation of combination SDNs suggests some potential for future LA formulations using nanosuspension approaches but the tailoring of release profiles is yet to be demonstrated [80, 81]. Equally, the formation of microparticles containing drug combinations using solvent evaporation techniques requires a solvent phase able to generate appropriate drug combinations to match final therapeutic need whilst preventing unequal losses to the aqueous phase during evaporation.…”

Section: Technological Challenges For La Deliverymentioning

confidence: 99%

“…This is driven by the bioanalytical challenges associated with quantification of dissolved versus particulate drug within the blood – conventional methods of drug detection such a HPLC and LC-MS/MS do not discriminate because of the solvent extraction process necessary in sample preparation, which dissolves this type of nanoparticles. Recently, the authors validated a flow cytometry method for detection of intact nanoparticles in plasma [95] and developed SDNs based on fluorescence resonance energy transfer [80] that may have utility in understanding this fundamental question. Nonetheless, if the majority of the pharmacokinetic variability stems from drug release from the depot there are a number of putative depot-specific physiological, anatomical or environmental factors that may contribute and these are hypothesised in this section of the review.…”

Section: Gaps In Knowledge Regarding the Pharmacology Of Solid Drumentioning

confidence: 99%

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Strengths, weaknesses, opportunities and challenges for long acting injectable therapies: Insights for applications in HIV therapy

Owen

Rannard

2016

Advanced Drug Delivery Reviews

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120

102

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Advances in solid drug nanoparticle technologies have resulted in a number of long-acting (LA) formulations with the potential for once monthly or longer administration. Such formulations offer great utility for chronic diseases, particularly when a lack of medication compliance may be detrimental to treatment response. Two such formulations are in clinical development for HIV but the concept of LA delivery has its origins in indications such as schizophrenia and contraception. Many terms have been utilised to describe the LA approach and standardisation would be beneficial. Ultimately, definitions will depend upon specific indications and routes of delivery, but for HIV we propose benchmarks that reflect perceived clinical benefits and available data on patient attitudes. Specifically, we propose dosing intervals of ≥ 1 week, ≥ 1 month or ≥ 6 months, for oral, injectable or implantable strategies, respectively. This review focuses upon the critical importance of potency in achieving the LA outcome for injectable formulations and explores established and emerging technologies that have been employed across indications. Key technological challenges such as the need for consistency and ease of administration for drug combinations, are also discussed. Finally, the review explores the gaps in knowledge regarding the pharmacology of drug release from particulate-based LA injectable suspensions. A number of hypotheses are discussed based upon available data relating to local drug metabolism, active transport systems, the lymphatics, macrophages and patient-specific factors. Greater knowledge of the mechanisms that underpin drug release and protracted exposure will help facilitate further development of this strategy to achieve the promising clinical benefits.

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Section: Technological Challenges For La Deliverymentioning

confidence: 99%

Section: Gaps In Knowledge Regarding the Pharmacology Of Solid Drumentioning

confidence: 99%

Strengths, weaknesses, opportunities and challenges for long acting injectable therapies: Insights for applications in HIV therapy

Owen

Rannard

2016

Advanced Drug Delivery Reviews

Self Cite

120

102

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“…[21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] Specifically, donors and acceptors can be co-encapsulated in the interior of the same nanocarriers to allow the transfer of energy from the former chromophores to latter upon excitation. Experimental conditions that encourage the dissociation of the supramolecular constructs into their individual components, however, can separate the donors from the acceptors and suppress energy transfer.…”

Section: Introductionmentioning

confidence: 99%

Energy-Transfer Schemes To Probe Fluorescent Nanocarriers and Their Emissive Cargo

et al. 2015

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A strategy to probe supramolecular nanocarriers and their cargo in the intracellular space was developed on the basis of fluorescence measurements and energy transfer. It relies on the covalent attachment of an energy donor, or acceptor, to the macromolecular backbone of amphiphilic polymers and the noncovalent encapsulation of a complementary acceptor, or donor, in the resulting micelles. In aqueous environments, these macromolecules self-assemble into nanostructured constructs and bring the complementary chromophores in close proximity to enable efficient energy transfer. These supramolecular assemblies travel from the extracellular to the intracellular space and retain their integrity in the process. Indeed, donors and acceptors remain close to each other after internalization, and excitation of the former chromophores translates into significant intracellular emission from the latter. Furthermore, these supramolecular assemblies exchange their components with fast kinetics in aqueous dispersions because of the reversible character of the noncovalent contacts holding them together. As a result, micelles incorporating exclusively the donors and nanocarriers containing only the acceptors scramble their chromophoric building blocks, upon mixing, to allow the transfer of energy. These dynamic processes can be reproduced in the intracellular environment with the sequential incubation of cells with the two sets of complementary nanostructured assemblies. Thus, these operating principles and choice of supramolecular synthons are particularly valuable to monitor self-assembling nanocarriers and their cargo inside living cells and can facilitate the elucidation of the behavior of these promising delivery vehicles in a diversity of biological specimens.

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“…ETFD is uniquely able to generate multiple-component SDNs by combining two or more hydrophobic compounds within the internal oil phase1112; other approaches to combination nanoparticle approaches have utilized lipid nanocarrier approaches for subcutaneous injection13. This is of high clinical relevance for HIV due to the need for drug combinations.…”

Section: Resultsmentioning

confidence: 99%

Accelerated oral nanomedicine discovery from miniaturized screening to clinical production exemplified by paediatric HIV nanotherapies

et al. 2016

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Considerable scope exists to vary the physical and chemical properties of nanoparticles, with subsequent impact on biological interactions; however, no accelerated process to access large nanoparticle material space is currently available, hampering the development of new nanomedicines. In particular, no clinically available nanotherapies exist for HIV populations and conventional paediatric HIV medicines are poorly available; one current paediatric formulation utilizes high ethanol concentrations to solubilize lopinavir, a poorly soluble antiretroviral. Here we apply accelerated nanomedicine discovery to generate a potential aqueous paediatric HIV nanotherapy, with clinical translation and regulatory approval for human evaluation. Our rapid small-scale screening approach yields large libraries of solid drug nanoparticles (160 individual components) targeting oral dose. Screening uses 1 mg of drug compound per library member and iterative pharmacological and chemical evaluation establishes potential candidates for progression through to clinical manufacture. The wide applicability of our strategy has implications for multiple therapy development programmes.

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Multicomponent Organic Nanoparticles for Fluorescence Studies in Biological Systems

Cited by 56 publications

References 42 publications

Strengths, weaknesses, opportunities and challenges for long acting injectable therapies: Insights for applications in HIV therapy

Strengths, weaknesses, opportunities and challenges for long acting injectable therapies: Insights for applications in HIV therapy

Energy-Transfer Schemes To Probe Fluorescent Nanocarriers and Their Emissive Cargo

Accelerated oral nanomedicine discovery from miniaturized screening to clinical production exemplified by paediatric HIV nanotherapies

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