High-Throughput Excipient Discovery Enables Oral Delivery of Poorly Soluble Pharmaceuticals

Ting, Jeffrey; Tale, Swapnil; Purchel, Anatolii A.; Jones, Seamus D.; Widanapathirana, Lakmini; Tolstyka, Zachary P.; Li, Guo; Guillaudeu, Steven J.; Bates, Frank S.; Reineke, Theresa M.

doi:10.1021/acscentsci.6b00268

Cited by 64 publications

(103 citation statements)

References 37 publications

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“…[4] These advanced polymer materials showh igh potentiali nadiverse range of applications,f rom excipientsi nt herapeutic formulations [5] to singlemolecule data-storaged evices. However,t he transition of these syntheses to automated, programmable, and high-throughput operating systemsi s ac hallenging step neededt ot ranslate the vast potential of precision polymers into machine-programmablep olymers for biological and functional applications.C haingrowth polymerizations are particularlya ppealing for their ability to form structurallya nd chemically well-defined macromolecules through living/controlled polymerization techniques.…”

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confidence: 99%

“…[4] These advanced polymer materials showh igh potentiali nadiverse range of applications,f rom excipientsi nt herapeutic formulations [5] to singlemolecule data-storaged evices. [1] Recent examples in the field of small-molecule organic chemistry demonstrate both the extraordinary engineering feats requiredf or system development, and also the remarkable benefits associated with such systems.…”

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confidence: 99%

“…[1] Recent examples in the field of small-molecule organic chemistry demonstrate both the extraordinary engineering feats requiredf or system development, and also the remarkable benefits associated with such systems. [4] These advanced polymer materials showh igh potentiali nadiverse range of applications,f rom excipientsi nt herapeutic formulations [5] to singlemolecule data-storaged evices. [4] These advanced polymer materials showh igh potentiali nadiverse range of applications,f rom excipientsi nt herapeutic formulations [5] to singlemolecule data-storaged evices.…”

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confidence: 99%

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Fenton‐RAFT Polymerization: An “On‐Demand” Chain‐Growth Method

Reyhani

McKenzie

Ranji‐Burachaloo

et al. 2017

Chemistry A European J

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Fine control over the architecture and/or microstructure of synthetic polymers is fast becoming a reality owing to the development of efficient and versatile polymerization techniques and conjugation reactions. However, the transition of these syntheses to automated, programmable, and high-throughput operating systems is a challenging step needed to translate the vast potential of precision polymers into machine-programmable polymers for biological and functional applications. Chain-growth polymerizations are particularly appealing for their ability to form structurally and chemically well-defined macromolecules through living/controlled polymerization techniques. Even using the latest polymerization technologies, the macromolecular engineering of complex functional materials often requires multi-step syntheses and purification of intermediates, and results in sub-optimal yields. To develop a proof-of-concept of a framework polymerization technique that is readily amenable to automation requires several key characteristics. In this study, a new approach is described that is believed to meet these requirements, thus opening avenues toward automated polymer synthesis.

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confidence: 99%

“…[4] These advanced polymer materials showh igh potentiali nadiverse range of applications,f rom excipientsi nt herapeutic formulations [5] to singlemolecule data-storaged evices. [1] Recent examples in the field of small-molecule organic chemistry demonstrate both the extraordinary engineering feats requiredf or system development, and also the remarkable benefits associated with such systems.…”

mentioning

confidence: 99%

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confidence: 99%

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Fenton‐RAFT Polymerization: An “On‐Demand” Chain‐Growth Method

Reyhani

McKenzie

Ranji‐Burachaloo

et al. 2017

Chemistry A European J

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“…Fenton‐RAFT represented an interesting new approach for the rapid synthesis of controlled, “living” polymers using cheap and relatively benign reagents. The aqueous conditions and rapid reaction times make this technique of particular and great interest in the development of high‐throughput or machine‐programmable synthesis of polymers required for biomedical applications …”

Section: Raft Polymerization Initiated By the Fenton Reactionmentioning

confidence: 99%

Fenton‐Chemistry‐Mediated Radical Polymerization

Reyhani

McKenzie

et al. 2019

Macromol. Rapid Commun.

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have been developed for the synthesis of polymers with diverse structures (linear, star, cyclic, etc.), compositions ( • mopolymer, gradient, alternating, block, etc.), and functionalities (thiol, amine, etc.). [11] The main mechanism of RDRP which results in controllable polymerization is the establishment of a dynamic equilibrium between the propagating radicals (active polymers) and the dormant species via a reversible activation-deactivation process with rate constants k act. and k deact. , respectively. [7,12] With the emergence of RDRP methods such as atom transfer radical polymerization (ATRP), [13][14][15] nitroxide-mediated polymerization (NMP), [16] and reversible addition-fragmentation transfer (RAFT) [11,17,18] there has been significant effort to control these techniques via different physical and chemical stimuli. [19][20][21][22][23][24][25][26][27] Of these, RAFT holds particular promise due to its compatibility with a diverse range of solvents, monomers, and operating conditions. [11,24,[28][29][30][31][32][33][34][35] Among RDRP methods, one might argue that RAFT is the most similar to traditional FRP, with the simple addition of a thiocarbonylthio-containing compound chain transfer agent (CTA, termed as RAFT agent) [36] that can mediate the polymerization, allowing the synthesis of well-defined polymers (Scheme 1). In fact, RAFT CTAs aid in achieving control of the radical polymerization via reversible addition of the thiocarbonylthio group and rapid fragmentation reactions. [37,38] Therefore, relatively analogous activation/initiation systems such as thermal, [4,11,[28][29][30][31][39][40][41] photo, [2,24,[32][33][34][42][43][44][45][46][47][48][49] enzyme, [5,23,[50][51][52][53][54] and redox [3,[55][56][57][58][59] based radical formation can be employed to initiate both FRP and RAFT processes. Despite the huge advances made in this field, new techniques that can overcome some of the drawbacks of these systems are continuously sought. For example, using a thermal initiator requires a high operating temperature, limiting the possibility for in situ FRP/RAFT methods in biological systems, where temperature control is limited. The rate of visible light-activated RAFT polymerization without using photocatalysts is relatively slow, [34,60] while photocatalysts, e.g. iridium and rutheniumbased ones, [24,61] employed in photo-activated processes are expensive. Moreover, photo-mediated polymerization faces difficulties in terms of the equipment requisite to perform photoinitiation at scale. [29] Redox-responsive polymerization systems have many advantages, including a low activation energy (40-85 kJ mol −1 ), easy and facile control over the polymerization at ambient temperatures, very short induction periods, etc. [56,62] Polymerizations initiated by a redox reaction between an oxidizing and a reducing agent are referred to as "redox polymerizations." [63] Use of Radical PolymerizationIn this review, the power of a classical chemical reaction, the Fenton reaction for initiating radical polymeriza...

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“…Numerous novel chemical compounds discovered in pharmaceutical programs are poorly soluble in water [1][2][3]. In order to obtain appropriate dissolution rates, a decrease in particle size and increase in surface area are usually implemented in various drug delivery systems [4,5].…”

Section: Introductionmentioning

confidence: 99%

Preparation and Characterization of Paclitaxel/Chitosan Nanosuspensions for Drug Delivery System and Cytotoxicity Evaluation In Vitro

Liu

Ding

et al. 2019

Adv. Fiber Mater.

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In this study, we prepared paclitaxel/chitosan (PTX/CS) nanosuspensions (NSs) with different mass ratios of PTX and CS (1.5:2, 2:2, and 2.5:2), for controlled drug delivery purposes. For attachment and dispersion in water medium, a simple ultrasonic disruption technique was employed. The water-dispersed PTX/CS NSs exhibited a rod-shape morphology with an average diameter of 170-210 nm and average length of about 1-10 µm. Transmission electron microscopy, differential scanning calorimetry and X-ray diffraction indicated that the obtained PTX/CS NSs contain a nanocrystalline PTX phase. It was also inferred that presence of CS can promotes the crystalline nature of PTX up to 80%. In addition, efficiency of PTX loading reached over 85% in freeze-dried PTX/CS NSs, showing a slow rate of drug release in vitro for 8 days. The MTT and LDH assessments revealed that PTX/CS NSs significantly inhibit the growth of tumor cells (HeLa), while it is slightly toxic for the normal cells (NIH/3T3). Therefore, PTX/CS NSs is suggested as a potential nanodrug delivery system for cancer therapy.

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High-Throughput Excipient Discovery Enables Oral Delivery of Poorly Soluble Pharmaceuticals

Cited by 64 publications

References 37 publications

Fenton‐RAFT Polymerization: An “On‐Demand” Chain‐Growth Method

Fenton‐RAFT Polymerization: An “On‐Demand” Chain‐Growth Method

Fenton‐Chemistry‐Mediated Radical Polymerization

Preparation and Characterization of Paclitaxel/Chitosan Nanosuspensions for Drug Delivery System and Cytotoxicity Evaluation In Vitro

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