Review: Nucleation in solutions revisited

Kashchiev, Dimo; Rosmalen, G.M. van

doi:10.1002/crat.200310070

Cited by 578 publications

(665 citation statements)

References 36 publications

(98 reference statements)

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“…If c o > c s , then the uniformly mixed solution of monomers is metastable and supersaturated with respect to the soluble phase. The parameter S quantifies the degree of metastability of the predominantly monomeric solution and hence provides an estimate of the magnitude of the driving force for aggregation and phase separation (16). If c o > c s , then S > 0, and the soluble phase is supersaturated, whereas if c o < c s , then S < 0, and the soluble phase is subsaturated.…”

Section: Significancementioning

confidence: 99%

“…The homogeneous nucleation model (16) has been used as a conceptual framework for explaining the kinetics of polyglutamine aggregation (21). In this model, an obligatory nucleus representing an embryo of the new aggregated/insoluble phase has to form within the homogeneously mixed, soluble phase.…”

Section: Comparative Kinetics Of Aggregation For Different Constructsmentioning

confidence: 99%

“…In this model, an obligatory nucleus representing an embryo of the new aggregated/insoluble phase has to form within the homogeneously mixed, soluble phase. The free energy of nucleation depends on the supersaturation value and the free-energy penalty associated with creating an interface between the new and old phases (16). Supersaturation is a prerequisite for a nucleated process.…”

Section: Comparative Kinetics Of Aggregation For Different Constructsmentioning

confidence: 99%

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Unmasking the roles of N- and C-terminal flanking sequences from exon 1 of huntingtin as modulators of polyglutamine aggregation

Crick

Ruff

Garai

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

203

274

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Huntington disease is caused by mutational expansion of the CAG trinucleotide within exon 1 of the huntingtin (Htt) gene. Exon 1 spanning N-terminal fragments (NTFs) of the Htt protein result from aberrant splicing of transcripts of mutant Htt. NTFs typically encompass a polyglutamine tract flanked by an N-terminal 17-residue amphipathic stretch (N17) and a C-terminal 38-residue proline-rich stretch (C38). We present results from in vitro biophysical studies that quantify the driving forces for and mechanisms of polyglutamine aggregation as modulated by N17 and C38. Although N17 is highly soluble by itself, it lowers the saturation concentration of soluble NTFs and increases the driving force, vis-à-vis homopolymeric polyglutamine, for forming insoluble aggregates. Kinetically, N17 accelerates fibril formation and destabilizes nonfibrillar intermediates. C38 is also highly soluble by itself, and it lends its high intrinsic solubility to lower the driving force for forming insoluble aggregates by increasing the saturation concentration of soluble NTFs. In NTFs with both modules, N17 and C38 act synergistically to destabilize nonfibrillar intermediates (N17 effect) and lower the driving force for forming insoluble aggregates (C38 effect). Morphological studies show that N17 and C38 promote the formation of ordered fibrils by NTFs. Homopolymeric polyglutamine forms a mixture of amorphous aggregates and fibrils, and its aggregation mechanisms involve early formation of heterogeneous distributions of nonfibrillar species. We propose that N17 and C38 act as gatekeepers that control the intrinsic heterogeneities of polyglutamine aggregation. This provides a biophysical explanation for the modulation of in vivo NTF toxicities by N17 and C38. (2). The Htt gene with expanded CAG tracts can undergo erroneous splicing, and the resultant aberrant messenger RNA is translated into a mutant exon 1 version of Htt that is similar to toxic NTFs found in neuronal intranuclear inclusions (3). Exon 1 spanning NTFs typically include a polyglutamine tract that is flanked on its N terminus by an amphipathic 17-residue stretch (MATLEKLMKAFESLKSF) denoted as N17 and by a 38-residue proline-rich stretch on its C terminus (P 11 -QLPQPPPQAQPLLPQPQ-P 10 ) denoted as C38. The N17 sequence is conserved among higher mammals (SI Appendix, Fig. S1), and mutations within N17 impact the properties of NTFs (4, 5). N17 enhances the overall rate of aggregation, as measured by the rate of forming large insoluble species both in vitro (6) and in yeast (7). The C-terminal proline-rich region of exon 1 modulates polyglutamine aggregation and reduces the cellular toxicity of Htt exon 1 even when the polyglutamine tract is significantly expanded (8, 9).A molecular-level understanding of the synergy between the length of polyglutamine tracts and its flanking sequences is essential for inferring the roles of N17 and C38 in vivo. This requires a quantitative understanding of the driving forces, mechanisms, and morphologies for homopolymeric polyglutamine and t...

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Section: Significancementioning

confidence: 99%

Section: Comparative Kinetics Of Aggregation For Different Constructsmentioning

confidence: 99%

Section: Comparative Kinetics Of Aggregation For Different Constructsmentioning

confidence: 99%

See 1 more Smart Citation

Unmasking the roles of N- and C-terminal flanking sequences from exon 1 of huntingtin as modulators of polyglutamine aggregation

Crick

Ruff

Garai

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

203

274

View full text Add to dashboard Cite

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“…Nucleation is an activated process [1,8,9]. As such, its rate has an exponential dependence on the free-energy barrier to nucleation ⌬F* the free energy of the critical nucleus.…”

Section: General Theorymentioning

confidence: 99%

“…The rate of nucleation at a site is proportional to the exponential of minus the free energy divided by the thermal energy k B T. See the book of Debenedetti [1] or the review of Oxtoby [8] or of Kashchiev and van Rosmalen [9] for an introduction to nucleation. Thus the rate at a particular site is proportional to the Boltzmann factor of the nucleus at that site and so a sum over different sites with different freeenergy barriers has the form of a sum over Boltzmann weights.…”

Section: Introductionmentioning

confidence: 99%

Statistical theory of nucleation in the presence of uncharacterized impurities

Sear

2004

Phys. Rev. E

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First order phase transitions proceed via nucleation. The rate of nucleation varies exponentially with the free-energy barrier to nucleation, and so is highly sensitive to variations in this barrier. In practice, very few systems are absolutely pure, there are typically some impurities present which are rather poorly characterized. These interact with the nucleus, causing the barrier to vary, and so must be taken into account. Here the impurity-nucleus interactions are modelled by random variables. The rate then has the same form as the partition function of Derrida's random energy model, and as in this model there is a regime in which the behavior is non-self-averaging. Non-self-averaging nucleation is nucleation with a rate that varies significantly from one realization of the random variables to another. In experiment this corresponds to variation in the nucleation rate from one sample to another. General analytic expressions are obtained for the crossover from a self-averaging to a non-self-averaging rate of nucleation.

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Nanocrystals Production, Characterization, and Application for Cancer Therapy

Hollis

2013

Pharmaceutical Sciences Encyclopedia

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The delivery of synthesized drugs exhibiting poor solubility in water is extremely difficult, limiting bioavailability and causing adverse effects when solubilized. A need was determined for developing a formulation to deliver poorly water‐soluble drugs without indiscriminately reaching healthy organs and tissues. Therefore, nanocrystal formulations have been a significant focus for delivering poorly water‐soluble drugs via oral, paraenteral, and alternative routes. Using nanocrystal formulations avoids potential side effects and instability related to many existing delivery systems. Currently, few cancer therapy products are approved by the Food and Drug Administration (FDA) in which poorly soluble drugs are formulated by nanoparticles. In this chapter, the production of nanocrystals of pharmaceutical organic compounds is reviewed. Thereafter, the chapter will focus on the application of nanocrystals for cancer therapy.

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Review: Nucleation in solutions revisited

Cited by 578 publications

References 36 publications

Unmasking the roles of N- and C-terminal flanking sequences from exon 1 of huntingtin as modulators of polyglutamine aggregation

Unmasking the roles of N- and C-terminal flanking sequences from exon 1 of huntingtin as modulators of polyglutamine aggregation

Statistical theory of nucleation in the presence of uncharacterized impurities

Nanocrystals Production, Characterization, and Application for Cancer Therapy

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