Mucus-Penetrating Nanosuspensions for Enhanced Delivery of Poorly Soluble Drugs to Mucosal Surfaces.

Mucus-penetrating nanosuspensions, consisting of pure hydrophobic therapeutics with dense muco-inert coatings that enable particles to effectively bypass the mucus barrier, demonstrate superior drug distribution and absorption at mucosal surfaces. With significantly increased drug load compared to polymeric systems and established clinical translation of nanosuspensions-based products, mucus-penetrating nanosuspensions are a promising vehicle for improving mucosal delivery of poorly soluble drugs.

Subconjunctival Delivery of Dorzolamide-Loaded Poly(ether-anhydride) Microparticles Produces Sustained Lowering of Intraocular Pressure in Rabbits.

Topical medications that inhibit the enzyme carbonic anhydrase (CAI) are widely used to lower intraocular pressure in glaucoma; however, their clinical efficacy is limited by the requirement for multiple-daily dosing, as well as side effects such as blurred vision and discomfort on drop instillation. We developed a biodegradable polymer microparticle formulation of the CAI dorzolamide that produces sustained lowering of intraocular pressure after subconjunctival injection. Dorzolamide was ion paired with sodium dodecyl sulfate (SDS) and sodium oleate (SO) with 0.8% and 1.5% drug loading in poly(lactic-co-glycolic acid) (PLGA), respectively. Encapsulating dorzolamide into poly(ethylene glycol)-co-poly(sebacic acid) (PEG3-PSA) microparticles in the presence of triethylamine (TEA) resulted in 14.9% drug loading and drug release that occurred over 12 days in vitro. Subconjunctival injection of dorzolamide-PEG3-PSA microparticles (DPP) in Dutch belted rabbits reduced IOP as much as 4.0 ± 1.5 mmHg compared to untreated fellow eyes for 35 days. IOP reduction after injection of DPP microparticles was significant when compared to baseline untreated IOPs (P < 0.001); however, injection of blank microparticles (PEG3-PSA) did not affect IOP (P = 0.9). Microparticle injection was associated with transient clinical vascularity and inflammatory cell infiltration in conjunctiva on histological examination. Fluorescently labeled PEG3-PSA microparticles were detected for at least 42 days after injection, indicating that in vivo particle degradation is several-fold longer than in vitro degradation. Subconjunctival DPP microparticle delivery is a promising new platform for sustained intraocular pressure lowering in glaucoma.

Small-molecule targeting of signal transducer and activator of transcription (STAT) 3 to treat non-small cell lung cancer.

OBJECTIVE: Lung cancer is the leading cause of cancer death in both men and women. Non-small cell lung cancer (NSCLC) has an overall 5-year survival rate of 15%. While aberrant STAT3 activation has previously been observed in NSCLC, the scope of its contribution is uncertain and agents that target STAT3 for treatment are not available clinically. METHODS: We determined levels of activated STAT3 (STAT3 phosphorylated on Y705, pSTAT3) and the two major isoforms of STAT3 (α and ß) in protein extracts of 8 NSCLC cell lines, as well as the effects of targeting STAT3 in vitro and in vivo in NSCLC cells using short hairpin (sh) RNA and two novel small-molecule STAT3 inhibitors, C188-9 and piperlongumine (PL). RESULTS: Levels of pSTAT3, STAT3α, and STATß were increased in 7 of 8 NSCLC cell lines. Of note, levels of pSTAT3 were tightly correlated with levels of STAT3ß, but not STAT3α. Targeting of STAT3 in A549 cells using shRNA decreased tSTAT3 by 75%; this was accompanied by a 47-78% reduction in anchorage-dependent and anchorage-independent growth and a 28-45% reduction in mRNA levels for anti-apoptotic STAT3 gene targets. C188-9 and PL (@30 µM) each reduced pSTAT3 levels in all NSCLC cell lines tested by ≥50%, reduced anti-apoptotic protein mRNA levels by 25-60%, and reduced both anchorage-dependent and anchorage-independent growth of NSCLC cell lines with IC50 values ranging from 3.06 to 52.44 µM and 0.86 to 11.66 µM, respectively. Treatment of nude mice bearing A549 tumor xenografts with C188-9 or PL blocked tumor growth and reduced levels of pSTAT3 and mRNA encoding anti-apoptotic proteins. CONCLUSION: STAT3 is essential for growth of NSCLC cell lines and tumors and its targeting using C188-9 or PL may be a useful strategy for treatment.

Nanoparticle penetration of human cervicovaginal mucus: the effect of polyvinyl alcohol.

Therapeutic nanoparticles must rapidly penetrate the mucus secretions lining the surfaces of the respiratory, gastrointestinal and cervicovaginal tracts to efficiently reach the underlying tissues. Whereas most polymeric nanoparticles are highly mucoadhesive, we previously discovered that a dense layer of low MW polyethylene glycol (PEG) conferred a sufficiently hydrophilic and uncharged surface to effectively minimize mucin-nanoparticle adhesive interactions, allowing well-coated particles to rapidly diffuse through human mucus. Here, we sought to investigate the influence of surface coating by polyvinyl alcohol (PVA), a relatively hydrophilic and uncharged polymer routinely used as a surfactant to formulate drug carriers, on the transport of nanoparticles in fresh human cervicovaginal mucus. We found that PVA-coated polystyrene (PS) particles were immobilized, with speeds at least 4000-fold lower in mucus than in water, regardless of the PVA molecular weight or incubation concentration tested. Nanoparticles composed of poly(lactide-co-glycolide) (PLGA) or diblock copolymers of PEG-PLGA were similarly immobilized when coated with PVA (slowed 29,000- and 2500-fold, respectively). PVA coatings could not be adequately removed upon washing, and the residual PVA prevented sufficient coating with Pluronic F127 capable of reducing particle mucoadhesion. In contrast to PVA-coated particles, the similar sized PEG-coated formulations were slowed only ~6- to 10-fold in mucus compared to in water. Our results suggest that incorporating PVA in the particle formulation process may lead to the formation of mucoadhesive particles for many nanoparticulate systems. Thus, alternative methods for particle formulation, based on novel surfactants or changes in the formulation process, should be identified and developed in order to produce mucus-penetrating particles for mucosal applications.