Light and pH responsive catanionic vesicles based on a chalcone/flavylium photoswitch for smart drug delivery: From molecular design to the controlled release of doxorubicin.

Spatially and temporally localized delivery is a promising strategy to circumvent adverse effects of traditional drug therapy such as drug toxicity and prolonged treatments. Stimuli-responsive colloidal nanocarriers can be crucial to attain such goals. Here, we develop a delivery system based on dual light and pH responsive vesicles having a cationic bis-quat gemini surfactant, 12-2-12, and a negatively charged amphiphilic chalcone, C4SCh. The premise is to exploit the chalcone/flavylium interconversion to elicit a morphological change of the vesicles leading to the controlled release of an encapsulated drug. First, the phase behavior of the catanionic system is studied and the desirable composition yielding stable unilamellar vesicles identified and selected for further studies. The solutions containing vesicles (Dh ≈ 200 nm, ζ-potential ≈ 80 mV) are in-depth characterized by light microscopy, cryo-transmission electron microscopy (cryo-TEM), dynamic light scattering (DLS) and surface tension measurements. Upon subjecting the vesicles to UV irradiation (λ = 365 nm) at near neutral pH (≈ 6.0), no morphological effects are observed, yet when irradiation is coupled with pH = 3.0, the majority of the vesicles are disrupted into bilayer fragments. The anticancer drug doxorubicin (DOX) is successfully entrapped in the non-irradiated vesicles, yielding an encapsulation efficiency of ≈ 25% and a loading capacity of ≈ 3%. The release profile of the drug-loaded vesicles is then studied in vitro in four conditions: i) no stimuli (pH = 6.0); ii) irradiation, pH = 6.0; iii) no irradiation and adjusted pH = 3.0; iv) irradiation and adjusted pH = 3.0 Crucially, irradiation at pH = 3.0 leads to a sustained release of DOX to ca. 80% (within 4 h), whereas cases i) and ii) lead to only ≈ 25 % release and case iii) to 50% release but precipitation of the vesicles. Thus, our initial hypothesis is confirmed: we present a proof of concept delivery system where light and pH act as inputs of an AND logic gate mechanism for the controlled release of a relevant biomedical drug (output). This may prove useful if the irradiated nanocarriers meet acidified physiological environments such as tumors sites, endosomes or lysosomes.

Surface charge tunable catanionic vesicles based on serine-derived surfactants as efficient nanocarriers for the delivery of the anticancer drug doxorubicin.

Self-assembled vesicles composed of amino acid-based cationic/anionic surfactant mixtures show promise as novel effective drug nanocarriers. Here, we report the in vitro performance of vesicles based on cationic (16Ser) and anionic (8-8Ser) serine-based surfactants using a cancer cell model for the delivery of the anticancer drug doxorubicin (DOX). This catanionic mixture yields both negatively (0.20 in the cationic surfactant molar fraction, x16Ser) and positively (x16Ser = 0.58) charged vesicles, hence providing a surface charge tunable system. Low toxicity is confirmed for concentration ranges below 32 µM in both formulations. DOX is successfully encapsulated in the vesicles, resulting in a surface charge switch to negative for the (0.58) system, making both (0.20) and (0.58) DOX-loaded vesicles highly interesting for systemic administration. High uptake by cells was demonstrated using flow cytometry and confocal microscopy. Drug accumulation results in an increase of cell uptake up to 250% and 200% for the (0.20) and (0.58) vesicles, respectively, compared to free DOX and with localizations near the nuclear regions in the cells. The in vitro cytotoxicity studies show that DOX-loaded vesicles induce cell death, confirming the therapeutic potential of the formulations. Furthermore, the efficient accumulation of the drug inside the cell compartments harbors the potential for optimization strategies including phased delivery for prolonged treatment periods or even on-demand release.

Block Copolymers as Dispersants for Single-Walled Carbon Nanotubes: Modes of Surface Attachment and Role of Block Polydispersity.

When using amphiphilic polymers to exfoliate and disperse carbon nanotubes in water, the balance between the hydrophobic and hydrophilic moieties is critical and nontrivial. Here, we investigate the mode of surface attachment of a triblock copolymer, Pluronics F127, composed of a central hydrophobic polypropylene oxide block flanked by hydrophilic polyethylene oxide blocks, onto single-walled carbon nanotubes (SWNTs). Crucially, we analyze the composition in dispersant of both the as-obtained dispersion (the supernatant) and the precipitate-containing undispersed materials. For this, we combine the carefully obtained data from 1H NMR peak intensities and self-diffusion and thermogravimetric analysis. The molecular motions behind the observed NMR features are clarified. We find that the hydrophobic blocks attach to the dispersed SWNT surface and remain significantly immobilized leading to 1H NMR signal loss. On the other hand, the hydrophilic blocks remain highly mobile and thus readily detectable by NMR. The dispersant is shown to possess significant block polydispersity that has a large effect on dispersibility. Polymers with large hydrophobic blocks adsorb on the surface of the carbonaceous particles that precipitate, indicating that although a larger hydrophobic block is good for enhancing adsorption, it may be less effective in dispersing the tubes. A model is also proposed that consistently explains our observations in SWNT dispersions and some contradicting findings obtained previously in carbon nanohorn dispersions. Overall, our findings help elucidating the molecular picture of the dispersion process for SWNTs and are of interest when looking for more effective (i.e., well-balanced) polymeric dispersants.

Modeling of ultra-small lipid nanoparticle surface charge for targeting glioblastoma.

Surface modification of ultra-small nanostructured lipid carriers (usNLC) via introduction of a positive charge is hypothesized to prompt site-specific drug delivery for glioblastoma multiforme (GBM) treatment. A more effective interaction with negatively charged lipid bilayers, including the blood-brain barrier (BBB), will facilitate the nanoparticle access to the brain. For this purpose, usNLC with a particle size of 43.82 ±â€¯0.03 nm and a polydispersity index of 0.224 were developed following a Quality by Design approach. Monomeric and gemini surfactants, either with conventional headgroups or serine-based ones, were tested for the surface modification, and the respective safety and efficacy to target GBM evaluated. A comprehensive in silico-in vitro approach is also provided based on molecular dynamics simulations and cytotoxicity studies. Overall, monomeric serine-derived surfactants displayed the best performance, considering altogether particle size, zeta potential, cytotoxic profile and cell uptake. Although conventional surfactants were able to produce usNLC with suitable physicochemical properties and cell uptake, their use is discouraged due to their high cytotoxicity. This study suggests that monomeric serine-derived surfactants are promising agents for developing nanosystems aiming at brain drug delivery.

Visual Performance and Rotational Stability of a Multifocal Toric Intraocular Lens.

PURPOSE: To evaluate the visual results, refractive predictability, rotational stability, and spectacle independence of patients who had cataract surgery with implantation of a diffractive multifocal toric intraocular lens (IOL) (Tecnis Multifocal Toric ZMT 150-400; Abbott Medical Optics, Santa Ana, CA). METHODS: This prospective study included 60 eyes of 30 patients with cataract and regular corneal astigmatism who had phacoemulsification with bilateral implantation of a Tecnis Multifocal Toric IOL. Over a 6-month follow-up period, the main outcome measures were uncorrected and corrected monocular and binocular distance (UDVA and DCVA), intermediate at 80 cm (UIVA and DCIVA), and near at 40 cm (UNVA and DCNVA) visual acuities, spherical equivalent (SE) refraction, residual astigmatism, rotational stability, defocus curves, contrast sensitivity, presence of photic phenomena, and use of spectacles. RESULTS: Results at 6 months showed mean UDVA of 0.07 ± 0.1 logMAR (range: 0.3 to 0.0 logMAR), mean UIVA of 0.18 ± 0.09 logMAR (range: 0.3 to -0.1 log-MAR, and mean UNVA of 0.03 ± 0.09 logMAR (range: 0.2 to -0.1 logMAR). Refractive predictability was excellent with a mean SE of 0.05 ± 0.47 diopters (D) (range: -0.75 to +1.00 D) and a mean refractive cylinder of -0.44 ± 0.49 D (range: -1.25 to 0.00). Mean rotation was 3.18° ± 3.28°. Photic phenomena were moderate or severe in 30% of patients. All patients were spectacle independent at the 6-month follow-up visit at all distances in this case series. CONCLUSIONS: The implantation of the Tecnis multifocal toric IOL in patients with cataract and corneal astigmatism provided excellent distance and near visual acuities with good intermediate visual acuity. Predictability of refractive results, rotational stability, and optical performance were excellent, allowing all patients in this series to achieve spectacle independence. [J Refract Surg. 2016;32(7):444-450.].

Enhancing glioblastoma cell sensitivity to chemotherapeutics: A strategy involving survivin gene silencing mediated by gemini surfactant-based complexes.

Glioblastoma (GBM), the highest grade astrocytoma, is one of the most aggressive and challenging cancers to treat. The standard treatment is usually limited due to the intrinsic resistance of GBM to chemotherapy and drug non-specific effects. Therefore, new therapeutic strategies need to be developed to target tumor cells, sparing healthy tissues. In this context, the inhibitor-of-apoptosis protein (IAP) survivin emerges as an ideal target for a gene silencing approach, since it is sharply differentially expressed in cancer tissues. In this work, two different families of cationic gemini surfactants (bis-quat conventional and serine-derived) were tested regarding their efficiency to deliver small interfering RNAs (siRNAs) in a human GBM cell line (U87), in order to select an effective siRNA anti-survivin carrier. Importantly, survivin downregulation combined with administration of the chemotherapeutic agents temozolomide or etoposide resulted in a synergistic cytotoxic effect, thus revealing to be a promising strategy to reduce the chemotherapeutic doses for GBM treatment.

Comparison of visual outcomes of 2 diffractive trifocal intraocular lenses.

PURPOSE: To compare the visual outcomes after cataract surgery with bilateral implantation of 1 of 2 diffractive trifocal intraocular lenses (IOLs). SETTING: Two clinical centers, Lisbon, Portugal. DESIGN: Prospective comparative case series. METHODS: Phacoemulsification with bilateral implantation of a Finevision Micro F IOL (Group 1) or an AT Lisa tri 839 MP IOL (Group 2) was performed. Over a 3-month follow-up, the main outcome measures were uncorrected distance visual acuity (UDVA), corrected monocular and binocular distance visual acuity, uncorrected intermediate visual acuity at 80 cm, distance-corrected intermediate visual acuity (DCIVA), uncorrected near visual acuity at 40 cm, distance-corrected near visual acuity (DCNVA), spherical equivalent (SE) refraction, defocus curves, contrast sensitivity, presence of dysphotopsia, and use of spectacles. RESULTS: Each group comprised 30 eyes (15 patients). The mean values at 3 months were UDVA, 0.03 logMAR ± 0.08 (SD) (Group 1) and 0.08 ± 0.12 (Group 2) (P = .765); DCIVA, 0.04 ± 0.07 logMAR and 0.18 ± 0.18 logMAR, respectively (P = .048); DCNVA, 0.03 ± 0.06 logMAR and 0.11 ± 0.08 logMAR, respectively (P = .032); SE, -0.25 ± 0.30 diopter (D) and -0.02 ± 0.39 D, respectively (P = .087). There was no significant difference in contrast sensitivity or dysphotopic phenomena between groups. CONCLUSIONS: Both trifocal IOL models provided excellent distance, intermediate, and near visual outcomes. Monocular DCIVA and DCNVA appeared slightly better in Group 1. Predictability of the refractive results and optical performance were excellent, and all patients achieved spectacle independence. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned.

New serine-derived gemini surfactants as gene delivery systems.

Gemini surfactants have been extensively used for in vitro gene delivery. Amino acid-derived gemini surfactants combine the special aggregation properties characteristic of the gemini surfactants with high biocompatibility and biodegradability. In this work, novel serine-derived gemini surfactants, differing in alkyl chain lengths and in the linker group bridging the spacer to the headgroups (amine, amide and ester), were evaluated for their ability to mediate gene delivery either per se or in combination with helper lipids. Gemini surfactant-based DNA complexes were characterized in terms of hydrodynamic diameter, surface charge, stability in aqueous buffer and ability to protect DNA. Efficient formulations, able to transfect up to 50% of the cells without causing toxicity, were found at very low surfactant/DNA charge ratios (1/1-2/1). The most efficient complexes presented sizes suitable for intravenous administration and negative surface charge, a feature known to preclude potentially adverse interactions with serum components. This work brings forward a new family of gemini surfactants with great potential as gene delivery systems.

Clinical performance of a new aspheric dual-optic accommodating intraocular lens.

PURPOSE: To describe the clinical performance of a new dual-optic intraocular lens (IOL) with an enhanced optic profile designed to mimic natural accommodation. PATIENTS AND METHODS: Prospective multicenter clinical study with the new dual-optic aspheric accommodating IOL (Synchrony Vu) in 74 patients (148 eyes) undergoing cataract surgery. Refractive target was emmetropia. Examinations at 1 month and 6 months included subjective refractions; visual acuities at near, intermediate, and far; mesopic contrast sensitivity with and without glare; safety data; and subjective survey on dysphotopsia (halos and glare). RESULTS: Clinical data at 6 months showed 89% of the eyes within ±1.0 D spherical equivalent refraction. Mean binocular uncorrected and distance-corrected visual acuity was 20/20 at far (0.00±0.11 logMAR and -0.06±0.08 logMAR, respectively), 20/20 at intermediate (0.01±0.13 logMAR and -0.01±0.10 logMAR, respectively), and 20/25 at near (0.10±0.14 logMAR and 0.14±0.15 logMAR, respectively). Mesopic contrast sensitivity was within normal limits. Seventy-eight percent of the patients had no spectacles and 70% had no dysphotopsia. One eye had IOL repositioning within 1 month of surgery. CONCLUSION: The new aspheric Synchrony Vu accommodating IOL provided good visual performance at a range of distances without affecting quality of vision and with minimal safety considerations.

Visualization of the macula during elective pars plana vitrectomy in the presence of a dual-optic accommodating intraocular lens.

UNLABELLED: We describe the case of a 69-year-old patient who had pars plana vitrectomy (PPV) for epiretinal membrane removal 18 months after cataract surgery with implantation of a dual-optic accommodating IOL (Synchrony). During PPV, visualization of the macula was perfect, and the postoperative visual outcome was excellent. To our knowledge, this is the first report of retinal visualization during PPV in the presence of a dual-optic accommodating IOL. When choosing a presbyopia-correcting IOL, surgeons should consider the advantage of macula visualization with an IOL with monofocal optics. FINANCIAL DISCLOSURE(S): Dr. Marques is a consultant to Abbott Medical Optics, Inc. No other author has a financial or proprietary interest in any material or method mentioned.

Combined corneal collagen crosslinking and secondary intraocular lens implantation for keratectasia after radial keratotomy.

We describe a case of corneal ectasia in a patient with previous radial keratotomy (RK). The uncorrected distance visual acuity (UDVA) was 20/400, the corrected visual acuity (CDVA) 20/50, and the spherical equivalent (SE) -5.125 diopters (D). Corneal topography revealed inferior corneal ectasia with corneal astigmatism of 9.2 D. Six months after corneal collagen crosslinking (CXL), the UDVA improved to 20/200, the CDVA to 20/40, and the SE to -4.625 D. Corneal astigmatism was reduced to 8.7 D. An add-on IOL was implanted to correct the residual cylindrical refractive error (-9.25 × 60; Torica-sPB IOL, Humanoptics), after which the UDVA improved to 20/32, the CDVA to 20/30, and the SE to -0.50 D. This case is the first to document the efficacy of CXL in corneal ectasia as a complication of primary RK in a nonkeratoconic or a keratoconus-suspect eye with an add-on IOL used to correct the residual refractive error.

Visual and optical outcomes of a diffractive multifocal toric intraocular lens.

PURPOSE: To evaluate the visual and wavefront outcomes after cataract surgery with implantation of a diffractive multifocal toric intraocular lens (IOL). SETTING: Two clinical centers, Lisbon, Portugal. DESIGN: Case series. METHODS: This study comprised patients with cataract and corneal astigmatism between 0.75 diopter (D) and 2.50 D who had phacoemulsification with implantation of an Acrysof IQ Restor toric IOL. Over a 3-month follow-up, the main outcome measures were uncorrected distance visual acuity (UDVA), uncorrected intermediate visual acuity (UIVA) at 80 cm, uncorrected near visual acuity (UNVA) at 40 cm, spherical equivalent (SE) refraction, residual astigmatism, rotational stability of the IOL, higher-order aberrations, and the presence of dysphotopic phenomena. RESULTS: The study included 38 eyes (19 patients). The mean UDVA was 0.07 logMAR ± 0.10 (SD), the mean UIVA was 0.16 ± 0.10 logMAR, and the mean UNVA was 0.02 ± 0.09 logMAR. Predictability of refractive results was very good, with an SE refraction within ± 0.50 D of the attempted spherical correction in 33 eyes (87%). The mean toric IOL axis rotation was 2.97 ± 2.33 degrees. One eye required a second surgery to align the IOL axis. Ocular aberrometry and dysphotopic phenomena results were similar to those published for the nontoric version of the toric IOL. CONCLUSION: Implantation of the diffractive multifocal toric IOL in patients with cataract and corneal astigmatism provided excellent distance, intermediate, and near visual outcomes; predictability of the refractive results; rotational stability; and good optical performance, allowing all patients to achieve complete spectacle independence. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.