In vitro release profiles of tenofovir (an HIV microbicide) from chitosan NPs with small (182
nm), medium (281
nm) and large size (602
nm) (
n
=
3). Percent mucoadhesion of chitosan particles with ...different sizes on porcine vaginal tissue. After fluorescence labeling, the mean diameters of small, medium, and large particles were 188, 273.5, and 900.2
nm, respectively (
n
=
3).
The objective of this study was to engineer a model anti-HIV microbicide (tenofovir) loaded chitosan based nanoparticles (NPs). Box–Behnken design allowed to assess the influence of formulation variables on the size of NPs and drug encapsulation efficiency (EE%) that were analyzed by dynamic light scattering and UV spectroscopy, respectively. The effect of the NPs on vaginal epithelial cells and
Lactobacillus
crispatus viability and their mucoadhesion to porcine vaginal tissue were assessed by cytotoxicity assays and fluorimetry, respectively. In the optimal aqueous conditions, the EE% and NPs size were 5.83% and 207.97
nm, respectively. With 50% (v/v) ethanol/water as alternative solvent, these two responses increased to 20% and 602
nm, respectively. Unlike small size (182
nm) exhibiting burst release, drug release from medium (281
nm) and large (602
nm)-sized NPs fitted the Higuchi (
r
2
=
0.991) and first-order release (
r
2
=
0.999) models, respectively. These NPs were not cytotoxic to both the vaginal epithelial cell line and
L. crispatus for 48
h. When the diameter of the NPs decreased from 900 to 188
nm, the mucoadhesion increased from 6% to 12%. However, the combinatorial effect of EE% and percent mucoadhesion for larger size NPs was the highest. Overall, large-size, microbicide loaded chitosan NPs appeared to be promising nanomedicines for the prevention of HIV transmission.
This study aims to characterize the rheological behavior of a novel phenylboronic acid (PBA)-based closomer nanoconjugate (Closogel) with potential application in pharmaceutical formulation. PBA was ...used as a cross-linking agent and model (antiviral) drug. The PBA loaded Closogel chemical structure was analyzed by boron (11B) NMR and Fourier transform infrared (FTIR) spectroscopy. The Closogel and control hydroxy ethyl cellulose (HEC) gel were analyzed under oscillatory and continuous shear rheometry followed by mathematical modeling to characterize the gel flow behavior. The chemical analysis confirmed the existence of characteristic borate esters peaks and Boron chemical shifts within Closogel spectra. Due to its more flexible molecular structure, undiluted Closogel exhibited lower viscosity and relaxation time (163 Pa.s & 0.21 s vs 301 Pa.s & 0.39 s for HEC). Both Closogel and HEC gels exhibited a thixotropic behavior. The undiluted and 25 mg/ml (2.5% w/v) Closogels were more viscous than elastic (tan (δ) > 1) in the linear viscoelastic range. The Herschel-Bulkley model showed a significant fitting to all experimental data (R2 > 0.95). The 2.5 mg/ml (0.25% w/v) Closogel nearly exhibited a Newtonian behavior with a flow index of 0.93. These data suggest that PBA loaded Closomer-based gels have similar rheological behavior, with lower complex modulus than that of HEC gels, and they can be a promising platform used for delivery of topical antiviral or other bioactive agents.
(A) Confocal microscopy showing coumarin-6 loaded pH-responsive NPs uptaken by vaginal epithelial cells after 4
h incubation. (B)
In vitro release profile at pH
=
4.2 (solid line) and pH
=
7.6 (dash ...line) of model microbicide (tenofovir) from pH responsive NPs (
n
=
3).
This study is designed to test the hypothesis that tenofovir (TNF) or tenofovir disoproxil fumarate (TDF) loaded nanoparticles (NPs) prepared with a blend of poly(lactic-
co-glycolic acid) (PLGA) and methacrylic acid copolymer (Eudragit® S-100, or S-100) are noncytotoxic and exhibit significant pH-responsive release of anti-HIV microbicides in the presence of human semen fluid simulant (SFS). After NPs preparation by emulsification diffusion, their size, encapsulation efficiency (EE%), drug release profile, morphology, and cytotoxicity are characterized by dynamic light scattering, spectrophotometry, transmission electron microscopy, and cellular viability assay/transepithelial electrical resistance measurement, respectively. Cellular uptake was elucidated by fluorescence spectroscopy and confocal microscopy. The NPs have an average size of 250
nm, maximal EE% of 16.1% and 37.2% for TNF and TDF, respectively. There is a 4-fold increase in the drug release rate from the 75% S-100 blend in the presence of SFS over 72
h. At a concentration up to 10
mg/ml, the PLGA/S-100 NPs are noncytotoxic for 48
h to vaginal endocervical/epithelial cells and
Lactobacillus crispatus. The particle uptake (∼50% in 24
h) by these vaginal cell lines mostly occurred through caveolin-mediated pathway. These data suggest the promise of using PLGA/S-100 NPs as an alternative controlled drug delivery system in intravaginal delivery of an anti-HIV/AIDS microbicide.
The current advances in chronobiology and the knowledge gained from chronotherapy of selected diseases strongly suggest that “the one size fits all at all times” approach to drug delivery is no ...longer substantiated, at least for selected bioactive agents and disease therapy or prevention. Thus, there is a critical and urgent need for chronopharmaceutical research (e.g., design and evaluation of robust, spatially and temporally controlled drug delivery systems that would be clinically intended for chronotherapy by different routes of administration). This review provides a brief overview of current drug delivery system intended for chronotherapy. In theory, such an ideal “magic pill” preferably with affordable cost, would improve the safety, efficacy and patient compliance of old and new drugs. However, currently, there are three major hurdles for the successful transition of such system from laboratory to patient bedside. These include the challenges to identify adequate (i) rhythmic biomaterials and systems, (ii) rhythm engineering and modeling, perhaps using system biology and (iii) regulatory guidance.
There is no comparative data available on the binding constants of Concanavalin A (Con A) and glycogen and Con A–mannan using quartz crystal microbalance (QCM), cost and time efficient system for ...biosensor analysis. It is hypothesized that a QCM can be used in its flow injection mode to monitor the binding affinity of polysaccharides to an immobilized lectin, Con A. The biosensor is prepared by immobilizing Con A on a 5MHz gold crystal by carbodiimide crosslinking chemistry. The attachment efficiency is monitored by Fourier Transform Infrared Spectroscopy. Equilibrium association and dissociation constants describing Con A–polysaccharides interaction are determined in a saturation binding experiment, where increasing concentrations of polysaccharides are run on a Con A-immobilized gold crystal surface, and the frequency shifts recorded on the frequency counter. The molecular weights (MW) of glycogen from Oyster and mannan from Saccharomyces cerevisiae are determined by size exclusion chromatography. The MW for glycogen and mannan are 604±0.002kDa and 54±0.002kDa, respectively. The equilibrium association and dissociation constants for Con A–glycogen and Con A–mannan interactions are KA=3.93±0.7×106M−1/KD=0.25±0.06μM and KA=3.46±0.22×105M−1/KD=2.89±0.20μM (n=3), respectively. Their respective frequency and motional resistance shifts relationship (ΔF/ΔR) are 37.29±1.55 and 34.86±0.85Hz/Ω (n=3), which support the validity of Sauerbrey׳s rigidity approximation. This work suggests that Con A–mannan complex could be potentially utilized for insulin delivery and the targeting of glucose-rich substances and glycoproteins when fast drug release is desired.
•Concanavalin A (Con A) is immobilized on a QCM crystal by EDC chemistry.•The lectin attachment is validated by FTIR spectroscopy.•Glycogen and mannan molecular weights are determined by GPC.•Binding affinity of glycogen and mannan to Con A are determined on a QCM.•Con A is found to have higher affinity to glycogen compared to mannan.
Once metastatic, melanoma remains one of the most aggressive and morbid malignancies. Moreover, in past decades, the overall survival for advanced unresectable melanoma exhibited a constancy of poor ...prognosis. Low response rates and serious adverse effects have been characteristic of standard therapy based on a combination of chemotherapeutic agents or immunotherapy with IL-2. For example, the chemotherapy including dacarbazine, carmustin, cisplatin and tamoxifen is known as 'Dartmouth regimen' while the CVD regimen comprises carmustine, vinblastine and dacarbazine. Thus, there is an urgent and critical need to reformulate these bioactive agents using nanoscience and nanotechnology as alternative strategies. This article overviews current design and evaluation of nanomedicine undertaken to address this unmet medical need. The nanomedicines studied include polymeric nanoparticles, liposomes, polymersomes, dendrimers, cubosomes, niosomes and nanodiamonds. In this preclinical article, nanotechnology provides hope for effective treatment of this aggressive and largely treatment-resistant disease.
Due to advances in chronobiology, chronopharmacology, and global market constraints, the traditional goal of pharmaceutics (e.g. design drug delivery systems with a constant drug release rate) is ...becoming obsolete. However, the major bottleneck in the development of drug delivery systems that match the circadian rhythm (chronopharmaceutical drug delivery systems: ChrDDS) may be the availability of appropriate technology. The last decade has witnessed the emergence of ChrDDS against several diseases. The increasing research interest surrounding ChrDDS may lead to the creation of a new sub-discipline in pharmaceutics known as chronopharmaceutics. This review introduces the concept of chronopharmaceutics, addresses theoretical/formal approaches to this sub-discipline, underscores potential disease-targets, revisits existing technologies and examples of ChrDDS. Future development in chronopharmaceutics may be made at the interface of other emerging disciplines such as system biology and nanomedicine. Such novel and more biological approaches to drug delivery may lead to safer and more efficient disease therapy in the future.
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