Dinesh Naidoo

A Review on Composite Liposomal Technologies for Specialized Drug Delivery

The combination of liposomes with polymeric scaffolds could revolutionize the current state of drug delivery technology. Although liposomes have been extensively studied as a promising drug delivery model for bioactive compounds, there still remain major drawbacks for widespread pharmaceutical application. Two approaches for overcoming the factors related to the suboptimal efficacy of liposomes in drug delivery have been suggested. The first entails modifying the liposome surface with functional moieties, while the second involves integration of pre-encapsulated drug-loaded liposomes within depot polymeric scaffolds. This attempts to provide ingenious solutions to the limitations of conventional liposomes such as short plasma half-lives, toxicity, stability, and poor control of drug release over prolonged periods. This review delineates the key advances in composite technologies that merge the concepts of depot polymeric scaffolds with liposome technology to overcome the limitations of conventional liposomes for pharmaceutical applications.

Nanotechnological applications for the treatment of neurodegenerative disorders.

Nanotechnology employs engineered materials or devices that interact with biological systems at a molecular level and could revolutionize the treatment of neurodegenerative disorders (NDs) by stimulating, responding to and interacting with target sites to induce physiological responses while minimizing side-effects. Conventional drug delivery systems do not provide adequate cyto-architecture restoration and connection patterns that are essential for functional recovery in NDs, due to limitations posed by the restrictive blood-brain barrier. This review article provides a concise incursion into the current and future applications of nano-enabled drug delivery systems for the treatment of NDs, in particular Alzheimers and Parkinsons diseases, and explores the application of nanotechnology in clinical neuroscience to develop innovative therapeutic modalities for the treatment of NDs.

An antimicrobial investigation of plants used traditionally in southern Africa to treat sexually transmitted infections

AIM OF THE STUDY Eighteen plants were assessed for antimicrobial activity against pathogens associated with prevalent urogenital/sexually transmitted infections. Plant selection was based on information obtained from the ethnobotanical literature. MATERIALS AND METHODS Dried plant material was submerged in a 1:1 mixture of methanol and dichloromethane for 24 h. Aqueous extracts were prepared by submerging dried plant material in sterile distilled water for 24 h followed by lyophilization. Essential oils were distilled from the two aromatic plant species (Tarchonanthus camphoratus and Croton gratissimus). Antimicrobial activity was assessed using the micro-well minimum inhibitory concentration (MIC) assay with specific modifications to facilitate fastidious growth of pathogens. RESULTS Tarchonanthus camphoratus (solvent extract) showed the most significant broad spectrum activity with MIC values ranging between 0.50 and 0.70 mg/ml against five of the six pathogens tested. Other noteworthy activity was found for Hypericum aethiopicum (root) at 0.3 mg/ml (Neisseria gonorrhoeae).Polygala fruticosa and the solvent root extract of Hypericum aethiopicum showed highest sensitivities towards Gardnerella vaginalis at 0.2 mg/ml. Efficacy of the solvent extracts against the pathogen Oligella ureolytica demonstrated antimicrobial activity (MIC values <or=1.0 mg/ml) for seven plant species. The highest activity noted against Ureaplasma urealyticum was for Psidium guajava (solvent extract) at 0.8 mg/ml. In general the aqueous extracts displayed mostly poor anti-STI activity. The most noteworthy susceptibility for the aqueous extracts was noted with the plant extract Syzygium cordatum (MIC value 0.1 mg/ml against Candida albicans). The most noteworthy activity for the essential oils was observed for Tarchonanthus camphoratus (0.8 mg/ml) against Oligella ureolytica. CONCLUSIONS Antimicrobial activity was observed for a number of the plant samples against at least one or more pathogen, thus validating the ethnobotanical use as an anti-infective to treat sexually transmitted diseases.

In Silico Theoretical Molecular Modeling for Alzheimer’s Disease: The Nicotine-Curcumin Paradigm in Neuroprotection and Neurotherapy

The aggregation of the amyloid-β-peptide (AβP) into well-ordered fibrils has been considered as the key pathological marker of Alzheimer‘s disease. Molecular attributes related to the specific binding interactions, covalently and non-covalently, of a library of compounds targeting of conformational scaffolds were computed employing static lattice atomistic simulations and array constructions. A combinatorial approach using isobolographic analysis was stochastically modeled employing Artificial Neural Networks and a Design of Experiments approach, namely an orthogonal Face-Centered Central Composite Design for small molecules, such as curcumin and glycosylated nornicotine exhibiting concentration-dependent behavior on modulating AβP aggregation and oligomerization. This work provides a mathematical and in silico approach that constitutes a new frontier in providing neuroscientists with a template for in vitro and in vivo experimentation. In future this could potentially allow neuroscientists to adopt this in silico approach for the development of novel therapeutic interventions in the neuroprotection and neurotherapy of Alzheimer‘s disease. In addition, the neuroprotective entities identified in this study may also be valuable in this regard.

Design, biometric simulation and optimization of a nano-enabled scaffold device for enhanced delivery of dopamine to the brain.

This study focused on the design, biometric simulation and optimization of an intracranial nano-enabled scaffold device (NESD) for the site-specific delivery of dopamine (DA) as a strategy to minimize the peripheral side-effects of conventional forms of Parkinsons disease therapy. The NESD was modulated through biometric simulation and computational prototyping to produce a binary crosslinked alginate scaffold embedding stable DA-loaded cellulose acetate phthalate (CAP) nanoparticles optimized in accordance with Box-Behnken statistical designs. The physicomechanical properties of the NESD were characterized and in vitro and in vivo release studies performed. Prototyping predicted a 3D NESD model with enhanced internal micro-architecture. SEM and TEM revealed spherical, uniform and non-aggregated DA-loaded nanoparticles with the presence of CAP (FTIR bands at 1070, 1242 and 2926 cm(-1)). An optimum nanoparticle size of 197 nm (PdI=0.03), a zeta potential of -34.00 mV and a DEE of 63% was obtained. The secondary crosslinker BaCl(2) imparted crystallinity resulting in significant thermal shifts between native CAP (T(g)=160-170 degrees C; T(m)=192 degrees C) and CAP nanoparticles (T(g)=260 degrees C; T(m)=268 degrees C). DA release displayed an initial lag phase of 24 h and peaked after 3 days, maintaining favorable CSF (10 microg/mL) versus systemic concentrations (1-2 microg/mL) over 30 days and above the inherent baseline concentration of DA (1 microg/mL) following implantation in the parenchyma of the frontal lobe of the Sprague-Dawley rat model. The strategy of coupling polymeric scaffold science and nanotechnology enhanced the site-specific delivery of DA from the NESD.

Self-assembling peptides: implications for patenting in drug delivery and tissue engineering.

In this paper, a comprehensive review of recent patents concerning the molecular self-assembly of peptides, peptide amphiphiles and peptidomimetics into molecules through nanoarchitectures to hydrogels is provided. Their potential applications in the field of drug delivery and tissue engineering have been highlighted. The design rules of this rapidly growing field are centered mainly on the construction of peptides in the form of peptide amphiphiles, aromatic short peptide derivatives, all-amino acid peptide amphiphiles, lipidated peptides with single and multiple alkyl chains and peptide-based block copolymers and polymer peptide conjugates. The interest in patenting of self-assembling peptides is also driven by their type (I, II, III and IV) and their ability to form well-regulated highly-ordered structures such as β-sheets/β-hairpins, α-helices/coiled coils and to hierarchically self-organize into supra-molecular structures. The applicability of these systems in cell culture scaffolds for tissue engineering, drug and gene delivery and as templates for nanofabrication and biomineralization has inspired various groups over the globe. This resulted in development of self-assembling peptides as synthetic replacements of biological tissues, designing materials for specific medical applications, and materials for new applications such as diagnostic technologies. Furthermore, biologically derived and commercially available systems are also discussed herein along with a brief account of various awarded and pending patents in the past 10 years. An overview of the diversity of the patent applications is also provided for self-assembling systems based on nano- and/or micro-scale such as fibers, fibrils, gels, hydrogels, vesicles, particles, micelles, bilayers and scaffolds.

Trends in the molecular pathogenesis and clinical therapeutics of common neurodegenerative disorders.

The term neurodegenerative disorders, encompasses a variety of underlying conditions, sporadic and/or familial and are characterized by the persistent loss of neuronal subtypes. These disorders can disrupt molecular pathways, synapses, neuronal subpopulations and local circuits in specific brain regions, as well as higher-order neural networks. Abnormal network activities may result in a vicious cycle, further impairing the integrity and functions of neurons and synapses, for example, through aberrant excitation or inhibition. The most common neurodegenerative disorders are Alzheimer’s disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis and Huntington’s disease. The molecular features of these disorders have been extensively researched and various unique neurotherapeutic interventions have been developed. However, there is an enormous coercion to integrate the existing knowledge in order to intensify the reliability with which neurodegenerative disorders can be diagnosed and treated. The objective of this review article is therefore to assimilate these disorders’ in terms of their neuropathology, neurogenetics, etiology, trends in pharmacological treatment, clinical management, and the use of innovative neurotherapeutic interventions.

Plants traditionally used individually and in combination to treat sexually transmitted infections in northern Maputaland, South Africa: antimicrobial activity and cytotoxicity.

ETHNOPHARMACOLOGICAL RELEVANCE Although medicinal plants are used extensively to treat sexually transmitted infections (STIs) in rural northern Maputaland, KwaZulu-Natal, the efficacy and safety of these plants have not previously been evaluated. AIM OF STUDY A study was designed to investigate the in vitro antimicrobial activity and cytotoxicity profiles of a selection (individual plants and selected combinations) of traditionally used plants in this study area. MATERIALS AND METHODS Aqueous and organic (dichloromethane: methanol, 1:1) extracts were prepared. Antimicrobial activity was assessed using the minimum inhibitory concentration (MIC) assay against the STI associated pathogens; Candida albicans ATCC 10231, Ureaplasma urealyticum clinical strain, Oligella ureolytica ATCC 43534, Trichomonas vaginalis clinical strain, Gardnerella vaginalis ATCC 14018 and Neisseria gonorrhoeae ATCC 19424. For the combination study, interactions were assessed using the fractional inhibitory concentration (ΣFIC). The plant species were assessed for safety using the 3-[4,5-dimethyl-2-thiazol-yl]-2,5-diphenyl-2H-tetrazolium bromide (MTT) cellular viability assay on the human embryonic kidney epithelial (Graham, HEK-293) cell line. RESULTS For the antimicrobial studies, U. urealyticum was the most sensitive of the six test organisms, with the aqueous extract of Ranunculus multifidus (0.02mg/ml) and the organic extract of Peltophorum africanum (0.04mg/ml) being the most antimicrobially active plant species studied. Sclerocarya birrea was found to have the broadest spectrum of activity (mean MIC of 0.89mg/ml). The only plant species to exhibit some degree of cytotoxicity against the kidney epithelial cell line was Kigelia africana (100µg/ml), with 22% and 16% cell death for the aqueous and organic extracts, respectively. Of the 13 combinations studied, several synergistic combinations were evident, the most prominent being the combination of Albizia adianthifolia and Trichilia dregeana (aqueous extract) with an ΣFIC value of 0.15 against O. ureolytica. Synergistic interactions were observed regardless of the ratio of the aqueous mixtures of the two plants. Syzygium cordatum and S. birrea (aqueous extract) was also a combination of interest, demonstrating synergistic (ΣFIC=0.42) interactions against O. ureolytica. This combination, however, also displayed some cytotoxicity towards the human epithelial cell line. CONCLUSION This study demonstrated that anecdotal evidence of plant use does not always correlate with in vitro activity. Furthermore, the toxicological profiling is of utmost importance as if not combined in its correct ratio can lead to potential adverse effects.

Novel High-Viscosity Polyacrylamidated Chitosan for Neural Tissue Engineering: Fabrication of Anisotropic Neurodurable Scaffold via Molecular Disposition of Persulfate-Mediated Polymer Slicing and Complexation

Macroporous polyacrylamide-grafted-chitosan scaffolds for neural tissue engineering were fabricated with varied synthetic and viscosity profiles. A novel approach and mechanism was utilized for polyacrylamide grafting onto chitosan using potassium persulfate (KPS) mediated degradation of both polymers under a thermally controlled environment. Commercially available high molecular mass polyacrylamide was used instead of the acrylamide monomer for graft copolymerization. This grafting strategy yielded an enhanced grafting efficiency (GE = 92%), grafting ratio (GR = 263%), intrinsic viscosity (IV = 5.231 dL/g) and viscometric average molecular mass (MW = 1.63 × 106 Da) compared with known acrylamide that has a GE = 83%, GR = 178%, IV = 3.901 dL/g and MW = 1.22 × 106 Da. Image processing analysis of SEM images of the newly grafted neurodurable scaffold was undertaken based on the polymer-pore threshold. Attenuated Total Reflectance-FTIR spectral analyses in conjugation with DSC were used for the characterization and comparison of the newly grafted copolymers. Static Lattice Atomistic Simulations were employed to investigate and elucidate the copolymeric assembly and reaction mechanism by exploring the spatial disposition of chitosan and polyacrylamide with respect to the reactional profile of potassium persulfate. Interestingly, potassium persulfate, a peroxide, was found to play a dual role initially degrading the polymers—“polymer slicing”—thereby initiating the formation of free radicals and subsequently leading to synthesis of the high molecular mass polyacrylamide-grafted-chitosan (PAAm-g-CHT)—“polymer complexation”. Furthermore, the applicability of the uniquely grafted scaffold for neural tissue engineering was evaluated via PC12 neuronal cell seeding. The novel PAAm-g-CHT exhibited superior neurocompatibility in terms of cell infiltration owing to the anisotropic porous architecture, high molecular mass mediated robustness, superior hydrophilicity as well as surface charge due to the acrylic chains. Additionally, these results suggested that the porous PAAm-g-CHT scaffold may act as a potential neural cell carrier.

Levodopa delivery systems: advancements in delivery of the gold standard

Importance of the field: Despite the fact that Parkinsons disease (PD) was discovered almost 200 years ago, its treatment and management remain immense challenges because progressive loss of dopaminergic nigral neurons, motor complications experienced by the patients as the disease progresses and drawbacks of pharmacotherapeutic management still persist. Various therapeutic agents have been used in the management of PD, including levodopa (l-DOPA), selegiline, amantadine, bromocriptine, entacapone, pramipexole dihydrochloride and more recently istradefylline and rasagiline. Of all agents, l-DOPA although the oldest, remains the most effective. l-DOPA is easier to administer, better tolerated, less expensive and is required by almost all PD patients. However, l-DOPAs efficacy in advanced PD is significantly reduced due to metabolism, subsequent low bioavailability and irregular fluctuations in its plasma levels. Significant strides have been made to improve the delivery of l-DOPA in order to enhance its bioavailability and reduce plasma fluctuations as well as motor complications experienced by patients purportedly resulting from pulsatile stimulation of the striatal dopamine receptors. Areas covered in this review: Drug delivery systems that have been instituted for the delivery of l-DOPA include immediate release formulations, liquid formulations, dispersible tablets, controlled release formulations, dual-release formulations, microspheres, infusion and transdermal delivery, among others. In this review, the l-DOPA-loaded drug delivery systems developed over the past three decades are elaborated. What the reader will gain: The ultimate aim was to assess critically the attempts made thus far directed at improving l-DOPA absorption, bioavailability and maintenance of constant plasma concentrations, including the drug delivery technologies implicated. Take home message: This review highlights the fact that neuropharmaceutics is at a precipice, which is expected to spur investigators to take that leap to enable the generation of innovative delivery systems for the effective management of PD.