Sreekanth Pentlavalli
Queen's University Belfast
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Publication
Featured researches published by Sreekanth Pentlavalli.
Journal of Controlled Release | 2014
Helen O. McCarthy; Joanne McCaffrey; Cian M. McCrudden; Aleksey Zholobenko; Ahlam A. Ali; John W. McBride; Ashley S. Massey; Sreekanth Pentlavalli; Kun-Hong Chen; Grace Cole; Stephen Patrick Loughran; Nicholas Dunne; Ryan F. Donnelly; Victoria Kett; Tracy Robson
The design of a non-viral gene delivery vehicle capable of delivering and releasing a functional nucleic acid cargo intracellularly remains a formidable challenge. For systemic gene therapy to be successful a delivery vehicle is required that protects the nucleic acid cargo from enzymatic degradation, extravasates from the vasculature, traverses the cell membrane, disrupts the endosomal vesicles and unloads the cargo at its destination site, namely the nucleus for the purposes of gene delivery. This manuscript reports the extensive investigation of a novel amphipathic peptide composed of repeating RALA units capable of overcoming the biological barriers to gene delivery both in vitro and in vivo. Our data demonstrates the spontaneous self-assembly of cationic DNA-loaded nanoparticles when the peptide is complexed with pDNA. Nanoparticles were <100nm, were stable in the presence of serum and were fusogenic in nature, with increased peptide α-helicity at a lower pH. Nanoparticles proved to be non-cytotoxic, readily traversed the plasma membrane of both cancer and fibroblast cell lines and elicited reporter-gene expression following intravenous delivery in vivo. The results of this study indicate that RALA presents an exciting delivery platform for the systemic delivery of nucleic acid therapeutics.
Molecular Pharmaceutics | 2016
Ashley S. Massey; Sreekanth Pentlavalli; Richard Cunningham; Cian M. McCrudden; Emma M. McErlean; Philip Redpath; Ahlam A. Ali; Stephanie Annett; John W. McBride; Joanne McCaffrey; Tracy Robson; Marie E. Migaud; Helen O. McCarthy
Bisphosphonates (BPs) are a class of bone resorptive drug with a high affinity for the hydroxyapatite structure of bone matrices that are used for the treatment of osteoporosis. However, clinical application is limited by a common toxicity, BP-related osteonecrosis of the jaw. There is emerging evidence that BPs possess anticancer potential, but exploitation of these antiproliferative properties is limited by their toxicities. We previously reported the utility of a cationic amphipathic fusogenic peptide, RALA, to traffic anionic nucleic acids into various cell types in the form of cationic nanoparticles. We hypothesized that complexation with RALA could similarly be used to conceal a BPs hydroxyapatite affinity, and to enhance bioavailability, thereby improving anticancer efficacy. Incubation of RALA with alendronate, etidronate, risedronate, or zoledronate provoked spontaneous electrostatic formation of cationic nanoparticles that did not exceed 100 nm in diameter and that were stable over a range of temperatures and for up to 6 h. The nanoparticles demonstrated a pH responsiveness, possibly indicative of a conformational change, that could facilitate release of the BP cargo in the endosomal environment. RALA/BP nanoparticles were more potent anticancer agents than their free BP counterparts in assays investigating the viability of PC3 prostate cancer and MDA-MB-231 breast cancer cells. Moreover, RALA complexation potentiated the tumor growth delay activity of alendronate in a PC3 xenograft model of prostate cancer. Taken together, these findings further validate the use of BPs as repurposed anticancer agents.
Journal of Materials Chemistry B | 2017
Binulal N. Sathy; Dinorath Olvera; Tomas Gonzalez-Fernandez; Gráinne M. Cunniffe; Sreekanth Pentlavalli; Philip Chambers; Oju Jeon; Eben Alsberg; Helen O. McCarthy; Nicholas Dunne; Tammy L. Haut Donahue; Daniel J. Kelly
A range of bone regeneration strategies, from growth factor delivery and/or mesenchymal stem cell (MSC) transplantation to endochondral tissue engineering, have been developed in recent years. Despite their tremendous promise, the clinical translation and future use of many of these strategies is being hampered by concerns such as off target effects associated with growth factor delivery. Therefore the overall objective of this study was to investigate the influence of alpha-tricalcium phosphate (α-TCP) nanoparticle delivery into MSCs using an amphipathic cell penetrating peptide RALA, on osteogenesis in vitro and both intramembranous and endochondral bone formation in vivo. RALA complexed α-TCP nanoparticle delivery to MSCs resulted in an increased expression of bone morphogenetic protein-2 (BMP-2) and an upregulation in a number of key osteogenic genes. When α-TCP stimulated MSCs were encapsulated into alginate hydrogels, enhanced mineralization of the engineered construct was observed over a 28 day culture period. Furthermore, the in vivo bone forming potential of RALA complexed α-TCP nanoparticle delivery to MSCs was found to be comparable to growth factor delivery. Recognizing the potential and limitations associated with endochondral bone tissue engineering strategies, we then sought to explore how α-TCP nanoparticle delivery to MSCs influences early mineralization of engineered cartilage templates in vitro and their subsequent ossification in vivo. Despite accelerating mineralization of engineered cartilage templates in vitro, RALA complexed α-TCP nanoparticle delivery did not enhance endochondral bone formation in vivo. Therefore the potential of RALA complexed α-TCP nanoparticle delivery appears to be as an alternative to growth factor delivery as a single stage strategy for promoting bone generation.
Macromolecular Bioscience | 2017
Sreekanth Pentlavalli; Philip Chambers; Binulal N. Sathy; Michelle O'Doherty; Marine Chalanqui; Daniel J. Kelly; Tammy Haut-Donahue; Helen O. McCarthy; Nicholas Dunne
In this study, thermoresponsive copolymers that are fully injectable, biocompatible, and biodegradable and are synthesized via graft copolymerization of poly(N-isopropylacrylamide) onto alginate using a free-radical reaction are presented. This new synthesis method does not involve multisteps or associated toxicity issues, and has the potential to reduce scale-up difficulties. Chemical and physical analyses verify the resultant graft copolymer structure. The lower critical solution temperature, which is a characteristic of sol-gel transition, is observed at 32 °C. The degradation properties indicate suitable degradation kinetics for drug delivery and bone tissue engineering applications. The synthesized P(Alg-g-NIPAAm) hydrogel is noncytotoxic with both human osteosarcoma (MG63) cells and porcine bone marrow derived mesenchymal stem cells (pBMSCs). pBMSCs encapsulated in the P(Alg-g-NIPAAm) hydrogel remain viable, show uniform distribution within the injected hydrogel, and undergo osteogenic and chondrogenic differentiation under appropriate culture conditions. Furthermore, for the first time, this work will explore the influence of alginate viscosity on the viscoelastic properties of the resulting copolymer hydrogels, which influences the rate of medical device formation and subsequent drug release. Together the results of this study indicate that the newly synthesized P(Alg-g-NIPAAm) hydrogel has potential to serve as a versatile and improved injectable platform for drug delivery and bone tissue engineering applications.
Journal of Materials Science: Materials in Medicine | 2014
James Clements; Gavin Walker; Sreekanth Pentlavalli; Nicholas Dunne
The initial composition of acrylic bone cement along with the mixing and delivery technique used can influence its final properties and therefore its clinical success in vivo. The polymerisation of acrylic bone cement is complex with a number of processes happening simultaneously. Acrylic bone cement mixing and delivery systems have undergone several design changes in their advancement, although the cement constituents themselves have remained unchanged since they were first used. This study was conducted to determine the factors that had the greatest effect on the final properties of acrylic bone cement using a pre-filled bone cement mixing and delivery system. A design of experiments (DoE) approach was used to determine the impact of the factors associated with this mixing and delivery method on the final properties of the cement produced. The DoE illustrated that all factors present within this study had a significant impact on the final properties of the cement. An optimum cement composition was hypothesised and tested. This optimum recipe produced cement with final mechanical and thermal properties within the clinical guidelines and stated by ISO 5833 (International Standard Organisation (ISO), International standard 5833: implants for surgery—acrylic resin cements, 2002), however the low setting times observed would not be clinically viable and could result in complications during the surgical technique. As a result further development would be required to improve the setting time of the cement in order for it to be deemed suitable for use in total joint replacement surgery.
Acta Biomaterialia | 2018
Simon Porter; Sophie M. Coulter; Sreekanth Pentlavalli; Thomas P. Thompson; Garry Laverty
Biofilms present a major problem to industry and healthcare worldwide. Composed of a population of surface-attached microbial cells surrounded by a protective extracellular polysaccharide matrix, they are responsible for increased tolerance to antibiotics, treatment failure and a resulting rise in antimicrobial resistance. Here we demonstrate that self-assembled peptide nanostructures composed of a diphenylalanine motif provide sufficient antibacterial activity to eradicate mature biofilm forms of bacteria widely implicated in hospital infections. Modification of terminal functional groups to amino (-NH2), carboxylic acid (-COOH) or both modalities, and switch to d-isomers, resulted in changes in antibacterial selectivity and mammalian cell toxicity profiles. Of the three peptide nanotubes structures studied (NH2-FF-COOH, NH2-ff-COOH and NH2-FF-NH2), NH2-FF-COOH demonstrated the most potent activity against both planktonic (liquid, free-floating) and biofilm forms of bacteria, possessing minimal mammalian cell toxicity. NH2-FF-COOH resulted in greater than 3 Log10 CFU/mL viable biofilm reduction (>99.9%) at 5 mg/mL and total biofilm kill at 10 mg/mL against Staphylococcus aureus after 24 h exposure. Scanning electron microscopy proved that antibiofilm activity was primarily due to the formation of ion channels and/or surfactant-like action, with NH2-FF-COOH and NH2-ff-COOH capable of degrading the biofilm matrix and disrupting cell membranes, leading to cell death in Gram-positive bacterial isolates. Peptide-based nanotubes are an exciting platform for drug delivery and engineering applications. This is the first report of using peptide nanotubes to eradicate bacterial biofilms and provides evidence of a new platform that may alleviate their negative impact throughout society. STATEMENT OF SIGNIFICANCE We outline, for the first time, the antibiofilm activity of diphenylalanine (FF) peptide nanotubes. Biofilm bacteria exhibit high tolerance to antimicrobials 10-10,000 times that of free-flowing planktonic forms. Biofilm infections are difficult to treat using conventional antimicrobial agents, leading to a rise in antimicrobial resistance. We discovered nanotubes composed of NH2-FF-COOH demonstrated potent activity against staphylococcal biofilms implicated in hospital infections, resulting in complete kill at concentrations of 10 mg/mL. Carboxylic acid terminated FF nanotubes were able to destroy the exopolysaccharide architecture of staphylococcal biofilms expressing minimal toxicity, highlighting their potential for use in patients. Amidated (NH2-FF-NH2) forms demonstrated reduced antibiofilm efficacy and significant toxicity. These results contribute significantly to the development of innovative antibacterial technologies and peptide nanomaterials.
Materials Science and Engineering: C | 2017
Marine Chalanqui; Sreekanth Pentlavalli; Cian M. McCrudden; Philip Chambers; M. Ziminska; Nicholas Dunne; Helen O. McCarthy
Alginate grafted poly(N-isopropylacrylamide) hydrogels (Alg-g-P(NIPAAm)) form three-dimensional networks in mild conditions, making them suitable for incorporation of labile macromolecules, such as DNA. The impact of P(NIPAAm) on copolymer characteristics has been well studied, however the impact of alginate backbone characteristics on copolymer properties has to-date not been investigated. Six different Alg-g-P(NIPAAm) hydrogels were synthesised with 10% alginate, which varied in terms of molecular weight (MW) and mannuronate/guluronate (M/G) monomer ratio, and with 90% NIPAAm in order to develop an injectable and thermo-responsive hydrogel formulation for localised gene delivery. Hydrogel stiffness was directly proportional to MW and the M/G ratio of the alginate backbone. Hydrogels with a high MW or low M/G ratio alginate backbone demonstrated a greater stiffness than those hydrogels comprising low MW alginates and high M/G ratio. Hydrogels with a high M/G ratio also produced a complexed and meshed hydrogel network while hydrogels with a low M/G ratio produced a simplified structure with the superposition of Alg-g-P(NIPAAm) sheets. This study was designed to produce the optimal Alg-g-P(NIPAAm) hydrogel with respect to localised delivery of DNA nanoparticles as a potential medical device for those with castrate resistant prostate cancer (CRPC). Given that CRPC typically disseminates to bone causing pain, morbidity and a plethora of skeletal related events, a copolymer based hydrogel was designed to for long term release of therapeutic DNA nanoparticles. The nanoparticles were comprised of plasmid DNA (pDNA), complexed with an amphipathic cell penetrating peptide termed RALA that is designed to enter cells with high efficiency. Alginate MW and M/G ratio affected stiffness, structure, injectability and degradation of the Alg-g-P(NIPAAm) hydrogel. Algogel 3001, had the optimal characteristics for long-term application and was loaded with RALA/pDNA NPs. From the release profiles, it was evident that RALA protected the pDNA from degradation over a 30-day period and conferred a sustained and controlled release profile from the hydrogels compared to pDNA only. Taken together, we have designed a slowly degrading hydrogel suitable for sustained delivery of nucleic acids when incorporated with the RALA delivery peptide. This now opens up several opportunities for the delivery of therapeutic pDNA from this thermo-responsive hydrogel with numerous medical applications.
Archive | 2016
Sreekanth Pentlavalli; Helen O. McCarthy; Nicholas Dunne
Tissue engineering is a broad technology for tissue repair of diseased or injured tissues and organs by using composite scaffolds. The scaffold material provides stability and creates natural environment to promote cell-seeded population to develop fully functional new tissue or organ by restoring original tissue qualities. Generally, these scaffolds are biocompatible, three dimensional and biodegradable frameworks that act as template for ex-vivo cell expansion. Fibres or tubes reinforced scaffolds are gaining importance due to high mechanical stability and eco-economic reasons. This tailored made technology is a combination of both natural and synthetic material which helps to design the scaffold based on needs. To achieve this, fibres or tubes have been used to provide suitable mechanical properties during entire duration of tissue repair. Ideally, fibres reinforced scaffolds must meet following criteria: (i) 3D network with interconnected pore network for cell attachment and growth; (ii) biocompatible and controlled degradation and resorption rate to match tissue growth; (iii) appropriate mechanical properties to match the native tissue at the site of implantation. In this article, we mainly discuss the impact of mechanical properties on various scaffolds such as hydrogel based, ceramic based composites with both natural and synthetic fibres. Also discussed are the various useful techniques used to measure mechanical properties of reinforced materials.
Journal of Physical Chemistry B | 2007
Sarah O'Toole; Sreekanth Pentlavalli; Andrew Doherty
Electrochimica Acta | 2010
Paolo Ugo; Ligia Maria Moretto; Manuela De Leo; Andrew Doherty; Chiara Vallese; Sreekanth Pentlavalli