An injectable and in situ-gelling biopolymer for sustained drug release following perineural administration (original) (raw)
Injectables and Depots to Prolong Drug Action of Proteins and Peptides
Pharmaceutics, 2020
Proteins and peptides have emerged in recent years to treat a wide range of multifaceted diseases such as cancer, diabetes and inflammation. The emergence of polypeptides has yielded advancements in the fields of biopharmaceutical production and formulation. Polypeptides often display poor pharmacokinetics, limited permeability across biological barriers, suboptimal biodistribution, and some proclivity for immunogenicity. Frequent administration of polypeptides is generally required to maintain adequate therapeutic levels, which can limit efficacy and compliance while increasing adverse reactions. Many strategies to increase the duration of action of therapeutic polypeptides have been described with many clinical products having been developed. This review describes approaches to optimise polypeptide delivery organised by the commonly used routes of administration. Future innovations in formulation may hold the key to the continued successful development of proteins and peptides wit...
Elastin-like polypeptides in drug delivery
Advanced Drug Delivery Reviews, 2016
Elastin-like polypeptides in drug delivery Contents 1. Introduction 2. Macroscopic devices for drug delivery 2.1 ELR-based depots and hydrogels 2.1.1 ELR-based depots and hydrogels for reducing systemic toxicity 2.1.2 ELR-based depots and hydrogels for improving therapeutic efficiency 3. Nanoparticle-based devices for drug delivery 3.1 Nanocarriers derived from ELRs 3.1.1 ELR block copolymers 3.1.2 ELR monomers 3.2 Nanocarriers derived from SELRs 3.3 Hybrid nanocarriers containing ELRs 4. Drug-ELR conjugates for drug delivery. 4.1 Drug-ELR conjugates as chemotherapeutic agents 4.2 Drug-ELR conjugates with self-assembling capabilities upon conjugation 5. Conclusions Acknowledgements References
An injectable drug delivery platform for sustained combination therapy
Journal of Controlled Release, 2009
We report the development of a series of physical hydrogel blends composed of hyaluronan (HA) and methyl cellulose (MC) designed for independent delivery of one or more drugs, from 1 to 28 days, for ultimate application in spinal cord injury repair strategies. To achieve a diversity of release profiles we exploit the combination of fast diffusion-controlled release of dissolved solutes from the HAMC itself and slow drug release from poly(lactide-co-glycolide) particles dispersed within the gel. Delivery from the composite hydrogels was demonstrated using the neuroprotective molecules NBQX and FGF-2, which were released for 1 and 4 days, respectively; the neuroregenerative molecules dbcAMP and EGF, and proteins α-chymotrypsin and IgG, which were released for 28 days. α-chymotrypsin and IgG were selected as model proteins for the clinically relevant neurotrophin-3 and anti-NogoA. Particle loaded hydrogels were significantly more stable than HAMC alone and drug release was longer and more linear than from particles alone. The composite hydrogels are minimally swelling and injectable through a 30 gauge/200 µm inner diameter needle at particle loads up to 15 wt.% and particle diameters up to 15 µm.
Journal of Neurosurgery: Spine, 2008
ObjectBiochemical irritation of the dorsal root ganglion (DRG) after intervertebral disc herniation contributes to radiculopathy through tumor necrosis factor–α (TNFα)–mediated inflammation. Soluble TNF receptor Type II (sTNFRII) sequesters this cytokine, providing clinical benefit. Previous work involving conjugation of sTNFRII with thermally responsive elastin-like polypeptide (ELP) yielded a chimeric protein (ELP–sTNFRII) with in vitro anti-TNFα bioactivity. Furthermore, temperature-triggered ELP aggregation into a “depot” prolongs protein residence time following perineural injection. In this study the authors evaluated the inflammatory phenotype of DRG explants after TNFα stimulation, and assessed the abilities of sTNFRII or ELP–sTNFRII to attenuate these neuro-inflammatory changes.MethodsRat lumbar DRGs (35 animals) were treated in 6 groups, as follows: control; TNFα (25 ng/ml); TNFα with low-(0.2 μg/ml) or high-dose (1 μg/ml) sTNFRII; and TNFα with low-(52.5 μg/ml) or high-do...
Strategies for enhanced drug delivery to the central nervous system
Indian Journal of Pharmaceutical Sciences, 2008
Dwibhashyam, et al.: Drug delivery to CNS Treating central nervous system diseases is very challenging because of the presence of a variety of formidable obstacles that impede drug delivery. Physiological barriers like the blood-brain barrier and blood-cerebrospinal fl uid barrier as well as various effl ux transporter proteins make the entry of drugs into the central nervous system very diffi cult. The present review provides a brief account of the blood brain barrier, the P-glycoprotein effl ux and various strategies for enhancing drug delivery to the central nervous system.
Biochemistry, 2014
Elastin-like polypeptides (ELPs) are large, nonpolar polypeptides under investigation as components of a novel drug delivery system. ELPs are soluble at low temperatures, but they desolvate and aggregate above a transition temperature (T T). This aggregation is being utilized for targeting systemically delivered ELP−drug conjugates to heated tumors. We previously examined the structural, thermodynamic, and hydrodynamic properties of ELP[V 5 G 3 A 2-150] to understand its behavior as a therapeutic agent. In this study, we investigate the effect that adding basic cellpenetrating peptides (CPPs) to ELP[V 5 G 3 A 2-150] has on the polypeptide's solubility, structure, and aggregation properties. CPPs are known to enhance the uptake of ELP into cultured cells in vitro and into tumor tissue in vivo. Interestingly, the asymmetric addition of basic residues decreased the solubility of ELP[V 5 G 3 A 2-150], although below the T T we still observed a low level of self-association that increased with temperature. The ΔH of the aggregation process correlates with solubility, suggesting that the basic CPPs stabilize the aggregated state. This is potentially beneficial as the decreased solubility will increase the fraction aggregated and enhance drug delivery efficacy at a heated tumor. Otherwise, the basic CPPs did not significantly alter the biophysical properties of ELP. All constructs were monomeric at low temperatures but self-associate with increasing temperature through an indefinite isodesmic association. This self-association was coupled to a structural transition to type II βturns. All constructs reversibly aggregated in an endothermic reaction, consistent with a reaction driven by the release of water.
Structural and Hydrodynamic Analysis of a Novel Drug Delivery Vector: ELP[V 5 G 3 A 2 -150
The therapeutic potential of elastin-like polypeptide (ELP) conjugated to therapeutic compounds is currently being investigated as an approach to target drugs to solid tumors. ELPs are hydrophobic polymers that are soluble at low temperatures and cooperatively aggregate above a transition temperature (T T ), allowing for thermal targeting of covalently attached drugs. They have been shown to cooperatively transition from a disordered structure to a repeating type II b-turn structure, forming a b-spiral above the T T . Here we present biophysical measurements of the structural, thermodynamic, and hydrodynamic properties of a specific ELP being investigated for drug delivery, ELP[V 5 G 3 A 2 -150]. We examine the biophysical properties below and above the T T to understand and predict the therapeutic potential of ELP-drug conjugates. We observed that below the T T , ELP[V 5 G 3 A 2 -150] is soluble, with an extended conformation consisting of both random coil and heterogeneous b structures. Sedimentation velocity experiments indicate that ELP[V 5 G 3 A 2 -150] undergoes weak self-association with increasing temperature, and above the T T the hydrophobic effect drives aggregation entropically. These experiments also reveal a previously unreported temperature-dependent critical concentration (Cc) that resembles a solubility constant. Labeling ELP[V 5 G 3 A 2 -150] with fluorescein lowers the T T by 3.5 C at 20 mM, whereas ELP[V 5 G 3 A 2 -150] dissolution in physiological media (fetal bovine serum) increases the T T by~2.2 C.
Journal of …, 2008
Object-Biochemical irritation of the dorsal root ganglion (DRG) after intervertebral disc herniation contributes to radiculopathy through tumor necrosis factor-α (TNFα)-mediated inflammation. Soluble TNF receptor Type II (sTNFRII) sequesters this cytokine, providing clinical benefit. Previous work involving conjugation of sTNFRII with thermally responsive elastin-like polypeptide (ELP) yielded a chimeric protein (ELP-sTNFRII) with in vitro anti-TNFα bioactivity. Furthermore, temperature-triggered ELP aggregation into a "depot" prolongs protein residence time following perineural injection. In this study the authors evaluated the inflammatory phenotype of DRG explants after TNFα stimulation, and assessed the abilities of sTNFRII or ELP-sTNFRII to attenuate these neuroinflammatory changes.
Clinical & Investigative Medicine, 2007
Background: Tumor necrosis factor alpha (TNFα) is a cytokine that may mediate inflammatory histopathology of the dorsal root ganglion following lumbar disc herniation.1 Soluble TNF receptor II (sTNFRII) competitively binds TNFa with clinical value for painful radiculopathy.2 Bioactive peptides expressed with elastin-like polypeptides (ELP) fusion partners gain a thermally responsive domain, by which they can undergo hydrophobic collapse and separate from solution to aggregate at physiological temperatures.3 Protein release from such a depot may locally sustain drug presence, an effect demonstrated for non-fusion ELP after intra-articular injection.4 Methods: We expressed sTNFRII fused to ELP to demonstrate potential bidomain functionality. Protein Expression. A gene encoding ELP-(VPGVG)60 was subcloned adjacent to the sTNFRII and transformed into E.coli for expression.5 Protein Safety. Endotoxin content of purified fusion protein was evaluated using a limulus amebocyte lysate endpoi...