Chemical Degradation of Peptides and Proteins in PLGA: A Review of Reactions and Mechanisms

Houchin, M.L.; Topp, Elizabeth M.

doi:10.1002/jps.21176

Cited by 238 publications

(158 citation statements)

References 58 publications

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“…The disadvantage associated with PLGA is the production of acids upon degradation, as is the case of many other biodegradable polymers. Several methods for the stabilization of acid-sensitive drugs have been investigated, and this continues to be an area of concentrated research (Zhu and Schwendeman, 2000;Bilati et al, 2005;Houchin and Topp, 2008;Fredenberg et al, 2011). A novel subdiscipline of nanotechnology called "nanotoxicology" has emerged.…”

Section: Pitfallsmentioning

confidence: 99%

PLGA-Based Nanoparticles as Cancer Drug Delivery Systems

Mirakabad

Nejati-Koshki²,

Akbarzadeh³

et al. 2014

Asian Pacific Journal of Cancer Prevention

389

154

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Section: Pitfallsmentioning

confidence: 99%

PLGA-Based Nanoparticles as Cancer Drug Delivery Systems

Mirakabad

Nejati-Koshki²,

Akbarzadeh³

et al. 2014

Asian Pacific Journal of Cancer Prevention

389

154

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“…Polymeric biodegradable lactic-glycolic acid (PLGA) particles are attractive carriers due to their biodegradability, biocompatibility and approval by the Food and Drug administration (FDA) [21]. They maintain effective concentrations of the loaded proteins for prolonged periods of times by trapping them in a hydrated polymer network that enables their slow release [21].…”

Section: Introductionmentioning

confidence: 99%

Subcutaneous inverse vaccination with PLGA particles loaded with a MOG peptide and IL-10 decreases the severity of experimental autoimmune encephalomyelitis

Cappellano

Woldetsadik

Orilieri

et al. 2014

Vaccine

120

116

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a b s t r a c t "Inverse vaccination" refers to antigen-specific tolerogenic immunization treatments that are capable of inhibiting autoimmune responses. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), initial trials using purified myelin antigens required repeated injections because of the rapid clearance of the antigens. This problem has been overcome by DNA-based vaccines encoding for myelin autoantigens alone or in combination with "adjuvant" molecules, such as interleukin (IL)-4 or IL-10, that support regulatory immune responses. Phase I and II clinical trials with myelin basic protein (MBP)-based DNA vaccines showed positive results in reducing magnetic resonance imaging (MRI)-measured lesions and inducing tolerance to myelin antigens in subsets of MS patients. However, DNA vaccination has potential risks that limit its use in humans. An alternative approach could be the use of protein-based inverse vaccines loaded in polymeric biodegradable lactic-glycolic acid (PLGA) nano/microparticles (NP) to obtain the sustained release of antigens and regulatory adjuvants. The aim of this work was to test the effectiveness of PLGA-NP loaded with the myelin oligodendrocyte glycoprotein (MOG) autoantigen and recombinant (r) IL-10 to inverse vaccinate mice with EAE. In vitro experiments showed that upon encapsulation in PLGA-NP, both MOG 35-55 and rIL-10 were released for several weeks into the supernatant. PLGA-NP did not display cytotoxic or proinflammatory activity and were partially endocytosed by phagocytes. In vivo experiments showed that subcutaneous prophylactic and therapeutic inverse vaccination with PLGA-NP loaded with MOG 35-55 and rIL-10 significantly ameliorated the course of EAE induced with MOG 35-55 in C57BL/6 mice. Moreover, they decreased the histopathologic lesions in the central nervous tissue and the secretion of IL-17 and interferon (IFN)-␥ induced by MOG in splenic T cells in vitro. These data suggest that subcutaneous PLGA-NP-based inverse vaccination may be an effective tool to treat autoimmune diseases.

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“…The accumulation of these acidic byproducts within the film matrix then further catalyzes the hydrolysis of the PLGA backbone, a phenomenon commonly referred to as autocatalysis. [64][65][66] Hence, the fastest degradation rate (0.063 per day) was observed in the PCTX-PLGA control film. In the presence of extensive porosity in PLGA films due to the incorporation and dissolution of PEG additives, these acidic byproducts were able to diffuse out of the film through these water-filled pores or channels.…”

Section: Discussionmentioning

confidence: 86%

The influence of additives in modulating drug delivery and degradation of PLGA thin films

et al. 2013

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Poly( D,L -lactic-co-glycolic acid) (PLGA) is the most frequently used bioresorbable polymer for the controlled release of drugs. Hydrophilic additives such as poly(ethylene glycol) (PEG) are commonly incorporated into PLGA to enhance the release of hydrophobic drugs such as paclitaxel (PCTX). Understanding the factors and mechanisms that govern drug release in a blended system is important to be able to modify the delivery properties of the drugs. This study evaluated the mechanical properties of PCTX-eluting PLGA thin films that incorporate PEG additives under constant hydration, which mimics physiological conditions. The presence of additives resulted in varying extents of phase separation, which changed the degradation and release profiles of the PLGA films. The incorporation of long-chain additives resulted in large phase-separated additive-rich domains that gave rise to large pores, high mass loss, and a high burst release of PCTX from the extensive dissolution and leaching of additives upon hydration. Subsequently, the degradation rate of PLGA films was reduced by the out-diffusion of acidic byproducts through these water-filled pores and channels; these byproducts would otherwise accumulate and contribute to higher degradation rates due to the autocatalysis of PLGA. The preferential association between PCTX and PEG additives in the phase-separated PLGA films was exploited to enhance the release of hydrophobic PCTX, and statistical correlations were established between the simultaneous release of PCTX and additives. This significant correlation could provide useful information for the prediction of hydrophobic drug release profiles and the selection or preparation of localized drug delivery systems with the use of PEG additives.

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Chemical Degradation of Peptides and Proteins in PLGA: A Review of Reactions and Mechanisms

Cited by 238 publications

References 58 publications

PLGA-Based Nanoparticles as Cancer Drug Delivery Systems

PLGA-Based Nanoparticles as Cancer Drug Delivery Systems

Subcutaneous inverse vaccination with PLGA particles loaded with a MOG peptide and IL-10 decreases the severity of experimental autoimmune encephalomyelitis

The influence of additives in modulating drug delivery and degradation of PLGA thin films

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