PLGA: From a classic drug carrier to a novel therapeutic activity contributor.

Poly(lactic-co-glycolic acid) (PLGA) is well known for its biocompatibility and minimal toxicity. It is one of the most promising biodegradable polymeric drug delivery systems able to get endorsement from regulatory bodies to enter market. For many decades, PLGA has been functioning as an excipient, which by definition is pharmaceutically inert at a given dose of formulation. Lactate (one of the hydrolysis products of PLGA) has a key role in biochemical pathways and could improve physiological activities in certain illnesses by exerting therapeutic effects such as angiogenesis and promotion of healing. These activities, however, depend on the released amounts and metabolic clearance of lactate and route of formulation delivery. In the current commentary, along with several key notes on the lactate interactions, we would like to inform the PLGA research community that lactate (resulting from local delivery of physiologically significant amount of PLGA) may positively or negatively affect therapeutic efficacy of certain drugs. Hence, the excipient role of PLGA may be investigated for its potential pharmacological contributions in some biomedical applications.

PLGA based drug delivery systems: Promising carriers for wound healing activity.

Wound treatment remains one of the most prevalent and economically burdensome healthcare issues in the world. Current treatment options are limited and require repeated administrations which led to the development of new therapeutics to satisfy the unmet clinical needs. Many potent wound healing agents were discovered but most of them are fragile and/or sensitive to in vivo conditions. Poly(lactic-co-glycolic acid) (PLGA) is a widely used biodegradable polymer approved by food and drug administration and European medicines agency as an excipient for parenteral administrations. It is a well-established drug delivery system in various medical applications. The aim of the current review is to elaborate the applications of PLGA based drug delivery systems carrying different wound healing agents and also present PLGA itself as a wound healing promoter. PLGA carriers encapsulating drugs such as antibiotics, anti-inflammatory drugs, proteins/peptides, and nucleic acids targeting various phases/signaling cycles of wound healing, are discussed with examples. The combined therapeutic effects of PLGA and a loaded drug on wound healing are also mentioned.

Combined effects of PLGA and vascular endothelial growth factor promote the healing of non-diabetic and diabetic wounds.

Growth factor therapies to induce angiogenesis and thereby enhance the blood perfusion, hold tremendous potential to address the shortcomings of current impaired wound care modalities. Vascular endothelial growth factor stimulates (VEGF) wound healing via multiple mechanisms. Poly(lactic-co-glycolic acid) (PLGA) supplies lactate that accelerates neovascularization and promotes wound healing. Hence, we hypothesized that the administration of VEGF encapsulated in PLGA nanoparticles (PLGA-VEGF NP) would promote fast healing due to the sustained and combined effects of VEGF and lactate. In a splinted mouse full thickness excision model, compared with untreated, VEGF and PLGA NP, PLGA-VEGF NP treated wounds showed significant granulation tissue formation with higher collagen content, re-epithelialization and angiogenesis. The cellular and molecular studies revealed that PLGA-VEGF NP enhanced the proliferation and migration of keratinocytes and upregulated the expression of VEGFR2 at mRNA level. We demonstrated the combined effects of lactate and VEGF for active healing of non-diabetic and diabetic wounds. FROM THE CLINICAL EDITOR: The study of wound healing has been under a tremendous amount of research over recent years. In diabetic wounds, vasculopathy leading to localized ischemia would often result in delayed wound healing. In this article, the authors encapsulated vascular endothelial growth factor stimulates (VEGF) in PLGA nanoparticles and studies the potential pro-healing effects. It was found that the combination of these two components provided synergistic actions for healing. The encouraging results should provide a basis for combination therapy in the future.

PLGA nanoparticles loaded with host defense peptide LL37 promote wound healing.

Wound treatment remains one of the most prevalent and economically burdensome healthcare issues in the world. Poly (lactic-co-glycolic acid) (PLGA) supplies lactate that accelerates neovascularization and promotes wound healing. LL37 is an endogenous human host defense peptide that modulates wound healing and angiogenesis and fights infection. Hence, we hypothesized that the administration of LL37 encapsulated in PLGA nanoparticles (PLGA-LL37 NP) promotes wound closure due to the sustained release of both LL37 and lactate. In full thickness excisional wounds, the treatment with PLGA-LL37 NP significantly accelerated wound healing compared to PLGA or LL37 administration alone. PLGA-LL37 NP-treated wounds displayed advanced granulation tissue formation by significant higher collagen deposition, re-epithelialized and neovascularized composition. PLGA-LL37 NP improved angiogenesis, significantly up-regulated IL-6 and VEGFa expression, and modulated the inflammatory wound response. In vitro, PLGA-LL37 NP induced enhanced cell migration but had no effect on the metabolism and proliferation of keratinocytes. It displayed antimicrobial activity on Escherichia coli. In conclusion, we developed a biodegradable drug delivery system that accelerated healing processes due to the combined effects of lactate and LL37 released from the nanoparticles.

Skin electroporation of a plasmid encoding hCAP-18/LL-37 host defense peptide promotes wound healing.

Host defense peptides, in particular LL-37, are emerging as potential therapeutics for promoting wound healing and inhibiting bacterial growth. However, effective delivery of the LL-37 peptide remains limiting. We hypothesized that skin-targeted electroporation of a plasmid encoding hCAP-18/LL-37 would promote the healing of wounds. The plasmid was efficiently delivered to full-thickness skin wounds by electroporation and it induced expression of LL-37 in the epithelium. It significantly accelerated reepithelialization of nondiabetic and diabetic wounds and caused a significant VEGFa and interleukin (IL)-6 induction. IL-6 was involved in LL-37-mediated keratinocyte migration in vitro and IL-6 neutralizing antibodies delivered to mice were able to suppress the wound healing activity of the hCAP-18/LL-37 plasmid. In a hindlimb ischemia model, electroporation of the hCAP-18/LL-37 plasmid increased blood perfusion, reduced muscular atrophy, and upregulated the angiogenic chemokines VEGFa and SDF-1a, and their receptors VEGF-R and CXCR-4. These findings demonstrate that a localized gene therapy with LL-37 is a promising approach for the treatment of wounds.

Combined effect of PLGA and curcumin on wound healing activity.

Wound healing is a complex process involving many interdependent and overlapping sequences of physiological actions. The application of exogenous lactate released from poly (lactic-co-glycolic acid) (PLGA) polymer accelerated angiogenesis and wound healing processes. Curcumin is a well-known topical wound healing agent for both normal and diabetic-impaired wounds. Hence, we hypothesized that the PLGA nanoparticles encapsulating curcumin could much potentially accelerate the wound healing. In a full thickness excisional wound healing mouse model, PLGA-curcumin nanoparticles showed a twofold higher wound healing activity compared to that of PLGA or curcumin. Histology and RT-PCR studies confirmed that PLGA-curcumin nanoparticles exhibited higher re-epithelialization, granulation tissue formation and anti-inflammatory potential. PLGA nanoparticles offered various benefits for the encapsulated curcumin like protection from light degradation, enhanced water solubility and showed a sustained release of curcumin over a period of 8 days. In conclusion, we demonstrated the additive effect of lactic acid from PLGA and encapsulated curcumin for the active healing of wounds.