Molecular Dynamics Studies of Poly(Lactic Acid) Nanoparticles and Their Interactions with Vitamin E and TLR Agonists Pam1CSK4 and Pam3CSK4.

Poly(lactic acid) (PLA) nanoparticles (NPs) are widely investigated due to their bioresorbable, biocompatible and low immunogen properties. Interestingly, many recent studies show that they can be efficiently used as drug delivery systems or as adjuvants to enhance vaccine efficacy. Our work focuses on the molecular mechanisms involved during the nanoprecipitation of PLA NPs from concentrated solutions of lactic acid polymeric chains, and their specific interactions with biologically relevant molecules. In this study, we evaluated the ability of a PLA-based nanoparticle drug carrier to vectorize either vitamin E or the Toll-like receptor (TLR) agonists Pam1CSK4 and Pam3CSK4, which are potent activators of the proinflammatory transcription factor NF-κB. We used dissipative particle dynamics (DPD) to simulate large systems mimicking the nanoprecipitation process for a complete NP. Our results evidenced that after the NP formation, Pam1CSK4 and Pam3CSK4 molecules end up located on the surface of the particle, interacting with the PLA chains via their fatty acid chains, whereas vitamin E molecules are buried deeper in the core of the particle. Our results allow for a better understanding of the molecular mechanisms responsible for the formation of the PLA NPs and their interactions with biological molecules located either on their surfaces or encapsulated within them. This work should allow for a rapid development of better biodegradable and safe vectorization systems with new drugs in the near future.

Nanoparticle-Based Dressing: The Future of Wound Treatment?

Reconstructing functional skin after a wound remains a challenge due to the complexity of healing. In this regard, biocompatible nanoparticles (NPs) carrying and releasing bioactive drugs in a controlled and sustained manner may significantly improve the efficacy of wound therapies compared with current treatments. Topical administration of drug-loaded NPs allows optimal delivery to the dermis and improves product efficacy. Furthermore, associating NPs with scaffolds represents a new concept of 'dressing'. Experimental in vivo, ex vivo, and in vitro models have been developed in preclinical assays to evaluate the beneficial effects of nanoparticulate dressings. Drug-loaded NPs are promising tools for innovative wound healing treatment, especially with regard to their multifunctional properties.

Drug loaded composite oxidized pectin and gelatin networks for accelerated wound healing.

Biocomposite interactive wound dressings have been designed and fabricated using oxidized pectin (OP), gelatin and nonwoven cotton fabric. Due to their inherent virtues of antimicrobial activity and cytocompatibility, these composite structures are capable of redirecting the healing cascade and influencing cell attachment and proliferation. A novel in situ reduction process has been followed to synthesize oxidized pectin-gelatin-nanosilver (OP-Gel-NS) flower like nanohydrocolloids. This encapsulation technology controls the diffusion and permeation of nanosilver into the surrounding biological tissues. Ciprofloxacin hydrochloride has also been incorporated into the OP-Gel matrix to produce OP-Gel-Cipro dressings. While OP-Gel-NS dressings exhibited 100% antimicrobial activity at extremely low loadings of 3.75µg/cm(2), OP-Gel-Cipro dressings were highly antimicrobial at 1% drug loading. While NIH3T3 mouse fibroblasts proliferated remarkably well when cultured with OP-Gel and OP-Gel-Cipro dressings, OP-Gel-NS hindered cell growth and Bactigras(®) induced complete lysis. Full thickness excisional wounds were created on C57BL/6J mice and the wound healing potential of the OP-Gel-NS dressings led to accelerated healing within 12days, while OP-Gel-Cipro dressings healed wounds at a rate similar to that of Bactigras(®). Histological examination revealed that OP-Gel-NS and OP-Gel-Cipro treatment led to organized collagen deposition, neovascularization and nuclei migration, unlike Bactigras(®). Therefore, the OP-Gel-NS and OP-Gel-Cipro biocomposite dressings exhibiting good hydrophilicity, sustained antimicrobial nature, promote cell growth and proliferation, and lead to rapid healing, can be considered viable candidates for effective management.

Composite wound dressings of pectin and gelatin with aloe vera and curcumin as bioactive agents.

Aloe vera and curcumin loaded oxidized pectin-gelatin (OP-Gel) matrices were used as antimicrobial finishes on nonwoven cotton fabrics to produce composite wound care devices. The drug release characteristics of the biocomposite dressings indicated that curcumin is released through a biphasic mechanism - erosion of the polymeric matrix, followed by diffusion, while aloe vera is released upon leaching of the polymeric matrix. A 50/50 composition of aloe vera/curcumin was used to fabricate OP-Gel-Aloe Curcumin dressings. However, contrary to our expectations, OP-Gel-Aloe Curcumin dressings exhibited lesser antimicrobial activity compared to OP-Gel-Aloe and OP-Gel-Curcumin dressings. The cytocompatibility of the fabricated dressings was evaluated using NIH3T3 mouse fibroblast cells. OP-Gel-Aloe treated fibroblasts had the highest viability, with the matrices providing a substrate for good cell attachment and proliferation. On the other hand, OP-Gel-Curcumin and OP-Gel-Aloe Curcumin seemed to have induced apoptosis in NIH3T3 cells. In vivo wound healing analysis was carried out using an excisional splint wound model on C57BL/6J mice. OP-Gel-Aloe treated wounds exhibited very rapid healing with 80% of the wound healing in just 8 days. Furthermore, aloe vera exerted a strong anti-inflammatory effect and prominent scar prevention. Histological examination revealed that an ordered collagen formation and neovascularization could be observed along with migration of nuclei. Therefore, OP-Gel-Aloe biocomposite dressings are proposed as viable materials for effective wound management.

Poly(lactic acid) and poly(lactic-co-glycolic acid) particles as versatile carrier platforms for vaccine delivery.

The development of safe and effective vaccines for cancer and infectious diseases remains a major goal in public health. Over the last two decades, controlled release of vaccine antigens and immunostimulant molecules has been achieved using nanometer or micron-sized delivery vehicles synthesized using biodegradable polymers. In addition to achieving a depot effect, enhanced vaccine efficacy using such delivery vehicles has been attributed to efficient targeting of antigen presenting cells such as dendritic cells. Biodegradable and biocompatible poly(lactic acid) and poly(lactic-co-glycolic acid) polymers belong to one such family of polymers that have been a popular choice of material used in the design of these delivery vehicles. This review summarizes research findings from ourselves and others highlighting the promise of poly(lactic acid)- and poly(lactic-co-glycolic acid)-based vaccine carriers in enhancing immune responses.