Suitably Incorporated Hydrophobic, Redox-Active Drug in Poly Lactic Acid-Graphene Nanoplatelet Composite Generates 3D-Printed Medicinal Patch for Electrostimulatory Therapeutics.

Polymer carbon composites have been reported for improved mechanical, thermal and electrical properties to provide reduced side effect by 3D printing personalized biomedical drug delivery devices. But control on homogeneity in loading and release of dopants like carbon allotropes and drugs, respectively, in the bulk and on the surface has always been a challenge. Herein, we are reporting a methodological cascade to achieve a model, customizable, 3D printed, homogeneously layered and electrically stimulatory, PLA-Graphene nanoplatelet (hl-PLGR) based drug delivery device, called 3D-est-MediPatch. The medicinal patch has been prepared by 3D-printing a Nic-hl-PLGR composite obtained by incorporating a redox active model drug, niclosamide (Nic) in hl-PLGR. The composite of Nic-hl-PLGR was characterized in three sequentially complex forms─composite film, hot melt extruded (HME) filament, and 3D printed (3DP) patches to understand the effect of filament extrusion and 3D-printing processes on Nic-hl-PLGR composite and overall drug incorporation efficiency and control. The incorporation of graphene was found to improve the homogeneity of the drug, and the hot melt extrusion improved the dispersion of drug and graphene fillers in the composite. The electroresponsive drug release from the Nic-hl-PLGR composite was found to be controllably accelerated compared to the drug release by diffusion, in simulated buffer condition. The released drug concentration was found to reach within the IC50 range for malignant melanoma cell (A375) and showed in vitro selectively, with reduced effects in noncancerous, fibroblast cells (NIH3T3). Further, the feasibility of application for this system was assessed in generating personalized 3D-est-MediPatch for skin, liver and spleen tissues in ex-vivo scenario. It showed excellent feasibility and efficacy of the 3D-est-MediPatch in controlled and personalized release of drugs during electrostimulation. Thus, a model platform, 3D-est-MediPatch, could be achieved by suitably incorporating a hydrophobic, redox-active drug (niclosamide) in poly lactic acid-graphene nanoplatelet composite for electrostimulatory therapeutics with reduced side effects.

Nanocarbon-Enforced Anisotropic MusCAMLR for Rapid Rescue of Mechanically Damaged Skeletal Muscles.

Mechanical damages to skeletal muscles could be detrimental to the active work hours and lifestyle of athletes, mountaineers, and security personnel. In this regard, the slowness of conventional treatment strategies and drug-associated side effects greatly demand the design and development of novel biomaterials, which can rescue such mechanically damaged skeletal muscles. To accomplish this demand, we have developed a musculoresponsive polymer-carbon composite for assisting myotubular regeneration (MusCAMLR). The MusCAMLR is enforced to attain anisotropic muscle-like characteristics while incorporating a smartly passivated nanoscale carbon material in the PNIPAM gel under physiological conditions as a stimulus, which is not achieved by the pristine nanocarbon system. The MusCAMLR establishes a specific mechanical interaction with muscle cells, supports myotube regeneration, maintains excellent mechanical similarity with the myotube, and restores the structural integrity and biochemical parameters of mechanically damaged muscles in a delayed onset muscle soreness (DOMS) rat model within a short period of 72 h. Concisely, this study discloses the potential of smartly passivated nanocarbon in generating an advanced biomaterial system, MusCAMLR, from a regularly used polymeric hydrogel system. This engineered polymer-carbon composite reveals its possible potential to be used as a nondrug therapeutic alternative for rescuing mechanically damaged muscles and probably can be extended for therapy of various other diseases including muscular dystrophy.

Use of acidic nanoparticles to rescue macrophage lysosomal dysfunction in atherosclerosis.

Dysfunction in the macrophage lysosomal system including reduced acidity and diminished degradative capacity is a hallmark of atherosclerosis, leading to blunted clearance of excess cellular debris and lipids in plaques and contributing to lesion progression. Devising strategies to rescue this macrophage lysosomal dysfunction is a novel therapeutic measure. Nanoparticles have emerged as an effective platform to both target specific tissues and serve as drug delivery vehicles. In most cases, administered nanoparticles are taken up non-selectively by the mononuclear phagocyte system including monocytes/macrophages leading to the undesirable degradation of cargo in lysosomes. We took advantage of this default route to target macrophage lysosomes to rectify their acidity in disease states such as atherosclerosis. Herein, we develop and test two commonly used acidic nanoparticles, poly-lactide-co-glycolic acid (PLGA) and polylactic acid (PLA), both in vitro and in vivo. Our results in cultured macrophages indicate that the PLGA-based nanoparticles are the most effective at trafficking to and enhancing acidification of lysosomes. PLGA nanoparticles also provide functional benefits including enhanced lysosomal degradation, promotion of macroautophagy/autophagy and protein aggregate removal, and reduced apoptosis and inflammasome activation. We demonstrate the utility of this system in vivo, showing nanoparticle accumulation in, and lysosomal acidification of, macrophages in atherosclerotic plaques. Long-term administration of PLGA nanoparticles results in significant reductions in surrogates of plaque complexity with reduced apoptosis, necrotic core formation, and cytotoxic protein aggregates and increased fibrous cap formation. Taken together, our data support the use of acidic nanoparticles to rescue macrophage lysosomal dysfunction in the treatment of atherosclerosis.Abbreviations: BCA: brachiocephalic arteries; FACS: fluorescence activated cell sorting; FITC: fluorescein-5-isothiocyanatel; IL1B: interleukin 1 beta; LAMP: lysosomal associated membrane protein; LIPA/LAL: lipase A, lysosomal acid type; LSDs: lysosomal storage disorders; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MFI: mean fluorescence intensity; MPS: mononuclear phagocyte system; PEGHDE: polyethylene glycol hexadecyl ether; PLA: polylactic acid; PLGA: poly-lactide-co-glycolic acid; SQSTM1/p62: sequestosome 1.