Zoledronic Acid Implant Coating Results in Local Medullary Bone Growth.

Osteoarthritis (OA) can necessitate surgical interventions to restore the function of the joint in severe cases. Joint replacement surgery is one of the procedures implemented to replace the damaged joint with prosthetic implants in severe cases of OA. However, after successful implantation, a fraction of OA patients still require revision surgery due to aseptic prosthetic loosening. Insufficient osseointegration is one of the factors that contribute to such loosening of the bone implant, which is commonly made from titanium-based materials. Zoledronic acid (ZA), a potent bisphosphonate agent, has been previously shown to enhance osseointegration of titanium implants. Herein, we fabricated ZA/Ca composites using a reverse microemulsion method and coated them with 1,2-dioleoyl-sn-glycero-3-phosphate monosodium salt (DOPA) to form ZA/Ca/DOPA composites. Titanium alloy screws were subsequently dip-coated with a suspension of the ZA/Ca/DOPA composites and poly(lactic-co-glycolic) acid (PLGA) in chloroform to yield Za/PLGA-coated screws. The coated screws exhibited a biphasic in vitro release profile with an initial burst release within 48 h, followed by a sustained release over 1 month. To assess their performance in vivo, the Za/PLGA screws were then implanted into the tibiae of Sprague-Dawley rats. After 8 weeks, microCT imaging showed new bone growth along the medullary cavity around the implant site, supporting the local release of ZA to enhance bone growth around the implant. Histological staining further confirmed the presence of new mineralized medullary bone growth resembling the cortical bone. Such local medullary growth represents an opportunity for future studies with alternative coating methods to fine-tune the local release of ZA from the coating and enhance complete osseointegration of the implant.

Surface Modification of Nanoparticles Enhances Drug Delivery to the Brain and Improves Survival in a Glioblastoma Multiforme Murine Model.

Glioblastoma multiforme (GBM) is the most malignant type of brain tumor and has an extremely poor prognosis. Current treatment protocols lack favorable outcomes, and alternative treatments with superior efficacy are needed. In this study, we demonstrate that loading paclitaxel (PTX) in a polymeric, nanoparticulate delivery system is capable of improving its brain accumulation and therapeutic activity. We independently incorporated two different positively charged surface modifiers, poly(amidoamine) (PAMAM) and poly(ethylenimine) (PEI), onto poly(lactic-co-glycolic acid) (PLGA)-polyethylene glycol (PEG), PLGA-PEG, nanoparticles (NPs) using a modified nanoprecipitation technique that assures the formation of nanosized particles while exposing the positively charged polymer on the surface. The prepared NPs underwent comprehensive analyses of their size, charge, in vitro permeability against a BBB cell line, and in vivo biodistribution. Our results demonstrated the successful fabrication of positively charged NPs using PAMAM or PEI. Importantly, significant improvement in brain accumulation (in vivo) was associated with NPs containing PAMAM compared to unmodified NPs or NPs containing PEI. Finally, the efficacy of PAMAM-modified NPs loaded with PTX was evaluated with orthotopic human GBM xenografts in a mouse model, and the data demonstrated improved survival and equivalent safety compared to soluble PTX. Our data substantiate the importance of surface chemistry on the magnitude of NP accumulation in the brain and pave the way for further in vivo evaluation of chemotherapeutic drugs against GBM that have previously been overlooked because of their limited ability to cross the BBB.

The MEK 1/2 inhibitor PD98059 exhibits synergistic anti-endometrial cancer activity with paclitaxel in vitro and enhanced tissue distribution in vivo when formulated into PAMAM-coated PLGA-PEG nanoparticles.

Endometrial cancer is the most common gynecological cancer that affects the female reproductive organs. The standard therapy for EC for the past two decades has been chemotherapy and/or radiotherapy. PD98059 is a reversible MEK inhibitor that was found in these studies to increase the cytotoxicity of paclitaxel (PTX) against human endometrial cancer cells (Hec50co) in a synergistic and dose-dependent manner. Additionally, while PD98059 arrested Hec50co cells at the G0/G1 phase, and PTX increased accumulation of cells at the G2/M phase, the combination treatment increased accumulation at both the G0/G1 and G2/M phases at low PTX concentrations. We recently developed poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) modified with polyethylene glycol (PEG) and coated with polyamidoamine (PAMAM) (referred to here as PGM NPs) which have favorable biodistribution profiles in mice, compared to PD98059 solution. Here, in order to enhance tissue distribution of PD98059, PD98059-loaded PGM NPs were prepared and characterized. The average size, zeta potential, and % encapsulation efficiency (%EE) of these NPs was approximately 184 nm, + 18 mV, and 23%, respectively. The PD98059-loaded PGM NPs released ~ 25% of the total load within 3 days in vitro. In vivo murine studies revealed that the pharmacokinetics and biodistribution profile of intravenous (IV) injected PD98059 was improved when delivered as PD98059-loaded PGM NPs as opposed to soluble PD98059. Further investigation of the in vivo efficacy and safety of this formulation is expected to emphasize the potential of its clinical application in combination with commercial PTX formulations against different cancers.

HPLC-UV Method Validation for Amobarbital and Pharmaceutical Stability Evaluation When Dispersed in a Hyaluronic Acid Hydrogel: A New Concept for Post-Traumatic Osteoarthritis Prevention.

A mitochondrial electron transport chain member complex I inhibitor, amobarbital, can reduce oxidative damage and chondrocyte death, eventually preventing post-traumatic osteoarthritis (PTOA). Viscosupplementation using a crosslinked hyaluronic acid (HA) hydrogel is currently applied clinically for knee OA pain relief. In this work, we utilized the HA hydrogel as a drug delivery vehicle to improve the long-term efficacy of amobarbital. Here we evaluated the pharmaceutic stability of amobarbital when dispersed in a crosslinked HA hydrogel formulated in proportions intended for clinical use. We validated a high-performance liquid chromatography with an ultraviolet detector (HPLC-UV) method following International Conference for Harmonization Q2(R1) guidelines to ensure its suitability for amobarbital detection. The feasibility of this formulation's drug delivery capability was proven by measuring the release, solubility, and drug uniformity. The amobarbital/HA hydrogel showed comparable amobarbital stability in different biological fluids compared to amobarbital solution. In addition, the amobarbital/HA hydrogel imparted significantly greater drug stability when stored at 70°C for 24 hours. In conclusion, we confirmed the pharmaceutical stability of the amobarbital/HA hydrogel in various conditions and biological fluids using a validated HPLC-UV method. This data provides essential evidence in support of the use of this amobarbital/HA formulation in future clinical trials for PTOA treatment.

Enhancement of Therapies for Glioblastoma (GBM) Using Nanoparticle-based Delivery Systems.

Glioblastoma multiforme (GBM) is the most aggressive type of malignant brain tumor. Current FDA-approved treatments include surgical resection, radiation, and chemotherapy, while hyperthermia, immunotherapy, and most relevantly, nanoparticle (NP)-mediated delivery systems or combinations thereof have shown promise in preclinical studies. Drug-carrying NPs are a promising approach to brain delivery as a result of their potential to facilitate the crossing of the blood-brain barrier (BBB) via two main types of transcytosis mechanisms: adsorptive-mediated transcytosis (AMT) and receptor-mediated transcytosis (RMT). Their ability to accumulate in the brain can thus provide local sustained release of tumoricidal drugs at or near the site of GBM tumors. NP-based drug delivery has the potential to significantly reduce drug-related toxicity, increase specificity, and consequently improve the lifespan and quality of life of patients with GBM. Due to significant advances in the understanding of the molecular etiology and pathology of GBM, the efficacy of drugs loaded into vectors targeting this disease has increased in both preclinical and clinical settings. Multitargeting NPs, such as those incorporating multiple specific targeting ligands, are an innovative technology that can lead to decreased off-target effects while simultaneously having increased accumulation and action specifically at the tumor site. Targeting ligands can include antibodies, or fragments thereof, and peptides or small molecules, which can result in a more controlled drug delivery system compared to conventional drug treatments. This review focuses on GBM treatment strategies, summarizing current options and providing a detailed account of preclinical findings with prospective NP-based approaches aimed at improving tumor targeting and enhancing therapeutic outcomes for GBM patients.

Applications of nanotechnology in 3D printed tissue engineering scaffolds.

Tissue engineering is an interdisciplinary field that aims to combine life sciences and engineering to create therapies that regenerate functional tissue. Early work in tissue engineering mostly used materials as inert scaffolding structures, but research has shown that constructing scaffolds from biologically active materials can help with regeneration by enabling cell-scaffold interactions or release of factors that aid in regeneration. Three-dimensional (3D) printing is a promising technique for the fabrication of structurally intricate and compositionally complex tissue engineering scaffolds. Such scaffolds can be functionalized with techniques developed by nanotechnology research to further enhance their ability to stimulate regeneration and interact with cells. Nanotechnological components, nanoscale textures, and microscale/nanoscale printing can all be incorporated into the manufacture of 3D printed scaffolds. This review discusses recent advancements in the merging of nanotechnology with 3D printed tissue engineering scaffolds, with a focus on applications of nanoscale components, nanoscale texture, and innovative printing techniques and the effects observed in vitro and in vivo.

Evolution of drug-eluting biomedical implants for sustained drug delivery.

In the field of drug delivery, the most commonly used treatments have traditionally been systemically delivered using oral or intravenous administration. The problems associated with this type of delivery is that the drug concentration is controlled by first pass metabolism, and therefore may not always remain within the therapeutic window. Implantable drug delivery systems (IDDSs) are an excellent alternative to traditional delivery because they offer the ability to precisely control the drug release, deliver drugs locally to the target tissue, and avoid the toxic side effects often experienced with systemic administration. Since the creation of the first FDA-approved IDDS in 1990, there has been a surge in research devoted to fabricating and testing novel IDDS formulations. The versatility of these systems is evident when looking at the various biomedical applications that utilize IDDSs. This review provides an overview of the history of IDDSs, with examples of the different types of IDDS formulations, as well as looking at current and future biomedical applications for such systems. Though there are still obstacles that need to be overcome, ever-emerging new technologies are making the manufacturing of IDDSs a rewarding therapeutic endeavor with potential for further improvements.

Modafinil potentiates cocaine self-administration by a dopamine-independent mechanism: possible involvement of gap junctions.

Modafinil and methylphenidate are medications that inhibit the neuronal reuptake of dopamine, a mechanism shared with cocaine. Their use as "smart drugs" by healthy subjects poses health concerns and requires investigation. We show that methylphenidate, but not modafinil, maintained intravenous self-administration in Sprague-Dawley rats similar to cocaine. Both modafinil and methylphenidate pretreatments potentiated cocaine self-administration. Cocaine, at self-administered doses, stimulated mesolimbic dopamine levels. This effect was potentiated by methylphenidate, but not by modafinil pretreatments, indicating dopamine-dependent actions for methylphenidate, but not modafinil. Modafinil is known to facilitate electrotonic neuronal coupling by actions on gap junctions. Carbenoxolone, a gap junction inhibitor, antagonized modafinil, but not methylphenidate potentiation of cocaine self-administration. Our results indicate that modafinil shares mechanisms with cocaine and methylphenidate but has a unique pharmacological profile that includes facilitation of electrotonic coupling and lower abuse liability, which may be exploited in future therapeutic drug design for cocaine use disorder.

Effects of ( R)-Modafinil and Modafinil Analogues on Dopamine Dynamics Assessed by Voltammetry and Microdialysis in the Mouse Nucleus Accumbens Shell.

Recent discoveries have improved our understanding of the physiological and pathological roles of the dopamine transporter (DAT); however, only a few drugs are clinically available for DAT-implicated disorders. Among those drugs, modafinil (MOD) and its ( R)-enantiomer (R-MOD) have been used off-label as therapies for psychostimulant use disorders, but they have shown limited effectiveness in clinical trials. Recent preclinical studies on MOD and R-MOD have led to chemically modified structures aimed toward improving their neurobiological properties that might lead to more effective therapeutics for stimulant use disorders. This study examines three MOD analogues (JJC8-016, JJC8-088, and JJC8-091) with improved DAT affinities compared to their parent compound. These compounds were investigated for their effects on the neurochemistry (brain microdialysis and FSCV) and behavior (ambulatory activity) of male Swiss-Webster mice. Our data indicate that these compounds have dissimilar effects on tonic and phasic dopamine in the nucleus accumbens shell and variability in producing ambulatory activity. These results suggest that small changes in the chemical structure of a DAT inhibitor can cause compounds such as JJC8-088 to produce effects similar to abused psychostimulants like cocaine. In contrast, other compounds like JJC8-091 do not share cocaine-like effects and have a more atypical DAT-inhibitor profile, which may prove to be an advancement in the treatment of psychostimulant use disorders.

Lack of Specific Involvement of (+)-Naloxone and (+)-Naltrexone on the Reinforcing and Neurochemical Effects of Cocaine and Opioids.

Effective medications for drug abuse remain a largely unmet goal in biomedical science. Recently, the (+)-enantiomers of naloxone and naltrexone, TLR4 antagonists, have been reported to attenuate preclinical indicators of both opioid and stimulant abuse. To further examine the potential of these compounds as drug-abuse treatments, we extended the previous assessments to include a wider range of doses and procedures. We report the assessment of (+)-naloxone and (+)-naltrexone on the acute dopaminergic effects of cocaine and heroin determined by in vivo microdialysis, on the reinforcing effects of cocaine and the opioid agonist, remifentanil, tested under intravenous self-administration procedures, as well as the subjective effects of cocaine determined by discriminative-stimulus effects in rats. Pretreatments with (+)-naloxone or (+)-naltrexone did not attenuate, and under certain conditions enhanced the stimulation of dopamine levels produced by cocaine or heroin in the nucleus accumbens shell. Furthermore, although an attenuation of either cocaine or remifentanil self-administration was obtained at the highest doses of (+)-naloxone and (+)-naltrexone, those doses also attenuated rates of food-maintained behaviors, indicating a lack of selectivity of TLR4 antagonist effects for behaviors reinforced with drug injections. Drug-discrimination studies failed to demonstrate a significant interaction of (+)-naloxone with subjective effects of cocaine. The present studies demonstrate that under a wide range of doses and experimental conditions, the TLR4 antagonists, (+)-naloxone and (+)-naltrexone, did not specifically block neurochemical or behavioral abuse-related effects of cocaine or opioid agonists.