Rapidly Dissolving Trans-scleral Microneedles for Intraocular Delivery of Cyclosporine A.

Cyclosporine A (CsA) is a cyclic peptide immunosuppressant drug that is beneficial in the treatment of various ocular diseases. However, its ocular bioavailability in the posterior eye is limited due to its poor aqueous solubility. Conventional CsA formulations such as a solution or emulsion permeate poorly across the eye due to various static and dynamic barriers of the eye. Dissolvable microneedle (MN)-based patches can be used to overcome barrier properties and, thus, enhance the ocular bioavailability of CsA in the posterior eye. CsA-loaded dissolvable MN patches were fabricated using polyvinylpyrrolidone (PVP) and characterized for MN uniformity and sharpness using SEM. Further characterization for its failure force, penetration force, and depth of penetration were analyzed using a texture analyzer. Finally, the dissolution time, ex vivo permeation, and ocular distribution of cyclosporine were determined in isolated porcine eyes. PVP MNs were sharp, uniform with good mechanical properties, and dissolved within 5 min. Ocular distribution of CsA in a whole porcine eye perfusion model showed a significant increase of CsA levels in various posterior segment ocular tissues as compared to a topically applied ophthalmic emulsion (Restasis®) (P < 0.001). Dissolving MNs of CsA were prepared, and the MN arrays can deliver CsA to the back of the eye offering potential for treating various inflammatory diseases.

Natural Product-Based Nanomedicine in Treatment of Inflammatory Bowel Disease.

: Many synthetic drugs and monoclonal antibodies are currently in use to treat Inflammatory Bowel Disease (IBD). However, they all are implicated in causing severe side effects and long-term use results in many complications. Numerous in vitro and in vivo experiments demonstrate that phytochemicals and natural macromolecules from plants and animals reduce IBD-related complications with encouraging results. Additionally, many of them modify enzymatic activity, alleviate oxidative stress, and downregulate pro-inflammatory transcriptional factors and cytokine secretion. Translational significance of natural nanomedicine and strategies to investigate future natural product-based nanomedicine is discussed. Our focus in this review is to summarize the use of phytochemicals and macromolecules encapsulated in nanoparticles for the treatment of IBD and IBD-associated colorectal cancer.

Development and validation of a high-performance liquid chromatography method for the quantification of talazoparib in rat plasma: Application to plasma protein binding studies.

A sensitive and selective RP-HPLC method has been developed and validated for the quantification of a highly potent poly ADP ribose polymerase inhibitor talazoparib (TZP) in rat plasma. Chromatographic separation was performed with isocratic elution method. Absorbance for TZP was measured with a UV detector (SPD-20A UV-vis) at a λmax of 227 nm. Protein precipitation was used to extract the drug from plasma samples using methanol-acetonitrile (65:35) as the precipitating solvent. The method proved to be sensitive and reproducible over a 100-2000 ng/mL linearity range with a lower limit of quantification (LLQC) of 100 ng/mL. TZP recovery was found to be >85%. Following analytical method development and validation, it was successfully employed to determine the plasma protein binding of TZP. TZP has a high level of protein binding in rat plasma (95.76 ± 0.38%) as determined by dialysis method.

Nanomedicine scale-up technologies: feasibilities and challenges.

Nanomedicine refers to biomedical and pharmaceutical applications of nanosized cargos of drugs/vaccine/DNA therapeutics including nanoparticles, nanoclusters, and nanospheres. Such particles have unique characteristics related to their size, surface, drug loading, and targeting potential. They are widely used to combat disease by controlled delivery of bioactive(s) or for diagnosis of life-threatening problems in their very early stage. The bioactive agent can be combined with a diagnostic agent in a nanodevice for theragnostic applications. However, the formulation scientist faces numerous challenges related to their development, scale-up feasibilities, regulatory aspects, and commercialization. This article reviews recent progress in the method of development of nanoparticles with a focus on polymeric and lipid nanoparticles, their scale-up techniques, and challenges in their commercialization.

SN-38-cyclodextrin complexation and its influence on the solubility, stability, and in vitro anticancer activity against ovarian cancer.

SN-38, an active metabolite of irinotecan, is up to 1,000-fold more potent than irinotecan. But the clinical use of SN-38 is limited by its extreme hydrophobicity and instability at physiological pH. To enhance solubility and stability, SN-38 was complexed with different cyclodextrins (CDs), namely, sodium sulfobutylether ß-cyclodextrin (SBEßCD), hydroxypropyl ß-cyclodextrin, randomly methylated ß-cyclodextrin, and methyl ß-cyclodextrin, and their influence on SN-38 solubility, stability, and in vitro cytotoxicity was studied against ovarian cancer cell lines (A2780 and 2008). Phase solubility studies were conducted to understand the pattern of SN-38 solubilization. SN-38-ßCD complexes were characterized by differential scanning calorimetry (DSC), X-ray powder diffraction analysis (XRPD), and Fourier transform infrared (FTIR). Stability of SN-38-SBEßCD complex in pH 7.4 phosphate-buffered saline was evaluated and compared against free SN-38. Phase solubility studies revealed that SN-38 solubility increased linearly as a function of CD concentration and the linearity was characteristic of an AP-type system. Aqueous solubility of SN-38 was enhanced by about 30-1,400 times by CD complexation. DSC, XRPD, and FTIR studies confirmed the formation of inclusion complexes, and stability studies revealed that cyclodextrin complexation significantly increased the hydrolytic stability of SN-38 at physiological pH 7.4. Cytotoxicity of SN-38-SBEßCD complex was significantly higher than SN-38 and irinotecan in both A2780 and 2008 cell lines. Results suggest that SBEßCD encapsulated SN-38 deep into the cavity forming stable inclusion complex and as a result increased the solubility, stability, and cytotoxicity of SN-38. It may be concluded that preparation of inclusion complexes with SBEßCD is a suitable approach to overcome the solubility and stability problems of SN-38 for future clinical applications.

Targeting Allosteric Site of PCSK9 Enzyme for the Identification of Small Molecule Inhibitors: An In Silico Drug Repurposing Study.

The primary cause of atherosclerotic cardiovascular disease (ASCVD) is elevated levels of low-density lipoprotein cholesterol (LDL-C). Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in this process by binding to the LDL receptor (LDL-R) domain, leading to reduced influx of LDL-C and decreased LDL-R cell surface presentation on hepatocytes, resulting higher circulating levels of LDL-C. As a consequence, PCSK9 has been identified as a crucial target for drug development against dyslipidemia and hypercholesterolemia, aiming to lower plasma LDL-C levels. This research endeavors to identify promising inhibitory candidates that target the allosteric site of PCSK9 through an in silico approach. To start with, the FDA-approved Drug Library from Selleckchem was selected and virtually screened by docking studies using Glide extra-precision (XP) docking mode and Smina software (Version 1.1.2). Subsequently, rescoring of 100 drug compounds showing good average docking scores were performed using Gnina software (Version 1.0) to generate CNN Score and CNN binding affinity. Among the drug compounds, amikacin, bestatin, and natamycin were found to exhibit higher docking scores and CNN affinities against the PCSK9 enzyme. Molecular dynamics simulations further confirmed that these drug molecules established the stable protein-ligand complexes when compared to the apo structure of PCSK9 and the complex with the co-crystallized ligand structure. Moreover, the MM-GBSA calculations revealed binding free energy values ranging from -84.22 to -76.39 kcal/mol, which were found comparable to those obtained for the co-crystallized ligand structure. In conclusion, these identified drug molecules have the potential to serve as inhibitors PCSK9 enzyme and these finding could pave the way for the development of new PCSK9 inhibitory drugs in future in vitro research.

Development of optimal in vitro release and permeation testing method for rectal suppositories.

Currently there are no compendial assays for testing drug release from rectal suppositories. It is therefore essential to study different in vitro release testing (IVRT) and in vitro permeation testing (IVPT) methods for identifying a suitable technique to compare in vitro drug release and to predict in vivo performance of rectal suppositories. In the present study, three different rectal suppository formulations of mesalamine (CANASA, Generic, and In-house) were studied for in vitro bioequivalence. All the different suppository products were characterized by performing weight variation, content uniformity, hardness, melting time, and pH tests. Viscoelastic behavior of the suppositories was also tested both in presence and absence of mucin. Four different IVRT techniques such as Dialysis, Horizontal Ussing Chamber, Vertical Franz cell, and USP apparatus 4. IVPT studies were performed using Horizontal Ussing chamber and Vertical Franz cell methods. Q1/Q2 equivalent products (CANASA, Generic) and a half-strength product were studied to understand the reproducibility, bio relevance, and discriminatory ability of the IVRT and IVPT methods. This study is the first of its kind where molecular docking studies were performed to determine the potential interactions of drug (mesalamine) with mucin, IVRT studies were conducted with and without the presence of mucin, and porcine rectal mucosa was used to perform IVPT tests. The USP 4 method and Horizontal Ussing chamber methods were found to be suitable IVRT and IVPT techniques, respectfully, for rectal suppositories. RLD (Reference Listed Drug) and Generic rectal suppositories were found to exhibit similar release rate and permeation profiles obtained from USP 4, and the IVPT studies, respectfully. Wilcoxon Rank Sum/Mann-Whitney rank test, conducted for the IVRT profiles obtained using USP 4 method, proved the sameness of RLD and Generic suppository products.

Biomedical applications of three-dimensional bioprinted craniofacial tissue engineering.

Anatomical complications of the craniofacial regions often present considerable challenges to the surgical repair or replacement of the damaged tissues. Surgical repair has its own set of limitations, including scarcity of the donor tissues, immune rejection, use of immune suppressors followed by the surgery, and restriction in restoring the natural aesthetic appeal. Rapid advancement in the field of biomaterials, cell biology, and engineering has helped scientists to create cellularized skeletal muscle-like structures. However, the existing method still has limitations in building large, highly vascular tissue with clinical application. With the advance in the three-dimensional (3D) bioprinting technique, scientists and clinicians now can produce the functional implants of skeletal muscles and bones that are more patient-specific with the perfect match to the architecture of their craniofacial defects. Craniofacial tissue regeneration using 3D bioprinting can manage and eliminate the restrictions of the surgical transplant from the donor site. The concept of creating the new functional tissue, exactly mimicking the anatomical and physiological function of the damaged tissue, looks highly attractive. This is crucial to reduce the donor site morbidity and retain the esthetics. 3D bioprinting can integrate all three essential components of tissue engineering, that is, rehabilitation, reconstruction, and regeneration of the lost craniofacial tissues. Such integration essentially helps to develop the patient-specific treatment plans and damage site-driven creation of the functional implants for the craniofacial defects. This article is the bird's eye view on the latest development and application of 3D bioprinting in the regeneration of the skeletal muscle tissues and their application in restoring the functional abilities of the damaged craniofacial tissue. We also discussed current challenges in craniofacial bone vascularization and gave our view on the future direction, including establishing the interactions between tissue-engineered skeletal muscle and the peripheral nervous system.

Pharmacological inhibition of KDM1A/LSD1 enhances estrogen receptor beta-mediated tumor suppression in ovarian cancer.

Ovarian cancer (OCa) is the most lethal gynecologic cancer. Emerging data indicates that estrogen receptor beta (ERß) functions as a tumor suppressor in OCa. Lysine-specific histone demethylase 1A (KDM1A) is an epigenetic modifier that acts as a coregulator for steroid hormone receptors. However, it remain unknown if KDM1A interacts with ERß and regulates its expression/functions in OCa. Analysis of TCGA data sets indicated KDM1A and ERß expression showed an inverse relationship in OCa. Knockout (KO), knockdown (KD), or inhibition of KDM1A increased ERß isoform 1 expression in established and patient-derived OCa cells. Further, KDM1A interacts with and functions as a corepressor of ERß, and its inhibition enhances ERß target gene expression via alterations of histone methylation marks at their promoters. Importantly, KDM1A-KO or -KD enhanced the efficacy of ERß agonist LY500307, and the combination of KDM1A inhibitor (KDM1Ai) NCD38 with ERß agonist synergistically reduced the cell viability, colony formation, and invasion of OCa cells. RNA-seq and DIA mass spectrometry analyses showed that KDM1A-KO resulted in enhanced ERß signaling and that genes altered by KDM1A-KO and ERß agonist were related to apoptosis, cell cycle, and EMT. Moreover, combination treatment significantly reduced the tumor growth in OCa orthotopic, syngeneic, and patient-derived xenograft models and proliferation in patient-derived explant models. Our results demonstrate that KDM1A regulates ERß expression/functions, and its inhibition improves ERß mediated tumor suppression. Overall, our findings suggest that KDM1Ai and ERß agonist combination therapy is a promising strategy for OCa.

Differential expression of caveolin-1 and caveolin-3: potential marker for cardiac toxicity subsequent to chronic ozone inhalation.

Earlier studies from our laboratory have shown myocardial dysfunction subsequent to chronic O(3) exposure in rats may be associated with a decrease in antioxidant reserve and increased activity of inflammatory mediators. The present study tested the hypothesis that O(3)-induced cardiac dysfunction in healthy adult rats may be due to changes in caveolin-1 and caveolin-3 levels. Sprague-Dawley rats were exposed 8 h/day for 28 and 56 days to filtered air or 0.8 ppm O(3). In order to assess the chronic effects to O(3), in vivo cardiac function was assessed by measuring LVDP, 24 h after termination of O(3) exposure. Compared to rats exposed to filtered air, LVDP values significantly decreased in all O(3)-exposed animals. This attenuation of cardiac function was associated with increased myocardial TNF-α levels and decreased myocardial activities of superoxidase dismutase. Progressive increases in the expression of myocardial TNF-α in 28 days and 56 days O(3)-exposed animals were followed by decreases in cardiac caveolin-1 levels. On the other hand, differential changes in the expression of caveolin-3 in hearts from 28 and 56 days O(3)-exposed animals were independent of intra-cardiac TNF-α levels. These novel findings suggest the interesting possibility that a balance between caveolin-1 and caveolin-3 may be involved in O(3)-mediated cardiac toxicity.

Advances in in-vitro bioequivalence testing methods for complex ophthalmic generic products.

The United States Food and Drug Administration (USFDA) demands that the generic industry prove topical ocular products' pharmaceutical and bioequivalence (BE). In contrast to generic oral drugs, topical ocular product BE testing has proved difficult. New generic versions are compared to an authorized drug product known as a Reference Listed Drug (RLD) to demonstrate their bioequivalence. If the excellent in-vitro results may support the presumption of equivalence in-vivo performance and the only clinically significant difference between the generic and RLD is in its physicochemical qualities and drug release rate, then in-vivo BE studies may be waived. Proving BE through dissolution tests is a golden standard for most conventional dosage forms. However, due to the limited number of biorelevant in-vitro drug release testing (IVRT) approaches capable of differentiating their performance based on product quality and physicochemical properties, the development of generic ophthalmic products has been slow and time-consuming. Often, BE of topical ophthalmic formulations cannot be proved using a single in-vitro test; therefore, an elaborated discussion on various IVRT methods performed to demonstrate bioequivalence of complex generis like ophthalmic emulsions, suspensions, ointments, and gels is necessary. This manuscript aims to review the status of biowaiver criteria for complex ophthalmic products concerning the product-specific FDA guidance to the generic industry.

KDM1A inhibition augments the efficacy of rapamycin for the treatment of endometrial cancer.

Endometrial cancer (EC) often exhibit aberrant activation of PI3K/Akt/mTOR signaling and targeted therapies using mTOR inhibitors showed limited success. The epigenetic modifier, lysine-specific histone demethylase-1A (KDM1A/LSD1) is overexpressed in EC, however, the mechanistic and therapeutic implications of KDM1A in EC are poorly understood. Here, using 119 FDA-approved drugs screen, we identified that KDM1A inhibition is highly synergistic with mTOR inhibitors. Combination therapy of KDM1A and mTOR inhibitors potently reduced the cell viability, survival, and migration of EC cells. Mechanistic studies demonstrated that KDM1A inhibition attenuated the activation of mTOR signaling cascade and abolished rapamycin induced feedback activation of Akt. RNA-seq analysis identified that KDM1A inhibition downregulated the expression of genes involved in rapamycin induced activation of Akt, including the mTORC2 complex. Chromatin immunoprecipitation experiments confirmed KDM1A recruitment to the promoter regions of mTORC2 complex genes and that KDM1A inhibition promoted enrichment of repressive H3K9me2 marks at their promoters. Combination therapy of KDM1A inhibitor and rapamycin reduced the tumor growth in EC xenograft and patient derived xenograft models in vivo and patient derived tumor explants ex vivo. Importantly, in silico analysis of TCGA EC patients data sets revealed that KDM1A expression positively correlated with the levels of PI3K/Akt/mTOR genes. Collectively, our results provide compelling evidence that KDM1A inhibition potentiates the activity of mTOR inhibitors by attenuating the feedback activation of Akt survival signaling. Furthermore, the use of concurrent KDM1A and mTOR inhibitors may be an attractive targeted therapy for EC patients.

Natural proteins and polysaccharides in the development of micro/nano delivery systems for the treatment of inflammatory bowel disease.

Treatments for inflammatory bowel disease (IBD) are typically immunosuppressive. Despite a range of treatment options, limited efficacy, systemic toxicities like bone marrow suppression, infections and malignancy are their serious setbacks. There exists an unmet medical need for novel therapeutic agents without safety concerns resulting from chronic, systemic immunosuppression. Of late, several natural agents with better therapeutic potential have been reported. It is very likely that restricting the release of the active molecules to the intestine would further improve their clinical efficacy and safety. To this end, novel polymer-based micro/nano formulations protect the drug from gastric environment and slowly release the drug in the colon. However, cost and side-effects associated to synthetic polymers have led to the development of biocompatible, economic and pharmaceutically well-accepted biomacromolecules in exploring their potential in IBD. Since last few years, biological proteins, polysaccharides and their combinations have shown great efficacy in colitis induced animal models. In this review, micro/nano formulations developed using biomacromolecules like chitosan, zein, pectin, casein, alginate, dextran, glucomannan and hyaluronic acid have been reviewed focusing on their potential in protecting active cargo, avoiding premature release, distal colon targeting along with their impact on reshaping the altered gut microbiota and how it can ameliorate the colitis conditions.

Nintedanib-cyclodextrin complex to improve bio-activity and intestinal permeability.

Cyclodextrin complex of nintedanib was prepared aiming for increased bio-activity and improved transport across intestinal membrane with reduced p-glycoprotein (p-gp) efflux. Based on preliminary phase solubility studies and molecular modeling, sulfobutyl ether derivative of ß-cyclodextrin (SBE-ß-CD, Captisol®) was selected to prepare inclusion complex. Complexation was confirmed using FTIR, 1H NMR, DSC, and XRD. Bioactivity of the formed complex was tested using lung fibroblast cells, WI-38 for anti-proliferative activity and effect on collagen deposition and cells migration. In-vitro permeability studies were performed using epiIntestinal tissue model to assess the effect of complexation on transport and p-gp efflux. Results of the study demonstrated that cyclodextrin complexation increased stability of nintedanib in PBS (pH 7.4) and simulated intestinal fluid (SIF). Further, bioactivity of nintedanib also improved. Interestingly, complexation has increased transport of nintedanib across intestinal membrane and reduced efflux ratio, suggesting the role of cyclodextrin complexation in modulating p-gp efflux.

Permeability of surface-modified polyamidoamine (PAMAM) dendrimers across Caco-2 cell monolayers.

Aim of this study was to prepare polyamine-conjugated PAMAM dendrimers and study their permeability across Caco-2 cell monolayers. Polyamines, namely, arginine and ornithine were conjugated to the amine terminals of the G4 PAMAM dendrimers by Fmoc synthesis. The apical-to-basolateral (AB) and basolateral-to-apical (BA) apparent permeability coefficients (P(app)) for the PAMAM dendrimers increased by conjugating the dendrimers with both of the polyamines. The enhancement in permeability was dependent on the dendrimer concentration and duration of incubation. The correlation between monolayer permeability and the decrease in transepithelial electrical resistance (TEER) with both the PAMAM dendrimers and the polyamine-conjugated dendrimers suggests that paracellular transport is one of the mechanisms of transport across the epithelial cells. Cytotoxicity of the polyamine-conjugated dendrimers was evaluated in Caco-2 cells by MTT (methylthiazoletetrazolium) assay. Arginine-conjugated dendrimers were slightly more toxic than PAMAM dendrimer as well as ornithine-conjugated dendrimers. Though investigations on the possible involvement of other transport mechanisms are in progress, results of the present study suggest the potential of dendrimer-polyamine conjugates as drug carriers to increase the oral absorption of drugs.

Target specificity of 188Re-labeled B27.1 monoclonal antibodies to ovarian cancer cells in vivo.

BACKGROUND: Currently we are exploring a new multistep pretargeting approach involving administration of a bispecific antibody (B27.1 x P54) which has an anti-CA-125 (B27.1) and antibiotin (P54) paratope. It is followed by the administration of radiolabeled biotinylated liposomes to target the 188Re to the ovarian cancer cells. As a preliminary step to realize this goal, we determined the target specificity of the monoclonal antibodies (B27.1) to the ovarian cancer cells in vivo. MATERIALS AND METHODS: B27.1 monoclonal antibodies were photoreduced using UV light and incubated with reduced 188Re for 30 min at 25degreesC. 188Re-labeled B27.1 antibodies were purified using size exclusion chromatography. A comparative biodistribution of Re-B27.1 and 188Re was performed in nude mice xenografted with NIH:OVCAR-3 cells. RESULTS: While free rhenium distributed preferentially into thyroid and stomach with insignificant accumulation in the cancer cells, about 20% of the injected dose of 188Re-B27.1 was recovered in ascites cells with insignificant localization in other organs four hours after administration. CONCLUSION: The study validates the affinity of the B27.1 antibodies to the ovarian cancer cells in vivo.

Development and Evaluation of Talazoparib Nanoemulsion for Systemic Therapy of BRCA1-mutant Cancer.

AIM: This is a debut study report on talazoparib (BMN-673)-loaded nanoemulsion (TZNE) for parenteral administration. MATERIALS AND METHODS: TZNE (0.05% drug, 151.4±0.7 nm droplet size, polydispersity index of 0.120±0.010 and zeta potential of -33.30±1.22 mV) was designed, developed and characterized using in vitro studies. A cumulative in vitro release study was performed in physiological phosphate buffer solution at different pH (5.3, 6.5 and 7.4) using a dialysis method. Cytotoxicity and apoptosis assays were performed on MDA-MB-231, NCI/ADR-RES, 2008 C13, CP-70 and SKOV-3 cell lines using CellTiter® Blue. Quantitative and qualitative cell uptake was studied using fluorescent probe, coumarin-6 (C-6). RESULTS: The drug release form TZNE nanoemulsion was slow and sustained for 24 h. Cytotoxicity and apoptosis were found to be concentration-dependent. The half-maximal inhibitory concentration of TZNE was 0.4852 and 1.35, 11.757 and 0.4696, and 1.169 and 0.7235 µM in MDA-MB-231, SKOV-3 and NCI/ADR-RES cells with 48 and 72 h incubation, respectively. Cellular uptake studies using fluorescent probe, coumarin-6 C-6, showed higher cellular uptake of TNZE compared with free C6. Results suggest that nanoemulsion could provide a new platform for systemic delivery of talazoparib.

Interactions between carbon nanotubes and bioactives: a drug delivery perspective.

Applications of carbon nanotubes (CNTs) in the biomedical arena have gained increased attention over the past decade. Surface engineering of CNTs by covalent and noncovalent modifications enables site-specific drug delivery and targeting. CNTs are available as single-, double-, triple-, and multiwalled carbon nanotubes (SWCNTs, DWCNTs, TWCNTs, and MWCNTs, respectively) and have unique physicochemical properties, including a high surface area, high loading efficiency, good biocompatibility, low toxicity, ultra lightweight, rich surface chemistry, non-immunogenicity, and photoluminescence. In this review, we highlight current understanding of the different types of physical and chemical interaction that occur between therapeutics and CNTs, and the potential application of the latter in drug delivery and imaging. Such understanding will aid exploration of the utility of multifunctional CNTs as pharmaceutical nanocarriers, and potential safety and toxicity issues.

Recent Advances in Topical Ocular Drug Delivery.

Topical ocular drug delivery has been considered to be an ideal route of administration for treatment of ocular diseases related to the anterior segment of the eye. However, topical ocular delivery is a challenging task because of barriers such as nasolacrimal drainage, corneal epithelium, blood-ocular barriers, and metabolism in the eye. Approaches to improve ocular bioavailability include physical approaches such as formulations of drugs as solutions (Zymaxid(™)), suspensions (Zigran(®)), gels (Akten(®)) and chemical approaches such as prodrugs (Xalatan(™)), chemical delivery systems, and soft drugs. The purpose of this review article is to summarize recent advances in topical drug delivery to the anterior segment of the eye. Functional transporters in the corneal epithelium were also discussed as they provide prospects in topical ocular delivery. In addition to conventional delivery systems, novel delivery systems involving nanocarriers were also investigated for topical ocular delivery. Furthermore, due to increased interest, gene therapy applications of topical ocular delivery of genes to the anterior segment of the eye were also discussed. Research in topical ocular delivery is active for more than 50 years and proven to be advantageous for the treatment of many ocular diseases. However, there is scope for innovation in topical drug delivery to develop delivery systems with a high patient safety profile and compliance for effective clinical usefulness.

Safety and toxicity of nanomaterials for ocular drug delivery applications.

Multifunctional nanomaterials are rapidly emerging for ophthalmic delivery of therapeutics to facilitate safe and effective targeting with improved patient compliance. Because of their extremely high area to volume ratio, nanomaterials often have physicochemical properties that are different from those of their larger counterparts. There exists a complex relationship between the physicochemical properties (composition, size, shape, charge, roughness, and porosity) of the nanomaterials and their interaction with the biological system. The eye is a very sensitive accessible organ and is subjected to intended and unintended exposure to nanomaterials. Currently, various ophthalmic formulations are available in the market, while some are underway in preclinical and clinical phases. However, the data on safety, efficacy, and toxicology of these advanced nanomaterials for ocular drug delivery are sparse. Focus of the present review is to provide a comprehensive report on the safety, biocompatibility and toxicities of nanomaterials in the eye.