Nanoscale Drug Delivery Systems Research Articles

Construction of Polymeric Micelles for Improving Cancer Chemotherapy by Promoting the Production of Intracellular Reactive Oxygen Species and Self‐Accelerating Drug Release

AbstractLots of efforts have been devoted to enhancing the antitumor efficacy of reactive oxygen species (ROS)‐responsive nanoscale drug delivery systems. Here, a ROS‐responsive amphiphilic polymer (mPEG‐b‐poly(thioacetal‐thioether), P2) with property of generation and self‐sustained high level of ROS, and a control material mPEG‐b‐poly(ester‐thioether) (P1) were constructed and characterized by proton nuclear magnetic resonance (1H NMR). The two polymers could self‐assemble into micelles and the doxorubicin loading content of P1 and P2 micelles were 13.08 % and 13.51 %, respectively. The two polymers could self‐assemble into micelles and exhibit good DOX loading capacity. ROS‐responsiveness of P1 and P2 micelles was investigated by1H NMR, dynamic light scattering (DLS), and scanning electron microscope (SEM). The results of in vitro ROS detection indicated that P2 micelles could ROS‐responsive release of cinnamaldehyde, and promote intracellular generation of ROS and maintain high level of ROS. DOX/P1 micelle shown comparable in vitro antitumor efficacy with DOX/P2 micelle, and a slightly lower IC50 value was due to DOX/P1 micelle has faster cell internalization, poorer micelle stability and integrality. Considering the stability of the nanoparticle circulation in vivo, the DOX/P2 micelle containing both thioether and thioacetal would be more suitable and could show better in vivo antitumor efficacy.

Stimuli-responsive nanoparticles based on poly acrylic derivatives for tumor therapy

Serve side effects caused by discriminate damage of chemotherapeutic drugs to normal cell and cancer cells remain a main obstacle in clinic. Hence, continuous efforts have been made to find ways to effectively enhance drug delivery and reduce side effects. Recent decades have witnessed impressive progresses in fighting against cancer, with improved understanding of tumor microenvironment and rapid development in nanoscale drug delivery system (DDS). Nanocarriers based on biocompatible materials provide possibilities to improve antitumor efficiency and minimize off-target effects. Among all kinds of biocompatible materials applied in DDS, polymeric acrylic derivatives such as poly(acrylamide), poly(acrylic acid), poly(N-isopropylacrylamide) present inherent biocompatibility and stimuli-responsivity, and relatively easy to be functionalized. Furthermore, nanocarrier based on polymeric acrylic derivatives have demonstrated high drug encapsulation, improved uptake efficiency, prolonged circulation time and satisfactory therapeutic outcome in tumor. In this review, we aim to discuss recent progress in design and development of stimulus-responsive poly acrylic polymer based nanocarriers for tumor targeting drug delivery.

Nano-Honokiol ameliorates the cognitive deficits in TgCRND8 mice of Alzheimer’s disease via inhibiting neuropathology and modulating gut microbiota

IntroductionHonokiol (HO) exerts neuroprotective effects in several animal models of Alzheimer’s disease (AD), but the poor dissolution hampers its bioavailability and therapeutic efficacy. ObjectivesA novel honokiol nanoscale drug delivery system (Nano-HO) with smaller size and excellent stability was developed in this study to improve the solubility and bioavailability of HO. The anti-AD effects of Nano-HO was determined. MethodsMale TgCRND8 mice were daily orally administered Nano-HO or HO at the same dosage (20 mg/kg) for 17 consecutive weeks, followed by assessment of the spatial learning and memory functions using the Morris Water Maze test (MWMT). ResultsOur pharmacokinetic study indicated that the oral bioavailability was greatly improved by Nano-HO. In addition, Nano-HO significantly improved cognitive deficits and inhibited neuroinflammation via suppressing the levels of TNF-α, IL-6 and IL-1β in the brain, preventing the activation of microglia (IBA-1) and astrocyte (GFAP), and reducing β-amyloid (Aβ) deposition in the cortex and hippocampus of TgCRND8 mice. Moreover, Nano-HO was more effective than HO in modulating amyloid precursor protein (APP) processing via suppressing β-secretase, as well as enhancing Aβ-degrading enzymes like neprilysin (NEP). Furthermore, Nano-HO more markedly inhibited tau hyperphosphorylation via decreasing the ratio of p-Tau (Thr 205)/tau and regulating tau-related apoptosis proteins (caspase-3 and Bcl-2). In addition, Nano-HO more markedly attenuated the ratios of p-JNK/JNK and p-35/CDK5, while enhancing the ratio of p-GSK-3β (Ser9)/GSK-3β. Finally, Nano-HO prevented the gut microflora dysbiosis in TgCRND8 mice in a more potent manner than free HO. ConclusionNano-HO was more potent than free HO in improving cognitive impairments in TgCRND8 mice via inhibiting Aβ deposition, tau hyperphosphorylation and neuroinflammation through suppressing the activation of JNK/CDK5/GSK-3β signaling pathway. Nano-HO also more potently modulated the gut microbiota community to protect its stability than free HO. These results suggest that Nano-HO has good potential for further development into therapeutic agent for AD treatment.

Fabrication of cisplatin-loaded polydopamine nanoparticles via supramolecular self-assembly for photoacoustic imaging guided chemo-photothermal cancer therapy

Nanoscale drug delivery system (nDDS) mediated combinatorial therapy shows great promise in cancer treatment to circumvent the drawbacks of conventional monotherapy. In this study, we reported the development of a supramolecular self-assembly strategy to construct multifunctional nDDS. Cisplatin prodrug (Pt-CD) was successfully loaded onto polydopamine nanoparticles (PDA NPs) through the host-guest supramolecular self-assembly between β-cyclodextrins (β-CD) and adamantyl groups. Two cancer therapeutic modalities, photothermal therapy (PTT) and chemotherapy, were integrated into the as-designed nanoplatform (PDA-Pt NPs) to endow combinatorial anticancer capacity. The excellent photothermal performance and redox responsive cisplatin release behavior of PDA-Pt NPs was fully validated. Moreover, PDA-Pt NPs exhibited photoacoustic imaging capacity for real-time in vivo monitoring of the accumulation of the nanodrug in the tumor site and facilitated the imaging-guided PTT at the optimal treatment window. Ultimately, the combinatorial chemo-photothermal therapy mediated by PDA-Pt NPs exhibited very potent anticancer activity against osteosarcoma 143B cells in vitro and complete ablation of the subcutaneous tumor xenograft in vivo. In conclusion, this study represents an innovative and facile supramolecular self-assembly strategy for fabrication of multifunctional nanotheranostics for efficient combined anticancer therapy, which could further inspire the development of other combinatorial nanotherapeutics.

Nanovaccine‐Based Strategies to Overcome Challenges in the Whole Vaccination Cascade for Tumor Immunotherapy

Nanovaccine-based immunotherapy (NBI) has received greater attention recently for its potential to prime tumor-specific immunity and establish a long-term immune memory that prevents tumor recurrence. Despite encouraging results in the recent studies, there are still numerous challenges to be tackled for eliciting potent antitumor immunity using NBI strategies. Based on the principles that govern immune response, here it is proposed that these challenges need to be addressed at the five critical cascading events: Loading tumor-specific antigens by nanoscale drug delivery systems (L); Draining tumor antigens to lymph nodes (D); Internalization by dendritic cells (DCs) (I); Maturation of DCs by costimulatory signaling (M); and Presenting tumor-peptide-major histocompatibility complexes to T cells (P) (LDIMP cascade in short). This review provides a detailed and objective overview of emerging NBI strategies to improve the efficacy of nanovaccines in each step of the LDIMP cascade. It is concluded that the balance between each step must be optimized by delicate designing and modification of nanovaccines and by combining with complementary approaches to provide a synergistic immunity in the fight against cancer.

Active Targeting Nanoparticle Self‐Assembled from Cisplatin‐Palbociclib Amphiphiles Ensures Optimal Drug Ratio for Combinatorial Chemotherapy

AbstractTriple negative breast cancer (TNBC) not only exhibits aggressive progression and metastasis, but also responds to neither hormone therapy nor checkpoint blockade therapy. Thus, combinatorial chemotherapy is indispensable for TNBC treatment. However, due to the different pharmacokinetics of individual drugs and weak synergistic effects caused by random drug molar ratio in tumor, direct coadministration is far from satisfactory. Constructing a nanoscale drug delivery system with fixed drug molar ratios and maximum drug content is an urgent problem. Herein, an active targeting nanoparticle self‐assembled from cisplatin‐palbociclib amphiphiles with optimal drug ratio is reported. The combination of cisplatin and palbociclib at a molar ratio of 1:2 is found to have the best synergistic effect and is selected for follow‐up studies. After conjugating two palbociclib molecules to one cisplatin molecule, a fixed cisplatin/palbociclib (1:2) molar ratio is enabled and this amphiphilic conjugate can self‐assemble into nanoparticles. A small amount of iRGD coupled 1,2‐distearoyl‐sn‐glycero‐3‐phosphoethanolamine‐N‐polyethylene glycol‐2000 (DSPE‐PEG‐iRGD) that further stabilizes the nanoparticle is introduced to fabricate the desired nanoparticle (iRGD‐PCN) and endow active tumor‐targeting ability. On an orthotopic TNBC mouse model, iRGD‐PCN efficiently accumulates in tumors and inhibits tumor growth. Additionally, the formation of lung metastasis nodes is also significantly suppressed. In general, the active targeting nanoparticles self‐assembled from cisplatin‐palbociclib amphiphiles provide options for combinatorial chemotherapy.

Microparticle formulations alter the toxicity of fenofibrate to the zebrafish Danio rerio embryo.

A wide variety of active pharmaceutical ingredients are released into the environment and pose a threat to aquatic organisms. Drug products using micro- and nanoparticle technology can lower these emissions into the environment by their increased bioavailability to the human patients. However, due to this enhanced efficacy, micro- and nanoscale drug delivery systems can potentially display an even higher toxicity, and thus also pose a risk to non-target organisms. Fenofibrate is a lipid-regulating agent and exhibits species-related hazards in fish. The ecotoxic effects of a fenofibrate formulation embedded into a hydroxypropyl methylcellulose microparticle matrix, as well as those of the excipients used in the formulation process, were evaluated. To compare the effects of fenofibrate without a formulation, fenofibrate was dispersed in diluted ISO water alone or dissolved in the solvent DMF and then added to diluted ISO water. The effects of these various treatments were assessed using the fish embryo toxicity test, acridine orange staining and gene expression analysis assessed by quantitative RT polymerase chain reaction. Exposure concentrations were assessed by chemical analysis. The effect threshold concentrations of fenofibrate microparticle precipitates were higher compared to the formulation. Fenofibrate dispersed in 20%-ISO-water displayed the lowest toxicity. For the fenofibrate formulation as well as for fenofibrate added as a DMF solution, greater ecotoxic effects were observed in the zebrafish embryos. The chemical analysis of the solutions revealed that more fenofibrate was present in the samples with the fenofibrate formulation as well as fenofibrate added as a DMF solution compared to fenofibrate dispersed in diluted ISO water. This could explain the higher ecotoxicity. The toxic effects on the zebrafish embryo thus suggested that the formulation as well as the solvent increased the bioavailability of fenofibrate.

A Brief Review on Advantages of Nano-based Drug Delivery Systems

Context: During the past two decades, the development of drug delivery systems based on nanomaterials has yielded nanocarriers for smart application in nanomedicine to treat diseases. Evidence Acquisition: The current review presents a summary of some advances in the development and application of nano-delivery systems for improving the efficacy of conventional drugs and reducing their adverse effects through the production of smart delivery carriers with targeting moieties and controlled release strategies used in therapy. The searches were conducted in ScienceDirect, Scopus, Google Scholar, and PubMed databases for relevant studies. Results: As reviewed in the present paper, the investigated targeted drug delivery systems have proven to be more effective than free drugs by enhancing efficacy and reducing the systemic toxicity of therapy. In addition, many studies have shown remarkable advantages of nanoscale drug delivery carriers regarding the possibility to improve properties such as solubility, stability, absorption, diffusivity, bioavailability, targeting, and controlled release of drugs. Conclusions: Despite many advantages of nanoscale drug delivery systems reported in the medical literature, deeper research about the composition, synthesis, characteristics, and clinical applications in this area is needed.

Extracellular Vesicle (EV) biohybrid systems for cancer therapy: Recent advances and future perspectives

Extracellular vesicles (EVs) are a class of cell-derived lipid-bilayer membrane vesicles secreted by almost all mammalian cells and involved in intercellular communication by shuttling various biological cargoes. Over the last decade, EVs - namely exosomes and microvesicles - have been extensively explored as next-generation nanoscale drug delivery systems (DDSs). This is in large due to their endogenous origin, which enables EVs to circumvent some of the limitations associated with existing cancer therapy approaches (i.e. by preventing recognition by the immune system and improving selectivity towards tumor tissue). However, successful translation of these cell-derived vesicles into clinical applications has been hindered by several factors, among which the loading of exogenous therapeutic molecules still represents a great challenge. In order to address this issue and to further advance these biologically-derived systems as drug carriers, EV-biohybrid nano-DDSs, obtained through the fusion of EVs with conventional synthetic nano-DDSs, have recently been proposed as a valuable alternative as DDSs. Building on the idea of "combining the best of both worlds", a combination of these two unique entities aims to harness the beneficial properties associated with both EVs and conventional nano-DDSs, while overcoming the flaws of the individual components. These biohybrid systems also provide a unique opportunity for exploitation of new synergisms, often leading to improved therapeutic outcomes, thus paving the way for advancements in cancer therapy. This review aims to describe the recent developments of EV-biohybrid nano-DDSs in cancer therapy, to highlight the most promising results and breakthroughs, as well as to provide a glimpse on the possible intrinsic targeting mechanisms of EVs that can be bequeathed to their hybrid systems. Finally, we also provide some insights in the future perspectives of EV-hybrid DDSs.

Biomimetic Drug Delivery Systems Oriented by Biological Function in Tumor Targeting

The emergence of nanoscale drug delivery systems provides new opportunities for targeting the delivery of chemotherapeutic drugs and has achieved excellent results. In recent years, with the rise in the concept of intelligent drug delivery systems, the design and preparation of carriers have become more and more complicated, which is not conducive to clinical transformation. Researchers are gradually focused on biomimetic nanoscale drug delivery systems, trying to combine the physicochemical properties of nanoscale carriers with the natural biological functions of endogenous substances, so as to boost tumor targeting delivery. In this article, we first classify and introduce biomimetic nanoscale drug delivery systems, and then emphasize their unique biological functions. The biomimetic nanoscale drug delivery systems have the advantages of simple preparation, powerful functions, and low immunogenicity, having a good application prospect.

Out-of-the-Box Nanocapsules Packed with On-Demand Hydrophobic Anticancer Drugs for Lung Targeting, Esterase Triggering, and Synergy Therapy.

Most anticancer drugs, particularly paclitaxel (PTX), are suffering the challenges of cancer chemotherapy due to their poor water-solubility, high toxicity under effective therapeutic dosages, and multi-drug resistance. Currently, nanoscale drug delivery systems (DDSs) represent an efficient platform to overcome the above challenges. However, those DDSs generally need a careful design of conjugation, complexation, or co-self-assembly. Herein, a facile out-of-the-box nanocapsule is developed not only to be easily packed with on-demand hydrophobic anticancer drugs (up to 76% of loading efficiency for PTX), but also to be loaded with other concomitant drugs for synergy therapy (Itraconazole (ITA) here as P-glycoprotein inhibitor for drug resistance and antiangiogenic agent for combination therapy with PTX). Three kinds of biocompatible poly(ethylene glycol) dimethacrylates (PEGDM) derivatives usually as cross-linking agents are selected and successfully constructed adequate nanocapsules with single monomer as shell materials. More importantly, as-prepared nanocapsules have abilities of esterase triggering and lung targeting. Both in vitro and in vivo studies showed that the drug-loaded nanocapsules can effectively inhibit tumor growth and vascular proliferation in PTX-resistant tumor models without apparent systemic toxicity. The above results demonstrate that the nanocapsule system provides an effective and universal strategy for lung targeting, esterase triggering, and synergy therapy.

Polymeric nanoparticles for Anti-cancer treatment-A review of its mechanisms

Nanoscale drug delivery system is one of the best methods because they are capable to enhance the drug accumulation at the site of action, decrease in off-target effects and help to increase the drug delivery in the cancer. The utilization of the drug is better as compared to the other methods. In these days, polymers are being extensively used to increase the bioavailability of drug molecules and to deliver the drug at specific site. Polymers are attached with drugs are administered in the body, so the leading aim of localized drug delivery to the tumor cell by a controlled release of drugs over a long time period. The polymeric nanoparticles have high anti-tumor activity to wipe out the cancer but very minimum toxicity to the other normal cells. In this review we discussed about method of preparation of nanoparticle like Single or double-emulsion-solvent evaporation method, Nanoprecipitation, Emulsification solvent diffusion [ESD] method, Dialysis, Supercritical fluid technique (SCF). Mechanism of action of polymeric nanoparticles made up of PEG, PLGA, HPMA, CHITOSAN, PLA, PCL on cancer cells.

ApoE-Targeting Increases the Transfer of Solid Lipid Nanoparticles with Donepezil Cargo across a Culture Model of the Blood-Brain Barrier.

Pharmacological treatment of central nervous system (CNS) disorders is difficult, because the blood–brain barrier (BBB) restricts the penetration of many drugs into the brain. To solve this unmet therapeutic need, nanosized drug carriers are the focus of research efforts to develop drug delivery systems for the CNS. For the successful delivery of nanoparticles (NPs) to the brain, targeting ligands on their surface is necessary. Our research aim was to design a nanoscale drug delivery system for a more efficient transfer of donepezil, an anticholinergic drug in the therapy of Alzheimer’s disease across the BBB. Rhodamine B-labeled solid lipid nanoparticles with donepezil cargo were prepared and targeted with apolipoprotein E (ApoE), a ligand of BBB receptors. Nanoparticles were characterized by measurement of size, polydispersity index, zeta potential, thermal analysis, Fourier-transform infrared spectroscopy, in vitro release, and stability. Cytotoxicity of nanoparticles were investigated by metabolic assay and impedance-based cell analysis. ApoE-targeting increased the uptake of lipid nanoparticles in cultured brain endothelial cells and neurons. Furthermore, the permeability of ApoE-targeted nanoparticles across a co-culture model of the BBB was also elevated. Our data indicate that ApoE, which binds BBB receptors, can potentially be exploited for successful CNS targeting of solid lipid nanoparticles.

Development of a graphene oxide-poly lactide nanocomposite as a Smart Drug Delivery System

In this study, a nanoscale graphene oxide polymer composite drug delivery system was synthesized and investigated for possible oral delivery of doxorubicin. A doxorubicin-loaded nanocomposite composed of graphene oxide/poly(2-hydroxyethylmethacrylate)-g-poly(lactide)-b-polyethyleneglycol-b-poly(2-hydroxyethylmethacrylate)-g-poly(lactide) GO/(PHEMA-g-PLA)-b-PEG-b-(PHEMA-g-PLA) was synthesized via reversible addition fragmentation chain (RAFT) and ring open polymerization (ROP). The GO/(PHEMA-g-PLA)-b-PEG-b- (PHEMA-g-PLA) nanocomposites was characterized by scanning electron microscopy (FE-SEM), thermogravimetry (TG), ultraviolet-visible (UV–Vis) spectroscopy, and dynamic light scattering (DLS). Doxorubicin was successfully loaded into the nanocomposite with a small particle size of 51 nm and an encapsulation efficiency (EE) of 82% ±1.12%. The results showed that DOX was attached to the graphene surface via hydrophobic interactions and π-π stacking. DOX release took place under neutral and acidic conditions, reaching 24.7% and 41.2% respectively after 72 h. Cytotoxicity experiments on 4T1 murine breast cancer cells demonstrated the antitumor activity of the DOX@GO nanocomposite. Biocompatibility, cell uptake, DAPI staining, Annexin V/PI double staining, intracellular reactive oxygen species (ROS) assay, and scratch healing assay were measured. The DOX@graphene nanocomposite system could be promising for breast cancer therapy.

Patient-Derived Prostate Cancer Explants: A Clinically Relevant Model to Assess siRNA-Based Nanomedicines.

Over the last thirty years, research in nanomedicine has widely been focused on applications in cancer therapeutics. However, despite the plethora of reported nanoscale drug delivery systems that can successfully eradicate solid tumor xenografts in vivo, many of these formulations have not yet achieved clinical translation. This issue particularly pertains to the delivery of small interfering RNA (siRNA), a highly attractive tool for selective gene targeting. One of the likely reasons behind the lack of translation is that current in vivo models fail to recapitulate critical elements of clinical solid tumors that may influence drug response, such as cellular heterogeneity in the tumor microenvironment. This study incorporates a more clinically relevant model for assessing siRNA delivery systems; ex vivo culture of prostate cancer harvested from patients who have undergone radical prostatectomy, denoted patient-derived explants (PDE). The model retains native human tissue architecture, microenvironment, and cell signaling pathways. Porous silicon nanoparticles (pSiNPs) behavior in this model is investigated and compared with commonly used 3D cancer cell spheroids for their efficacy in the delivery of siRNA directed against the androgen receptor (AR), a key driver of prostate cancer.

Nanotools for Sepsis Diagnosis and Treatment.

Sepsis is one of the leading causes of death worldwide with high mortality rates and a pathological complexity hindering early and accurate diagnosis. Today, laboratory culture tests are the epitome of pathogen recognition in sepsis. However, their consistency remains an issue of controversy with false negative results often observed. Clinically used blood markers, C reactive protein (CRP) and procalcitonin (PCT) are indicators of an acute-phase response and thus lack specificity, offering limited diagnostic efficacy. In addition to poor diagnosis, inefficient drug delivery and the increasing prevalence of antibiotic-resistant microorganisms constitute significant barriers in antibiotic stewardship and impede effective therapy. These challenges have prompted the exploration for alternative strategies that pursue accurate diagnosis and effective treatment. Nanomaterials are examined for both diagnostic and therapeutic purposes in sepsis. The nanoparticle (NP)-enabled capture of sepsis causative agents and/or sepsis biomarkers in biofluids can revolutionize sepsis diagnosis. From the therapeutic point of view, currently existing nanoscale drug delivery systems have proven to be excellent allies in targeted therapy, while many other nanotherapeutic applications are envisioned. Herein, the most relevant applications of nanomedicine for the diagnosis, prognosis, and treatment of sepsis is reviewed, providing a critical assessment of their potentiality for clinical translation.

Parallel Multiparameter Study of PEI-Functionalized Gold Nanoparticle Synthesis for Biomedical Applications: Part 2. Elucidating the Role of Surface Chemistry and Polymer Structure in Performance.

Elucidating the polyethyleneimine (PEI) chemistry to predictively and reproducibly synthesize gold nanoparticle (AuNP)-PEI conjugates with desired properties has been elusive despite evaluation in numerous studies and reported enhanced properties. The lack of reproducible methods to control the core size and stability has led to contradictory results for performance and safety; thus, advancement of the conjugate platform for commercial use has likely been hindered. Recently, we reported a robust, reproducible method for synthesizing PEI-functionalized AuNPs (Au-PEIs), providing an opportunity to investigate structure-function relationships and to further investigate synthesis parameters affecting performance, where only materials stable in biological media are candidates for use. The properties of Au-PEIs prepared by the optimized reduction of HAuCl4 using four different structural variants of PEI changed significantly with the PEI molar mass and backbone form (branched or linear). In the present study using our previously reported synthesis procedure, comprehensive analysis of properties such as size distribution, surface plasmon resonance (SPR), morphological state, surface functionality, and the shelf life has been systematically evaluated to elucidate the role of surface chemistry and reactive groups involved in conjugation, as a function of conjugate size and morphology. Being important for commercial adoption, the chemistry was related to the observed colloidal stability of the product in relevant media, including exposure to physiological variables such as salt, pH, proteins, and thermal changes. Overall, this work advances progress toward smart design of engineered nanoscale drug delivery systems and devices by providing unreported details of contributions affecting formation, stability, and fate.

Cargo Exosomes a Key Platform in Emerging Nanoscale Drug Delivery System

Cargo Exosomes a Key Platform in Emerging Nanoscale Drug Delivery System

Nanotechnology for the Treatment of Allergic Conjunctival Diseases.

Allergic conjunctivitis is one of the most common external eye diseases and the prevalence has been increasing. The mainstay of treatment is topical eye drops. However, low bioavailability, low ocular drug penetration, transient resident time on the ocular surface due to tear turnover, frequent topical applications and dependence on patient compliance, are the main drawbacks associated with topical administration. Nanotechnology-based medicine has emerged to circumvent these limitations, by encapsulating the drugs and preventing them from degradation and therefore providing sustained and controlled release. Using a nanotechnology-based approach to load the drug is particularly useful for the delivery of hydrophobic drugs such as immunomodulatory agents, which are commonly used in allergic conjunctival diseases. In this review, different nanotechnology-based drug delivery systems, including nanoemulsions, liposomes, nanomicelles, nanosuspension, polymeric and lipid nanoparticles, and their potential ophthalmic applications, as well as advantages and disadvantages, are discussed. We also summarize the results of present studies on the loading of immunomodulators or nonsteroidal anti-inflammatory drugs to nano-scaled drug delivery systems. For future potential clinical use, research should focus on the optimization of drug delivery designs that provide adequate and effective doses with safe and satisfactory pharmacokinetic and pharmaco-toxic profiles.

Fluorescent Dye Labeling Changes the Biodistribution of Tumor-Targeted Nanoparticles.

Fluorescent dye labeling is a common strategy to analyze the fate of administered nanoparticles in living organisms. However, to which extent the labeling processes can alter the original nanoparticle biodistribution has been so far neglected. In this work, two widely used fluorescent dye molecules, namely, ATTO488 (ATTO) and Sulfo-Cy5 (S-Cy5), have been covalently attached to a well-characterized CXCR4-targeted self-assembling protein nanoparticle (known as T22-GFP-H6). The biodistribution of labeled T22-GFP-H6-ATTO and T22-GFP-H6-S-Cy5 nanoparticles has been then compared to that of the non-labeled nanoparticle in different CXCR4+ tumor mouse models. We observed that while parental T22-GFP-H6 nanoparticles accumulated mostly and specifically in CXCR4+ tumor cells, labeled T22-GFP-H6-ATTO and T22-GFP-H6-S-Cy5 nanoparticles showed a dramatic change in the biodistribution pattern, accumulating in non-target organs such as liver or kidney while reducing tumor targeting capacity. Therefore, the use of such labeling molecules should be avoided in target and non-target tissue uptake studies during the design and development of targeted nanoscale drug delivery systems, since their effect over the fate of the nanomaterial can lead to considerable miss-interpretations of the actual nanoparticle biodistribution.