Targeted Nano-drug Delivery System Research Articles

Lyophilized Iron Oxide Nanoparticles Encapsulated in Amphotericin B: A Novel Targeted Nano Drug Delivery System for the Treatment of Systemic Fungal Infections.

We formulated and tested a targeted nanodrug delivery system to help treat life-threatening invasive fungal infections, such as cryptococcal meningitis. Various designs of iron oxide nanoparticles (IONP) (34–40 nm) coated with bovine serum albumin and coated and targeted with amphotericin B (AMB-IONP), were formulated by applying a layer-by-layer approach. The nanoparticles were monodispersed and spherical in shape, and the lead formulation was found to be in an optimum range for nanomedicine with size (≤36 nm), zeta potential (−20 mV), and poly dispersity index (≤0.2), and the drug loading was 13.6 ± 6.9 µg of AMB/mg of IONP. The drug release profile indicated a burst release of up to 3 h, followed by a sustained drug release of up to 72 h. The lead showed a time-dependent cellular uptake in C. albicans and C. glabrata clinical isolates, and exhibited an improved efficacy (16–25-fold) over a marketed conventional AMB-deoxycholate product in susceptibility testing. Intracellular trafficking of AMB-IONP by TEM and confocal laser scanning microscopy confirmed the successful delivery of the AMB payload at and/or inside the fungal cells leading to potential therapeutic advantages over the AMB-deoxycholate product. A short-term stability study at 5 °C and 25 °C for up to two months showed that the lyophilized form was stable.

Extracellular matrix-penetrating nanodrill micelles for liver fibrosis therapy

As hepatic stellate cells (HSCs) are essential for hepatic fibrogenesis, HSCs targeted nano-drug delivery system is a research hotspot in liver fibrosis therapy. However, the excessive deposition of fibrosis collagen (mainly collagen I) in the space of Disse associated with hepatic fibrogenesis would significantly hinder nano-formulation delivery to HSCs. Here, we have prepared a collagenase I and retinol co-decorated polymeric micelle that possess nanodrill-like and HSCs-target function based on poly-(lactic-co-glycolic)-b-poly (ethylene glycol)-maleimide (PLGA-PEG-Mal) (named CRM) for liver fibrosis therapy. Upon encountering collagen I barrier, CRM exerted a nanodrill-like function, efficiently degrading pericellular collagen I and showing greater uptake by human HSCs than other micelle formulations. Besides, CRM could realize excellent accumulation in the fibrotic liver and accurate targeting to activated HSCs in mouse hepatic fibrosis model. Moreover, CRM loaded with nilotinib (CRM/NIL), a second-generation tyrosine kinase inhibitor used in the treatment of liver fibrosis, showed optimal antifibrotic activity. This work suggests that CRM with dual function is an efficient carrier for liver fibrosis drug delivery and collagenase I decorating could be a new strategy for building more efficient HSCs targeted nano-drug delivery system.

HPA aptamer functionalized paclitaxel-loaded PLGA nanoparticles for enhanced anticancer therapy through targeted effects and microenvironment modulation

Breast cancer is a fairly common cancer with high mortality in women worldwide. Targeted nano-drug delivery system for breast cancer treatment has achieved encouraging results, because of increased drug concentration at the tumor site, thereby improving biocompatibility and blood half-life while reducing chemoresistance. However, the absence of available target on cancer cells is one of the major obstacles for triple-negative breast cancer (TNBC). Increasing studies have shown that heparanase (HPA) is highly expressed in many cancers, including TNBC. Thus paclitaxel(PTX) -encapsulated PEGylated PLGA nanoparticles were developed and further surface-functionalized with the HPA aptamers (Apt(S1.5)-PTX-NP). Moreover, targeting and cytotoxicity of Apt(S1.5)-PTX-NP to TNBC cells were evaluated with MDA-MB-231 as a model. These nanoparticles bonded to the HPA overexpressed on the surface of TNBC cells and were taken up by these cells, resulting in remarkably enhanced cellular toxicity compared with non-targeted PTX-NP that lack the HPA aptamer (P < 0.01). Furthermore, Apt(S1.5)-PTX-NP significantly exhibited enhanced anti-invasive and superior anti-angiogenesis activity compared with those of other experiment groups at low administration dosage. The Apt(S1.5)-PTX-NP demonstrated the most dramatic efficacy with the final mean tumor sizes of 157.30 ± 41.09 mm3 (mean ± SD; n = 10) in vivo treatment. Thus, the present study indicated that HPA is a promising target for drug delivery to TNBC cells, and nanoparticle-HPA-aptamer bioconjugates can provide new insights for TNBC treatment.

Development of Zwitterionic Polypeptide Nanoformulation with High Doxorubicin Loading Content for Targeted Drug Delivery.

Much attention has been drawn to targeted nanodrug delivery systems due to their high therapeutic efficacy in cancer treatment. In this work, doxorubicin (DOX) was incorporated into a zwitterionic arginyl-glycyl-aspartic acid (RGD)-conjugated polypeptide by an emulsion solvent evaporation technique with high drug loading content (45%) and high drug loading efficiency (95%). This zwitterionic nanoformulation showed excellent colloidal stability at high dilution and in serum. The pH-induced disintegration and enzyme-induced degradation of the nanoformulation were confirmed by dynamic light scattering and gel permeation chromatography. Efficient internalization of DOX in the cells and high antitumor activity in vitro was observed. Compared with the free drug, this nanoformulation showed higher accumulation in tumor and lower systemic toxicity in vivo. The DOX-loaded zwitterionic RGD-conjugated polypeptide vesicles show potential application for targeted drug delivery in the clinic.

Transporter-Guided Delivery of Nanoparticles to Improve Drug Permeation across Cellular Barriers and Drug Exposure to Selective Cell Types.

Targeted nano-drug delivery systems conjugated with specific ligands to target selective cell-surface receptors or transporters could enhance the efficacy of drug delivery and therapy. Transporters are expressed differentially on the cell-surface of different cell types, and also specific transporters are expressed at higher than normal levels in selective cell types under pathological conditions. They also play a key role in intestinal absorption, delivery via non-oral routes (e.g., pulmonary route and nasal route), and transfer across biological barriers (e.g., blood–brain barrier and blood–retinal barrier. As such, the cell-surface transporters represent ideal targets for nano-drug delivery systems to facilitate drug delivery to selective cell types under normal or pathological conditions and also to avoid off-target adverse side effects of the drugs. There is increasing evidence in recent years supporting the utility of cell-surface transporters in the field of nano-drug delivery to increase oral bioavailability, to improve transfer across the blood–brain barrier, and to enhance delivery of therapeutics in a cell-type selective manner in disease states. Here we provide a comprehensive review of recent advancements in this interesting and important area. We also highlight certain key aspects that need to be taken into account for optimal development of transporter-assisted nano-drug delivery systems.

Folic acid armed Fe3O4-HPG nanoparticles as a safe nano vehicle for biomedical theranostics

Abstract Targeted nano drug delivery systems can be considered as in vivo tiny physicians that can accurately detect the disease location and prescribe drugs at the same time. In some cases, these skilled doctors are equipped with diagnostic agents that can monitor the treatment process. These nano-robots are known as nanotheranostic agents. The aim of this study is to inset folic acid armed polymeric core–shell iron oxide nanoparticles as a new type of nanotheranostic agent. Here, iron oxide nanoparticles were synthesized by polyol method and coated with hyperbranched polyglycerol. Different in vitro tests (cell viability and hemocompatibility) were conducted on the nanoparticles to evaluate their biocompatibility. Then they were decorated with folic acid as targeting agents and examined with different in vitro test to detect the influence of targeting on cell uptake properties. Results represented that this new type of nano-robot with size around 11 nanometer was biocompatible and had a positive effect on cellular uptake of nanoparticles. Thus, these nanoparticles could be used as potentially useful nanotheranostic systems to defeat cancer cells with high folate expression.

Development of novel pH-sensitive thiolated chitosan/PMLA nanoparticles for amoxicillin delivery to treat Helicobacter pylori

The cysteine conjugated chitosan/PMLA multifunctional nanoparticles were synthesized as targeted Nano-drug delivery system to eradicate Helicobacter pylori. Helicobacter pylori specifically express urea transport protein on its membrane to carrying urea to the cytoplasm urease to supply ammonia that protects bacteria in the acid environment of the stomach. The clinical suitability of topical antimicrobial agents is required to get rid of Helicobacter pylori inside the inflamed basal region. In this work, cysteine conjugated chitosan derivative, Cys-CS for their mucoadhesive and anticoagulant properties was designed and synthesized, for the preparation of multifunctional nanoparticles. The technique turned into optimized to prepare Cys-CS/PMLA nanoparticles for encapsulation of amoxicillin. The results showed that amoxicillin-Cys-CS/PMLA nanoparticles exhibit favorable pH-sensitive properties that could procrastinate the release of amoxicillin at gastric acid and allow the drug to deliver and target to Helicobacter pylori at its survival region efficiently. In comparison with unmodified amoxicillin-chitosan/PMLA nanoparticles, effective inhibition of Helicobacter pylori growth was observed for amoxicillin-Cys-CS/PMLA nanoparticles. These results indicate that the multifunctional amoxicillin-loaded nanoparticles have great potential for the effective treatment of Helicobacter pylori infection. They can also be used as pharmacologically powerful nanocarriers for oral targeted delivery of different therapeutic drugs to treat Helicobacter pylori.

Targeted drug distribution in tumor extracellular fluid of GD2-expressing neuroblastoma patient-derived xenografts using SN-38-loaded nanoparticles conjugated to the monoclonal antibody 3F8

Neuroblastoma is a pediatric solid tumor with high expression of the tumor associated antigen disialoganglioside GD2. Despite initial response to induction therapy, nearly 50% of high-risk neuroblastomas recur because of chemoresistance. Here we encapsulated the topoisomerase-I inhibitor SN-38 in polymeric nanoparticles (NPs) surface-decorated with the anti-GD2 mouse mAb 3F8 at a mean density of seven antibody molecules per NP. The accumulation of drug-loaded NPs targeted with 3F8 versus with control antibody was monitored by microdialysis in patient-derived GD2-expressing neuroblastoma xenografts. We showed that the extent of tumor penetration by SN-38 was significantly higher in mice receiving the targeted nano-drug delivery system when compared to non-targeted system or free drug. This selective penetration of the tumor extracellular fluid translated into a strong anti-tumor effect prolonging survival of mice bearing GD2-high neuroblastomas in vivo.

PH-sensitive pHLIP® coated niosomes.

Nanomedicine is becoming very popular over conventional methods due to the ability to tune physico-chemical properties of nano vectors, which are used for encapsulation of therapeutic and diagnostic agents. However, the success of nanomedicine primarily relies on how specifically and efficiently nanocarriers can target pathological sites to minimize undesirable side effects and enhance therapeutic efficacy. Here, we introduce a novel class of targeted nano drug delivery system, which can be used as an effective nano-theranostic for cancer. We formulated pH-sensitive niosomes (80-90 nm in diameter) using nonionic surfactants Span20 (43-45 mol%), cholesterol (50 mol%) and 5 mol% of pH (Low) insertion peptide (pHLIP) conjugated with DSPE lipids (DSPE-pHLIP) or hydrophobic fluorescent dye, pyrene, (Pyr-pHLIP). In coating of niosomes, pHLIP was used as an acidity sensitive targeting moiety. We have demonstrated that pHLIP coated niosomes sense the extracellular acidity of cancerous cells. Intravenous injection of fluorescently labeled (R18) pHLIP-coated niosomes into mice bearing tumors showed significant accumulation in tumors with minimal targeting of kidney, liver and muscles. Tumor-targeting niosomes coated with pHLIP exhibited 2-3 times higher tumor uptake compared to the non-targeted niosomes coated with PEG polymer. Long circulation time and uniform bio-distribution throughout the entire tumor make pHLIP-coated niosomes to be an attractive novel delivery system.

Neutrophil targeted nano-drug delivery system for chronic obstructive lung diseases

The success of drug delivery to target airway cell(s) remains a significant challenge due to the limited ability of nanoparticle (NP) systems to circumvent protective airway-defense mechanisms. The size, density, surface and physical–chemical properties of nanoparticles are the key features that determine their ability to navigate across the airway-barrier. We evaluated here the efficacy of a PEGylated immuno-conjugated PLGA-nanoparticle (PINP) to overcome this challenge and selectively deliver drug to specific inflammatory cells (neutrophils). We first characterized the size, shape, surface-properties and neutrophil targeting using dynamic laser scattering, transmission electron microscopy and flow cytometry. Next, we assessed the efficacy of neutrophil-targeted PINPs in transporting through the airway followed by specific binding and release of drug to neutrophils. Finally, our results demonstrate the efficacy of PINP mediated non-steroidal anti-inflammatory drug‐(ibuprofen) delivery to neutrophils in murine models of obstructive lung diseases, based on its ability to control neutrophilic-inflammation and resulting lung disease.

Preparation and characterization of anti-HIV nanodrug targeted to microfold cell of gut-associated lymphoid tissue.

The human immunodeficiency virus 1 (HIV-1) still remains one of the leading life-threatening diseases in the world. The introduction of highly active antiretroviral therapy has significantly reduced disease morbidity and mortality. However, most of the drugs have variable penetrance into viral reservoir sites, including gut-associated lymphoid tissue (GALT). Being the largest lymphoid organ, GALT plays a key role in early HIV infection and host–pathogen interaction. Many different treatment options have been proposed to eradicate the virus from GALT. However, it becomes difficult to deliver traditional drugs to the GALT because of its complex physiology. In this regard, we developed a polymer-based Pluronic nanocarrier containing anti-HIV drug called efavirenz (EFV) targeting Microfold cells (M-cells) in the GALT. M-cells are specialized epithelial cells that are predominantly present in the GALT. In this work, we have exploited this paracellular transport property of M-cells for targeted delivery of Pluronic nanocarrier tagged EFV, bioconjugated with anti-M-cell-specific antibodies to the GALT (nanodrug). Preliminary characterization showed that the nanodrug (EFV-F12-COOH) is of 140 nm size with 0.3 polydispersion index, and the zeta potential of the particles was −19.38±2.2 mV. Further, drug dissolution study has shown a significantly improved sustained release over free drugs. Binding potential of nanodrug with M-cell was also confirmed with fluorescence microscopy and in vitro uptake and release studies. The anti-HIV activity of the nanodrug was also significantly higher compared to that of free drug. This novel formulation was able to show sustained release of EFV and inhibit the HIV-1 infection in the GALT compared to the free drug. The present study has potential for our in vivo targeted nanodrug delivery system by combining traditional enteric-coated capsule technique via oral administration.

Recent Advances and Strategies in Tumor Vasculature Targeted Nano-Drug Delivery Systems.

In recent decades, targeted nano-drug delivery systems have attracted extensive attention in cancer therapy for their efficient drug delivery and tumor site specificity. Tumor vasculature, including angiogenesis and vasculogenic mimicry is associated tightly with tumor growth, progression and metastasis. Therefore, nano-drug delivery systems targeting tumor vasculature are becoming a promising approach for tumor treatment. As complicated mechanisms and various factors are involved in the tumor vasculature, different ligands modified on the surface of nanocarriers acquire active targeting through binding to the receptors over-expressed by cancer cells or angiogenic endothelial cells. In this review, the tumor vasculature characteristics are briefly described and the recent advances and potential strategies in tumor vasculature targeted nano-drug delivery systems are introduced.

Synergistic effect of pH-responsive folate-functionalized poloxamer 407-TPGS-mixed micelles on targeted delivery of anticancer drugs.

BackgroundDoxorubicin (DOX), an anthracycline anticancer antibiotic, is used for treating various types of cancers. However, its use is associated with toxicity to normal cells and development of resistance due to overexpression of drug efflux pumps. Poloxamer 407 (P407) and vitamin E TPGS (D-α-tocopheryl polyethylene glycol succinate, TPGS) are widely used polymers as drug delivery carriers and excipients for enhancing the drug retention times and stability. TPGS reduces multidrug resistance, induces apoptosis, and shows selective anticancer activity against tumor cells. Keeping in view the problems, we designed a mixed micelle system encapsulating DOX comprising TPGS for its selective anticancer activity and P407 conjugated with folic acid (FA) for folate-mediated receptor targeting to cancer cells.MethodsFA-functionalized P407 was prepared by carbodiimide crosslinker chemistry. P407-TPGS/FA-P407-TPGS-mixed micelles were prepared by thin-film hydration method. Cytotoxicity of blank micelles, DOX, and DOX-loaded micelles was determined by alamarBlue® assay.ResultsThe size of micelles was less than 200 nm with encapsulation efficiency of 85% and 73% for P407-TPGS and FA-P407-TPGS micelles, respectively. Intracellular trafficking study using nile red-loaded micelles indicated improved drug uptake and perinuclear drug localization. The micelles show minimal toxicity to normal human cell line WRL-68, enhanced cellular uptake of DOX, reduced drug efflux, increased DOX–DNA binding in SKOV3 and DOX-resistant SKOV3 human ovarian carcinoma cell lines, and enhanced in vitro cytotoxicity as compared to free DOX.ConclusionFA-P407-TPGS-DOX micelles show potential as a targeted nano-drug delivery system for DOX due to their multiple synergistic factors of selective anticancer activity, inhibition of multidrug resistance, and folate-mediated selective uptake.

Multistep Targeted Nano Drug Delivery System Aiming at Leukemic Stem Cells and Minimal Residual Disease

Refractory leukemia remains the most common therapeutic problem in clinical treatment of leukemia. The key therapy of refractory leukemia is to kill, thoroughly, the minimal residual disease and leukemia stem cells in the highly vascularized red marrow areas. In this study, two new conjugates, alendronate-polyethylene glycol (100) monostearate and folate-polyethylene glycol (100) monostearate, were synthesized to develop a multistep targeting nanostructured lipid carriers by enhancing drug transport to the high bone turnover areas adjacent to the red marrow and targeting the minimal residual disease and leukemia stem cells. This dual targeting system demonstrated a great binding affinity to hydroxyapatite, a model component of bone minerals, and higher cell uptake (in the form of carriers but not drug) and cytotoxicity in the K562 cell line, a leukemia cell line with overexpressed folate receptors, were observed in vitro compared to unmodified carriers, especially when the cells were pretreated and the receptors were up-regulated by all-trans retinoic acid. The comodel test of K562 cells and HA showed that this dual targeting system could desorb from bone surface and be taken up by leukemia cells. For the in vivo study, this dual targeting system exhibited a significant increase in plasma half-life and could specifically accumulate in the bone tissue of rats or mice after intravenous injection. Ex vivo imaging of mice femurs and confocal laser scanning microscope imaging of mice femur slices further confirmed that this dual targeting system could favorably deposit to the osteoblast-enriched areas of high bone turnover in regions of trabecular bone surrounded by red marrow. In vivo antitumor activity in K562/BALB/c-nu leukemia mice showed that the treatment of this dual targeting system significantly reduced the white blood cell (WBC) number in peripheral blood and bone marrow to the normal level. In conclusion, this dual targeting system could precisely target to the regions where the minimal residual disease and leukemia stem cells are located and then be specifically uptaken in large amounts, which is a valuable target for refractory leukemia therapy.

Targeted nanodrug delivery systems for the treatment of tuberculosis

References Acknowledgements Yolandy Lemmer1,3, Boitumelo Semete1, Laetitia Booysen 1,2, Lonji Kalombo1, Lebogang Katata1, Arwyn T. Jones4,Cameron Alexander5, Makobetsa Khati6, Hulda. S. Swai1, Jan A. Verschoor3 1Council for Scientific and Industrial Research, Polymers and Bioceramics, Pretoria, 0001, South Africa, 2Department of Pharmaceutics, North-West University, Potchefstroom Campus, Potchefstroom, 2520, South Africa, 3Department of Biochemistry, University of Pretoria, Pretoria, 0001, South Africa, 4Welsh School of pharmacy, Cardiff University, United Kingdom, 5School of Pharmacy, University of Nottingham, UK, 6Council for Scientific and Industrial Research, Biosciences, Pretoria, 0001, South Africa