Nanoparticle oral absorption and its clinical translational potential.

Oral administration of pharmaceuticals is the most preferred route of administration for patients, but it is challenging to effectively deliver active ingredients (APIs) that i) have extremely high or low solubility in intestinal fluids, ii) are large in size, iii) are subject to digestive and/or metabolic enzymes present in the gastrointestinal tract (GIT), brush border, and liver, and iv) are P-glycoprotein substrates. Over the past decades, efforts to increase the oral bioavailability of APIs have led to the development of nanoparticles (NPs) with non-specific uptake pathways (M cells, mucosal, and tight junctions) and target-specific uptake pathways (FcRn, vitamin B12, and bile acids). However, voluminous findings from preclinical models of different species rarely meet practical standards when translated to humans, and API concentrations in NPs are not within the adequate therapeutic window.

Effect of modification of polystyrene nanoparticles with different bile acids on their oral transport.

Bile acid-modified nanomedicine is a promising strategy to improve oral bioavailability. However, the efficiencies of different bile acids have not been clarified. To clarify this issue, deoxycholic acid (DCA) and cholic acid (CA) and glycocholic acid (GCA) were conjugated to carboxylated polystyrene nanoparticle (CPN).

The tumor EPR effect for cancer drug delivery: Current status, limitations, and alternatives.

Over the past three decades, the enhanced permeability and retention (EPR) effect has been considered the basis of tumor-targeted drug delivery. Various cancer nanomedicines, including macromolecular drugs, have been designed to utilize this mechanism for preferential extravasation and accumulation in solid tumors. However, such nanomedicines have not yet achieved convincing therapeutic benefits in clinics.

Ovalbumin and Poly(i:c) Encapsulated Dendritic Cell-Targeted Nanoparticles for Immune Activation in the Small Intestinal Lymphatic System.

Here, antigen and adjuvant encapsulated dendritic cell-targeted nanoparticles for immune activation in the small intestinal lymphatic system to inhibit melanoma development are described. This strategy is demonstrated using chondroitin sulfate-coated nanoparticles (OPGMN) grafted with glycocholic acid and mannose for cationic liposomes encapsulated with ovalbumin as an antigen and polyinosine-polycytidylic acid as a cancer-specific adjuvant. OPGMN is absorbed in the gastrointestinal tract and delivered to the lymph nodes when orally administered.

Bile Acid Conjugation on Solid Nanoparticles Enhances ASBT-Mediated Endocytosis and Chylomicron Pathway but Weakens the Transcytosis by Inducing Transport Flow in a Cellular Negative Feedback Loop.

Bile acid-modified nanoparticles provide a convenient strategy to improve oral bioavailability of poorly permeable drugs by exploiting specific interactions with bile acid transporters. However, the underlying mechanisms are unknown, especially considering the different absorption sites of free bile acids (ileum) and digested fat molecules from bile acid-emulsified fat droplets (duodenum). Here, glycocholic acid (GCA)-conjugated polystyrene nanoparticles (GCPNs) are synthesized and their transport in Caco-2 cell models is studied.

Lipid raft-mediated and upregulated coordination pathways assist transport of glycocholic acid-modified nanoparticle in a human breast cancer cell line of SK-BR-3.

Bile acid transporter-targeting has been proven to be an effective strategy to improve drug delivery to hepatocytes and enterocytes. With increasing discoveries of bile acid transporter expression on tumor cells, bile acid-modified anticancer drugs are gradually attaining interests. In our previous study, we confirmed the efficacy of glycocholic acid-conjugated polystyrene nanoparticles (GCPN) on apical sodium bile acid transporter (ASBT)-expressed SK-BR-3 cells.

Selected Factors Affecting Oral Bioavailability of Nanoparticles Surface-Conjugated with Glycocholic Acid Intestinal Lymphatic Pathway.

Here, we describe the absorption pathways of nanoparticles whose surface is modified with bile acid and present environmental factors that influence oral bioavailability (BA) from the gastrointestinal tract (GIT). The approach utilized 100 nm sized fluorescence-labeled, carboxylated polystyrene nanoparticles (CPN) conjugated with glycocholic acid (G/CPN) to exclude potential artifacts, if existing, and instability issues in evaluating the transit of G/CPN in the GIT and measuring BA. The study using SK-BR-3 that expresses the apical sodium bile acid transporter showed that once G/CPN is internalized, it stayed 2.

Bile acid transporter-mediated oral drug delivery.

Bile acids are synthesized in the liver, stored in the gallbladder, and secreted into the duodenum at meals. Apical sodium-dependent bile acid transporter (ASBT), an ileal Na-dependent transporter, plays the leading role of bile acid absorption into enterocytes, where bile acids are delivered to basolateral side by ileal bile acid binding protein (IBABP) and then released by organic solute transporter OSTα/β. The absorbed bile acids are delivered to the liver via portal vein.

Advanced drug delivery 2020 and beyond: Perspectives on the future.

Drug delivery systems are developed to maximize drug efficacy and minimize side effects. As drug delivery technologies improve, the drug becomes safer and more comfortable for patients to use. During the last seven decades, extraordinary progress has been made in drug delivery technologies, such as systems for long-term delivery for months and years, localized delivery, and targeted delivery.

Multifunctional oral delivery systems for enhanced bioavailability of therapeutic peptides/proteins.

In last few years, therapeutic peptides/proteins are rapidly growing in drug market considering their higher efficiency and lower toxicity than chemical drugs. However, the administration of therapeutic peptides/proteins is mainly limited in parenteral approach. Oral therapy which was hampered by harsh gastrointestinal environment and poorly penetrating epithelial barriers often results in low bioavailability (less than 1%-2%).

Immune-triggered cancer treatment by intestinal lymphatic delivery of docetaxel-loaded nanoparticle.

The maximally tolerated dose (MTD) approach in conventional chemotherapy accompanies adverse effects, primarily due to high drug concentrations in the blood after intravenous administration and non-specific damages to highly proliferating cells, including immune cells. This causes the immune system to dysfunction. To rather boost intrinsic tumor-fighting immune capacity, we demonstrate a new oral route treatment regimen of docetaxel (DTX) without apparent toxicity.

Long-term oral administration of Exendin-4 to control type 2 diabetes in a rat model.

Exendin-4 is a glucagon-like peptide-1 (GLP-1) receptor agonist and potent insulinotropic agent for type 2 diabetes patients; however, its therapeutic utility is limited due to the frequent injections required. Long-acting agonists reduce the number of injections, but they can compromise potency. In this study, chondroitin sulfate-g-glycocholic acid-coated and Exendin-4 (Ex-4)-loaded liposomes (EL-CSG) were prepared for oral administration of Ex-4.

Immense Insulin Intestinal Uptake and Lymphatic Transport Using Bile Acid Conjugated Partially Uncapped Liposome.

We provide immense insulin absorption from the gastrointestinal tract, combining apical sodium-dependent bile acid transporter-mediated intestinal uptake and the lymphatic transport pathway. This strategy has proven to employ chondroitin sulfate- g-taurocholic acid coated, insulin-loaded partially uncapped liposome (IPUL-CST) for type 1 diabetes mellitus (T1DM) treatment. The loading efficiency of insulin in IPUL-CST increased significantly from 33% to 75% via the partially uncapped liposome preparation method.

Oral Nanoparticles Exhibit Specific High-Efficiency Intestinal Uptake and Lymphatic Transport.

Herein, we describe a simple and promising nanoparticle oral delivery phenomenon and propose pathways for oral nanoparticle absorption from the gastrointestinal tract (GIT), combining apical sodium-dependent bile acid transporter-mediated cellular uptake and chylomicron transport pathways. This strategy is proven to employ bile-acid-conjugated, solid fluorescent probe nanoparticles (100 nm diameter) to exclude any potential artifacts and instability issues in observing transport pathways and measuring oral bioavailability. The results of the in vitro studies showed that there is no interference from bile acid and no simultaneous uptake of nanoparticles and dextran.

Perspectives on the past, present, and future of cancer nanomedicine.

The justification of cancer nanomedicine relies on enhanced permeation (EP) and retention (R) effect and the capability of intracellular targeting due primarily to size after internalization (endocytosis) into the individual target cells. The EPR effect implies improved efficacy. Affinity targeting for solid tumors only occur after delivery to individual cells, which help internalization and/or retention.

Oral delivery of a therapeutic gene encoding glucagon-like peptide 1 to treat high fat diet-induced diabetes.

The number of people suffering from insulin-independent type 2 diabetes mellitus (T2DM) is ever increasing on a yearly basis. Current anti-diabetic medications often result in adverse weight gain and hypoglycemic episodes. Hypoglycemia can be avoided with glucagon-like peptide (GLP)-1 receptor agonists, which are expensive and require daily injections that may result immune activation.

Nano-sized drug carriers: Extravasation, intratumoral distribution, and their modeling.

Navigating intratumoral drug distribution has proven to be one of the most challenging aspects of drug delivery. The barriers are significant and varied; increased diffusional distances, elevated interstitial fluid pressure, regions of dense extracellular matrix and high cell density, and overall heterogeneity. Such a long list imposes significant requirements on nano-sized carriers.

Nanomedicine-based combination anticancer therapy between nucleic acids and small-molecular drugs.

Anticancer therapy has always been a vital challenge for the development of nanomedicine. Repeated single therapeutic agent may lead to undesirable and severe side effects, unbearable toxicity and multidrug resistance due to complex nature of tumor. Nanomedicine-based combination anticancer therapy can synergistically improve antitumor outcomes through multiple-target therapy, decreasing the dose of each therapeutic agent and reducing side effects.

Tempo-spatial Activation of Sequential Quadruple Stimuli for High Gene Expression of Polymeric Gene Nanocomplexes.

The clinical application of intracellular gene delivery via nanosized carriers is hindered by intracellular multistep barriers that limit high levels of gene expression. To solve these issues, four different intracellular or external stimuli that can efficiently activate a gene carrier, a gene, or a photosensitizer (pheophorbide A [PhA]) were assessed in this study. The designed nanosized polymeric gene complexes were composed of PhA-loaded thiol-degradable polycation (PhA@RPC) and cytomegalovirus (CMV) promoter-equipped pDNA.

Systemic siRNA Delivery with a Dual pH-Responsive and Tumor-targeted Nanovector for Inhibiting Tumor Growth and Spontaneous Metastasis in Orthotopic Murine Model of Breast Carcinoma.

Phenylboronic acid (PBA)-mediated tumor targeting nanovector is an attractive strategy for enhancing siRNA delivery and treatment of metastatic cancers. However, its nonspecific binding with various biological membranes containing -diol moieties restricts its potential application by systematic administration. Herein, we constructed a novel pH-activated "sheddable" PEG-coated nanoparticle for effective treatment of primary tumors and metastases, which was based on the conjugation of catechol group modified poly(ethylene glycol) (PEG-Cat) and PBA-terminated polyethylenimine (PEI-PBA) via the borate ester formed between PBA and Cat.

Enhanced cell survival of pH-sensitive bioenergetic nucleotide nanoparticles in energy/oxygen-depleted cells and their intranasal delivery for reduced brain infarction.

Unlabelled: Nucleotides (NTs) (e.g., adenosine triphosphate) are very important molecules in the body.

Evaluation of drug penetration with cationic micelles and their penetration mechanism using an in vitro tumor model.

Elevated interstitial fluid pressure (IFP) and abnormal extracellular matrix (ECM) are major factors causing significant barriers to penetration of nanomedicines in solid tumors. To better understand the barriers, various in vitro tumor models including multicellular spheroids and multilayered cell cultures (MCCs) have been developing. Recently, we have established a unique in vitro tumor model composed of a MCC and an Ussing chamber system which is modified to add a hydraulic pressure gradient through the MCC.