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Nowadays, the use of unfractionated low molecular weight heparins through intravenous and subcutaneous routes has been limited by several delivery challenges. These include pharmacological activity fluctuations, bleeding issues, and numerous manufacturing restrictions. To address these issues, several efforts have been taken to find alternative routes for this medication. Unfortunately, the past and recent reviews were mainly explored the oral dosage forms of heparin and the other possible indications in practice. This review focuses on emerging efficient and non-invasive heparin options such as buccal, sublingual, oral, rectal and vaginal, transdermal, pulmonary and nasal. To do that, the past and recent studies were categorized into three main groups: (1) Conventional invasive heparin delivery methods; (2) Novel non-invasive heparin delivery systems; and (3) Heparin-based nanoparticles. The main challenges to use non-invasive heparin delivery systems were found to be negative charge and high molecular weight of heparin. Besides, the biological, biophysical, and pharmacological constraints could also limit the benefits of these alternatives. To overcome these issues, the following mechanisms have been used to enhance the delivery of heparin through several routes: (1) Improvement of cell-membrane penetration, (2) Changing of the tight-junctions, (3) Promoting the lipophilicity and (4) Preserving against acidic pH of the stomach. The applicability of alternative delivery options for heparin was mainly affected by overcoming the main penetration barriers. Nanoparticles were found to be effective in increasing the permeability, absorption, bioavailability and bioactivity of heparin.

Background/Objectives: Docetaxel is a widely used chemotherapeutic agent for several malignancies and is an established treatment for castration-resistant prostate cancer. However, its poor aqueous solubility, systemic toxicity, and the emergence of drug resistance limit its clinical benefit. Zein, a prolamin, forms micelles that enhance the solubility and delivery of hydrophobic drugs. As PEG length and ligand presentation govern micelle behavior, we investigated transferrin-functionalized PEGylated zein micelles as docetaxel nanocarriers and examined how PEG chain length (5 K vs. 10 K) and transferrin-mediated targeting affect delivery to prostate cancer cells. Methods: Docetaxel-loaded zein micelles bearing 5 K or 10 K PEG chains were prepared and conjugated to transferrin. Formulations were characterized for size, charge, morphology, critical micelle concentration, colloidal stability, drug loading and transferrin density. Cellular uptake and mechanisms were assessed in PC-3-Luc, DU145 and LNCaP cells by confocal microscopy, flow cytometry and pharmacological inhibition. Anti-proliferative activity was determined by MTT assays. Results: Both PEG5K and PEG10K micelles formed micellar dispersions with low polydispersity and high encapsulation efficiency. PEG5K micelles achieved higher transferrin conjugation and drug loading. Transferrin-functionalized PEG5K micelles showed enhanced uptake in DU145 and LNCaP cells but lower internalization in PC-3-Luc cells. Inhibitor studies indicated receptor-dependent uptake via clathrin- and caveolae-mediated endocytosis. Free docetaxel remained the most potent. However, among nanocarriers, transferrin-targeted PEG5K micelles showed the greatest anti-proliferative efficacy relative to their non-targeted counterparts, whereas transferrin-targeted PEG10K micelles were less potent than the non-targeted PEG10K micelles across all three cell lines. Conclusions: PEG chain length and ligand presentation are key determinants of uptake and cytotoxicity of docetaxel-loaded zein micelles. Shorter PEG chains favor effective transferrin display and receptor engagement, whereas longer PEG likely induces steric hindrance and reduces targeting, supporting transferrin-conjugated PEG5K zein micelles (the lead formulation in this study) as a targeted delivery platform that improves performance relative to matched non-targeted micelles in vitro, while free docetaxel remains more potent in 2D monolayer assays.