Overcoming Biopotency Barriers: Advanced Oral Delivery Strategies for Enhancing the Efficacy of Bioactive Food Ingredients.

Bioactive food ingredients contribute to the promotion and maintenance of human health and wellbeing. However, these functional ingredients often exhibit low biopotency after food processing or gastrointestinal transit. Well-designed oral delivery systems can increase the ability of bioactive food ingredients to resist harsh environments inside and outside the human body, as well as allow for controlled or triggered release of bioactives to specific sites in the gastrointestinal tract or other tissues and organs. This review presents the characteristics of common bioactive food ingredients and then highlights the barriers to their biopotency. It also discusses various oral delivery strategies and carrier types that can be used to overcome these biopotency barriers, with a focus on recent advances in the field. Additionally, the advantages and disadvantages of different delivery strategies are highlighted. Finally, the current challenges facing the development of food-grade oral delivery systems are addressed, and areas where future research can lead to new advances and industrial applications of these systems are proposed.

Innovative Oral Nano/Gene Delivery System Based on Engineered Modified Saccharomyces cerevisiae for Colorectal Cancer Therapy.

The efficient delivery of RNA-based drugs to solid tumors remains a formidable obstacle. We aim to develop a safe and efficient oral drug delivery system compatible with RNA-based drugs that is urgently needed to overcome challenges such as enzymatic degradation and gastrointestinal barriers to facilitate effective treatment for treating colorectal cancer (CRC). To address these challenges, we utilized engineered modified Saccharomyces cerevisiae to evaluate the delivery efficacy of miR21-antagomir for treating CRC in preclinical mouse models, including adenomatosis polyposis coli mutant transgenic mice ApcMin/+ and in situ tumor-bearing mice. An orally deliverable gene delivery system, YS@NPs21, was designed. This gene delivery system demonstrated effectively suppressed tumor growth in both ApcMin/+ and in situ tumor-bearing mice models. This system exhibited tumor-targeting capability, effective inhibition of tumor growth, and low toxicity toward nontumor cells. Successful implementation of this innovative oral drug delivery system could offer a straightforward, safe, and RNA drug-compatible approach to CRC treatment, ultimately improving patient outcomes and reducing medical costs.

Oral colon-targeted pH-responsive polymeric nanoparticles loading naringin for enhanced ulcerative colitis therapy.

An oral colon-targeted drug delivery system holds great potential in preventing systemic toxicity and preserving the therapeutic benefits of ulcerative colitis (UC) treatment. In this study, we developed a negatively charged PLGA-PEG nanoparticle system for encapsulating naringin (Nar). Additionally, chitosan and mannose were coated on the surface of these nanoparticles to enhance their mucosal adsorption and macrophage targeting abilities. The resulting nanoparticles, termed MC@Nar-NPs, exhibited excellent resistance against decomposition in the strong acidic gastrointestinal environment and specifically accumulated at inflammatory sites. Upon payload release, MC@Nar-NPs demonstrated remarkable efficacy in alleviating colon inflammation as evidenced by reduced levels of pro-inflammatory cytokines in both blood and colon tissues, as well as the scavenging of reactive oxygen species (ROS) in the colon. This oral nanoparticle delivery system represents a novel approach to treating UC by utilizing Chinese herbal ingredient-based oral delivery and provides a theoretical foundation for local and precise intervention in specific UC treatment.

Novel sodium tauroursodeoxycholate-based multifunctional liposomal delivery system for encapsulation of oleanolic acid and combination therapy of type 2 diabetes mellitus.

Liposomes have demonstrated great potential for drug delivery and diabetes treatment. However, hydrolysis by enzymes and emulsification by endogenous bile salts make liposomes unstable in the gastrointestinal tract. In this study, sodium tauroursodeoxycholate (TUDCNa)-based multifunctional bilosomes were designed to address the deficiencies of conventional liposomes. In the designed bilosomes, cholesterol was replaced by TUDCNa, which served as both a membrane stabilizer and an antidiabetic drug. Oleanolic acid (OA) was encapsulated in both conventional liposomes (OA-Ch-Lip) and bilosomes (OA-Tu-Bil) to compare their properties. Firstly, OA-Tu-Bil exhibited similar encapsulation efficiency and drug loading compared to OA-Ch-Lip, but with a smaller particle size. Secondly, OA-Tu-Bil showed better stability than OA-Ch-Lip. Thirdly, bilosomes exhibited prolonged intestinal retention time and improved permeability and oral bioavailability. Fourthly, in type 2 diabetes mellitus (T2DM) mice model, TUDCNa synergized with OA to exhibit the strongest therapeutic effect. In conclusion, TUDCNa have demonstrated the ability to substitute cholesterol in conventional liposomes, it provided a new approach for oral delivery of hypoglycemic drugs, and offered an innovative strategy for combination therapy.

Intestinal distribution of anionic, cationic, and neutral polymer-stabilized nanocarriers measured with a lanthanide (europium) tracer assay.

Nanocarriers, more commonly called nanoparticles (NPs), have found increasing use as delivery vehicles which increase the oral bioavailability of poorly water-soluble and peptide therapeutics. Therapeutic bioavailability is commonly assessed by measuring plasma concentrations that reflect the absorption kinetics. This bioavailability is a convolution of the gastrointestinal distribution of the NP vehicle, the release rate of the encapsulated therapeutic cargo, and the absorption-metabolism-distribution kinetics of the released therapeutic. The spatiotemporal distribution of the NP vehicle in the gastrointestinal tract is not well studied and is a buried parameter in PK studies used to measure the effectiveness of an NP formulation. This work is a study of the intestinal distribution and fate of orally dosed NPs in male CD-1 mice over 24 h. NPs have identical hydrophobic cores - composed of poly(styrene) homopolymer, a naphthalocyanine dye, and oleate-coated europium oxide colloids - with one of four different surface stabilizers: neutral poly(styrene)-block-poly(ethylene glycol) (PS-b-PEG), moderately negative hydroxypropyl methylcellulose acetate succinate (HPMCAS), highly negative poly(styrene)-block-poly(acrylic acid) (PS-b-PAA), and highly cationic adsorbed chitosan HCl on PS-b-PAA stabilized NPs. NP hydrodynamic diameters are all below 200 nm, with some variation attributable to the molecular properties of the stabilizing polymer. The encapsulated hydrophobic europium oxide colloids do not release soluble europium ions, enabling the use of highly sensitive inductively coupled plasma mass spectrometry (ICP-MS) to detect NP concentrations in digested biological tissues. Highly anionically-charged PAA and cationically-charged chitosan stabilized NPs showed statistically significant increased retention compared to the neutral PEG-stabilized NPs at p < 0.05 significance and (1-ß) > 0.95 power. HPMCAS-stabilized NPs showed statistically insignificant greater retention than PEG-stabilized NPs, and all NP formulations showed clearance from the intestines within 24 h. Different surface charges preferentially reside in different segments of the intestines, where cationic chitosan-stabilized NPs showed increased retention in the small intestines (ileum) and anionic PAA-stabilized NPs in the large intestines (caecum and colon). Modifying the surface charge of a NP can be used to modulate mucoadhesion, total retention, and intestinal segment specific retention, which enables the rational design of delivery vehicles that maximize residence times in appropriate locations.

Hyaluronic acid-decorated lipid nanocarriers as novel vehicles for curcumin: Improved stability, cellular absorption, and anti-inflammatory effects.

This study aimed to investigate how hyaluronic acid interfacial decoration affects the stability, cellular absorption, and anti-inflammatory effects of curcumin-loaded nanostructured lipid carriers. Nanocarriers were synthesized with an ovalbumin single layer and ovalbumin/hyaluronic acid double, mixed, or conjugated layers. All nanocarriers were spherical (200-300 nm diameter), and their encapsulation efficiency exceeded 95 %. Among the layers, the conjugated one exhibited the highest elastic surface dilatational modulus of approximately 40 mN/m, and the longest curcumin half-life of 186.07 days at 4 °C. Spearman's correlation analysis showed a negative correlation (r = -0.6698) between the recrystallization index and curcumin stability. The layer's mechanical strength improved curcumin stability by preventing crystal transition. Hyaluronic acid decoration enhanced the curcumin uptake of Caco-2 cells by 1.96-2.48 folds. Among the layers, the conjugate one was the most effective because of its strong binding constant with the receptor. Hyaluronic acid decoration improved the anti-inflammatory effects of curcumin.

Oral Live-Carrier Vaccine of Recombinant Lactococcus lactis Inducing Prophylactic Protective Immunity Against Helicobacter pylori Infection.

Helicobacter pylori infects the gastric mucosa and induces chronic gastritis, peptic ulcers, and gastric cancer. Research has demonstrated that vaccination can induce a protective immune response and prevent H. pylori infection. Oral administration of the Lactococcus lactis live-carrier vaccine is safe and easily complied with by the public. In this study, two recombinant L. lactis strains were constructed that expressed antigens of H. pylori urease subunit alpha (UreA) and UreA fused with Escherichia coli heat-labile toxin B subunit (LTB-UreA), named LL-UreA and LL-LTB-UreA, respectively. The expression of antigen proteins was confirmed by Western blotting analysis. Survival assessment indicated that the engineered L. lactis could colonize in the digestive tract of BALB/c mice up to 10 days after the last oral administration with our immunization protocol. The ability to induce immune response and immune protective efficacy of the L. lactis were confirmed. These results indicated that oral administration with LL-UreA or LL-LTB-UreA could induce UreA-specific mucosal secretory IgA (sIgA) and cellular immune response, significantly increasing the cytokines levels of interferon-gamma (IFN-γ), interleukin (IL)-17A, and IL-10, together with the proportion of CD4+IFN-γ+ T cells and CD4+IL17A+ T cells. More importantly, oral administration of LL-UreA and LL-LTB-UreA brought about effective protection in mice to prevent H. pylori infection, especially LL-UreA, resulting in 70% of mice showing no H. pylori colonization and the remaining 30% showing only low levels of colonization. These findings underscore the potential of using orally administered engineered L. lactis vaccines to prevent H. pylori infection.

Oral nano-formulations for endocrine therapy of endometrioid adenocarcinomas.

Endometrial cancer is one of the three major malignant tumors of the reproductive system that threaten women's lives and health. The incidence of this disease is on the rise globally. Most cases of endometrial cancer comprise endometrioid adenocarcinomas, whose treatment is challenged by factors such as their high recurrence rate and the need to preserve fertility among young patients. Thus, oral endocrine therapy has become the main treatment modality. The main drugs used in oral endocrine therapy are progestins, selective estrogen receptor antagonists, and aromatase inhibitors. However, their clinical use is hindered by their low solubility and low oral utilization. The rapid development of nanotechnology allows the combination of these drugs with oral nano-formulations to create a good carrier. Such nanocarriers, including nanospheres, nanocapsules, and micelles can protect the drug against clearance and increase the site specificity of drug delivery. This paper reviews the pathogenesis of endometrioid endometrial cancer (EEC) and oral nano-formulations for endocrine therapy.

Design and Evaluation of Inorganic/Organic Hybrid Bio-composite for Site-Specific Oral Delivery of Darifenacin.

Benign hyperplasia (BHP) is a common disorder that affects men over the age of 60 years. Transurethral resection of the prostate (TURP) is the gold standard for operative treatment, but a range of drugs are also available to improve quality of life and to reduce BHP-associated urinary tract infections and complications. Darifenacin, an anti-muscarinic agent, has been found effective for relieving symptoms of overactive bladder associated with BHP, but the drug has poor solubility and bioavailability, which are major challenges in product development. An inorganic/organic bio-composite with gastric pH-resistant property was synthesized for the targeted oral delivery of Darifenacin to the lower gastrointestinal tract (GIT). This development was accomplished through co-precipitation of calcium carbonate in quince seed-based mucilage. The FTIR, XRD, DSC, and TGA results showed good drug-polymer compatibility, and the SEM images showed calcite formation in the quince hydrogel system. After 72 h, the drug release of 34% and 75% were observed in acidic (0.1N HCl) and 6.8 pH phosphate buffer, respectively. A restricted/less drug was permeated through gastric membrane (21.8%) as compared to permeation through intestinal membrane (65%.) The developed composite showed significant reduction in testosterone-induced prostatic hyperplasia (2.39 ± 0.12***) as compared to untreated diseased animal group. No sign of organ toxicity was observed against all the developed composites. In this study, we developed an inorganic-organic composite system that is highly biocompatible and effective for targeting the lower GIT, thereby avoiding the first-pass metabolism of darifenacin.

Effect of microencapsulation techniques on the different properties of bioactives, vitamins and minerals.

This paper explores the impact of encapsulation techniques on bioactive compounds, vitamins, and minerals, which are crucial for delivering bioactive compounds. Due to their instability and reactivity with the environment, encapsulation is often necessary to make these compounds suitable for medical or dietary applications. The evaluation of the kinetic model of bioactives reveals that encapsulation can significantly enhance their stability. However, encapsulation is not without its drawbacks. Incomplete encapsulation can reduce the effectiveness of the bioactives, and complexity of encapsulation processes can hinder widespread adoption. Interactions between the encapsulated materials and the encapsulating agents may also impact the release and bioavailability of the bioactives. It also presents perspectives for future research aimed at overcoming the limitations and enhancing the effectiveness of encapsulation. As research continues to advance, encapsulation is poised to play critical role in improving the delivery and stability of bioactive compounds, benefiting the food, pharmaceutical, and cosmetic industries.

Design of Auto-Adaptive Drug Delivery System for Effective Delivery of Peptide Drugs to Overcoming Mucus and Epithelial Barriers.

Oral administration of peptide represents a promising delivery route, however, it is hindered by the harsh gastrointestinal environment, leading to low in vivo absorption. In this study, auto-adaptive protein corona-AT 1002-cationic liposomes (Pc-AT-CLs) are constructed with the characteristic of hydrophilic and electrically neutral surface properties for the encapsulation of liraglutide. BSA protein corona is used to coat AT-CLs reducing the adherence of mucus, and may fall off after penetrating the mucus layer. Transmucus transport experiment demonstrated that the mucus penetration amount of Pc-AT-CLs are 1.45 times that of AT-CLs. After penetrating the mucus layer, AT-CLs complete transmembrane transport by the dual action of AT and cationic surface properties. Transmembrane transport experiment demonstrated that the apparent permeability coefficient (Papp) of AT-CLs is 2.03 times that of CLs. In vivo tests demonstrated that Pc-AT-CLs exhibited a significant hypoglycemic effect and enhanced the relative bioavailability comparing to free liraglutide. Pc-AT-CLs protect liraglutide from degradation, facilitate its absorption, and ultimately improve its oral bioavailability.

Development of oral pH-sensitive redox nanotherapeutics for gastric ulcer therapy.

Gastric ulcer is a common gastrointestinal disorder worldwide. Although its pathogenesis is unclear, the overproduction of reactive oxygen species (ROS), which results in an oxidative imbalance, has been reported as a central driving mechanism. Within the scope of this investigation, we developed two different self-assembling redox nanoparticles (RNPs) with ROS-scavenging features for the oral treatment of gastric ulcers. One of them, referred to as RNPN, disintegrates in response to acidic pH, whereas the other, denoted as RNPO, remains intact regardless of pH variations. Both types of RNPs showed different free radical scavenging activities in vitro. Protonation of the amino linkages in the side chains of RNPN caused the micelle structure to collapse and the nitroxide radicals encapsulated in the core were exposed to the outside, resulting in a significant increase in antioxidant capacity as the pH decreases. In contrast, RNPO maintained its spherical structure and consistent antioxidant reactivity irrespective of pH changes. The in vivo gastric retention of orally administered RNPN was significantly improved compared to that of RNPO which might be explained by the increased exposure of cationic protonating segments in RNPN on the negatively charged gastric mucosal surface. Owing to its improved gastric retention and enhanced ROS scavenging capacity under acidic pH conditions, RNPN exhibited superior protective effects against oxidative stress induced by aspirin in a gastric ulcer mouse model compared to RNPO. In addition, neither RNPN nor RNPO resulted in severe lethal effects or significant changes in the morphology of zebrafish embryos, indicating their biosafety. Our results suggest that the oral administration of RNPs has a high therapeutic potential for gastric ulcer treatment.

Oral delivery of stabilized lipid nanoparticles for nucleic acid therapeutics.

Gastrointestinal disorders originate in the gastrointestinal tract (GIT), and the therapies can benefit from direct access to the GIT achievable through the oral route. RNA molecules show great promise therapeutically but are highly susceptible to degradation and often require a carrier for cytoplasmic access. Lipid nanoparticles (LNPs) are clinically proven drug-delivery agents, primarily administered parenterally. An ideal Orally Delivered (OrD) LNP formulation should overcome the diverse GI environment, successfully delivering the drug to the site of action. A versatile OrD LNP formulation has been developed to encapsulate and deliver siRNA and mRNA in this paper. The formulations were prepared by the systematic addition of cationic lipid to the base LNP formulation, keeping the total of cationic lipid and ionizable lipid to 50 mol%. Biorelevant media stability depicted increased resistance to bile salt mediated destabilization upon the addition of the cationic lipid, however the in vitro efficacy data underscored the importance of the ionizable lipid. Based on this, OrD LNP was selected comprising of 20% cationic lipid and 30% ionizable lipid. Further investigation revealed the enhanced efficacy of OrD LNP in vitro after incubation in different dilutions of fasted gastric, fasted intestinal media, and mucin. Confocal imaging and flow cytometry confirmed uptake while in vivo studies demonstrated efficacy with siRNA and mRNA as payloads. Taken together, this research introduces OrD LNP to deliver nucleic acid locally to the GIT.

Transepithelial transport of nanoparticles in oral drug delivery: From the perspective of surface and holistic property modulation.

Despite the promising prospects of nanoparticles in oral drug delivery, the process of oral administration involves a complex transportation pathway that includes cellular uptake, intracellular trafficking, and exocytosis by intestinal epithelial cells, which are necessary steps for nanoparticles to enter the bloodstream and exert therapeutic effects. Current researchers have identified several crucial factors that regulate the interaction between nanoparticles and intestinal epithelial cells, including surface properties such as ligand modification, surface charge, hydrophilicity/hydrophobicity, intestinal protein corona formation, as well as holistic properties like particle size, shape, and rigidity. Understanding these properties is essential for enhancing transepithelial transport efficiency and designing effective oral drug delivery systems. Therefore, this review provides a comprehensive overview of the surface and holistic properties that influence the transepithelial transport of nanoparticles, elucidating the underlying principles governing their impact on transepithelial transport. The review also outlines the chosen of parameters to be considered for the subsequent design of oral drug delivery systems.

Development of mucoadhesive 3D-printed Carbopol/Eudragit/SNAC tablets for the oral delivery of enoxaparin: In vitro and ex vivo evaluation.

3D-printed dosage forms comprised of Carbopol and Eudragit were fabricated through semi-solid extrusion, combining Enoxaparin (Enox) and the permeation enhancer SNAC in a single-step process without subsequent post-processing. Inks were characterized using rheology and Fourier-transform infrared (FTIR) spectroscopy. The stability of Enox in the fabricated dosage forms was assessed by means of Nuclear Magnetic Resonance (NMR) and Circular Dichroism (CD) analysis. In vitro release studies revealed the release of Enox in a sustained manner, whereas ex vivo experiments demonstrated the mucoadhesive properties of the 3D-printed dosage forms and their ability to enhance Enox permeability across intestinal mucosa. Cellular assays (CCK-8 assay) revealed a dose- and time-dependent response following incubation with the 3D-printed dosage forms. The encapsulation of SNAC in the 3D-printed dosage forms demonstrated their capacity to increase the transcellularly transport of macromolecule across Caco-2 monolayer in a reversible manner, as confirmed by Transepithelial Resistance (TEER) measurements.

Contrasting the pharmacokinetic performance and gut microbiota effects of an amorphous solid dispersion and lipid nanoemulsion for a poorly water-soluble anti-psychotic.

Increasing attention is being afforded to understanding the bidirectional relationship that exists between oral drugs and the gut microbiota. Often overlooked, however, is the impact that pharmaceutical excipients exert on the gut microbiota. Subsequently, in this study, we contrasted the pharmacokinetic performance and gut microbiota interactions between two commonly employed formulations for poorly soluble compounds, namely 1) an amorphous solid dispersion (ASD) stabilised by poly(vinyl pyrrolidone) K-30, and 2) a lipid nanoemulsion (LNE) comprised of medium chain glycerides and lecithin. The poorly soluble antipsychotic, lurasidone, was formulated with ASD and LNE due to its rate-limiting dissolution, poor oral bioavailability, and significant food effect. Both the ASD and LNE were shown to facilitate lurasidone supersaturation within in vitro dissolution studies simulating the gastrointestinal environment. This translated into profound improvements in oral pharmacokinetics in rats, with the ASD and LNE exerting comparable âˆ¼ 2.5-fold improvements in lurasidone bioavailability, compared to the pure drug. The oral formulations imparted contrasting effects on the gut microbiota, with the LNE depleting the richness and abundance of the microbial ecosystem, as evidenced through reductions in alpha diversity (Chao1 index) and operational taxonomical units (OTUs). In contrast, the ASD exerted a 'gut neutral' effect, whereby a mild enrichment of alpha diversity and OTUs was observed. Importantly, this suggests that ASDs are effective solubility-enhancing formulations that can be used without comprising the integrity of the gut microbiota - an integral consideration in the treatment of mental health disorders, such as schizophrenia, due to the role of the gut microbiota in regulating mood and cognition.

Dual-Sensitive Carbohydrate-Based Nanosystem for Targeted Drug Delivery to Potentiate the Therapeutic Efficacy of Ulcerative Colitis.

Purpose: Conventional oral formulations for inflammatory bowel disease (IBD) treatment are less than satisfactory, due to the poor controllability of drug release and lack of specificity to the inflammation sites in the gastrointestinal (GI) tract. To overcome these limitations, we developed a multiple carbohydrate-based nanosystem with pH/ROS dual responsibility and charge-mediated targeting ability for IBD-specific drug delivery. Methods: In view of the overproduction of ROS and overexpression of cationic proteins in the inflammatory colon, the designed nanosystem was composed of oxidation-sensitive cyclodextrin (OX-CD), chitosan (CS) and pectin (AHP). OX-CD was utilized to load dexamethasone (DM) by the solvent evaporation method. CS and AHP with opposite charges were sequentially coated onto OX-CD to generate the nanosystems by the electrostatic self-assembly method. The physicochemical properties, stability, dual-sensitive drug release behavior, cytotoxicity, cellular uptake and anti-inflammatory activity were investigated in vitro. In vivo bio-distribution and therapeutic efficacy of the nanosystem were further evaluated in the ulcerative colitis (UC) mice. Results: The obtained AHP/CS/OX-CD-DM nanosystem (ACOC-DM) could maintain stability under the GI pH environments, and release drug in the inflammatory colon with pH/ROS sensitivity. Dual polysaccharide-coated ACOC-DM exhibited higher cellular uptake and anti-inflammatory efficacy in macrophages than single polysaccharide-coated CS/OX-CD-DM nanosystem (COC-DM). Orally administrated ACOC-DM could enhance inflammation targeting ability and therapeutic efficacy of DM in the UC mice. Conclusion: This carbohydrate-based nanosystem with pH/ROS dual sensitivity and inflammation targeting capacity may serve as a safe and versatile nanoplatform for IBD therapy.

Co-Delivery of Docetaxel and Curcumin Functionalized Mixed Micelles for the Treatment of Drug-Resistant Breast Cancer by Oral Administration.

Background: Chemotherapeutic drugs have some drawbacks in antineoplastic therapy, mainly containing seriously toxic side effects caused by injection and multi-drug resistance (MDR). Co-delivery with two or more drugs via nanomicelles is a promising strategy to solve these problems. Oral chemotherapy is increasingly preferred owing to its potential to enhance the life quality of patients. Methods and Results: The study intended to develop mixed micelles using D-α-Tocopherol poly(ethylene glycol) 1000 succinate (TPGS) and soluplus for the co-encapsulation of docetaxel (DTX) and curcumin (CUR), marked as (DTX+CUR)-loaded mixed micelles, treating drug-resistant breast cancer by oral administration. The (DTX+CUR)-loaded mixed micelles had a uniform particle size (~64 nm), high drug loading and encapsulation efficiency, in vitro sustained-release properties and good pH-dependent stability. In vitro cell study, the (DTX+CUR)-loaded mixed micelles displayed the highest cellular uptake, cytotoxicity, cell apoptosis-inducing rates and cell ROS-inducing levels on MCF-7/Adr cells. Notably, in vivo pharmacokinetic studies, (DTX+CUR)-loaded mixed micelles enhanced markedly the oral absorption of DTX compared to pure DTX, with a relative oral bioavailability of 574%. The (DTX+CUR)-loaded mixed micelles by oral administration had the same anticancer efficacy as taxotere by injection in resistant breast cancer bearing mice. Conclusion: (DTX+CUR)-loaded mixed micelles could provide a potential formulation for treating drug-resistant breast cancers by oral administration.

Natural Coptidis Rhizoma Nanoparticles Improved the Oral Delivery of Docetaxel.

Purpose: Docetaxel (DTX) is a valuable anti-tumor chemotherapy drug with limited oral bioavailability. This study aims to develop an effective oral delivery system for DTX using natural nanoparticles (Nnps) derived from Coptidis Rhizoma extract. Methods: DTX-loaded self-assembled nanoparticles (Nnps-DTX) were created using an optimized heat-induction strategy. Nnps-DTX's shape, size, Zeta potential, and in vitro stability were all carefully examined. Additionally, the study investigated the encapsulation efficiency, loading capacity, crystal form, and intermolecular interactions of DTX in Nnps-DTX. Subsequently, the solubility, release, cellular uptake, metabolic stability, and preclinical pharmacokinetics of DTX in Nnps-DTX were systematically evaluated. Finally, the cytotoxicity of Nnps-DTX was assessed in three tumor cell lines. Results: Nnps-DTX was spherical in shape, 138.6 ± 8.2 nm in size, with a Zeta potential of -20.8 ± 0.6 mV, a DTX encapsulation efficiency of 77.6 ± 8.5%, and a DTX loading capacity of 6.8 ± 1.9%. Hydrogen bonds, hydrophobic interactions, and electrostatic interactions were involved in the formation of Nnps-DTX. DTX within Nnps-DTX was in an amorphous form, resulting in enhanced solubility (23.3 times) and release compared to free DTX. Following oral treatment, the mice in the Nnps-DTX group had DTX peak concentrations 8.8, 23.4, 44.6, and 5.7 times higher in their portal vein, systemic circulation, liver, and lungs than the mice in the DTX group. Experiments performed in Caco-2 cells demonstrated a significant increase in DTX uptake by Nnps-DTX compared to free DTX, which was significantly inhibited by indomethacin, an inhibitor of caveolae-mediated endocytosis. Furthermore, compared to DTX, DTX in Nnps-DTX demonstrated better metabolic stability in liver microsomes. Notably, Nnps-DTX significantly reduced the viability of MCF-7, HCT116, and HepG2 cells. Conclusion: The novel self-assembled nanoparticles considerably enhanced the cellular absorption, solubility, release, metabolic stability, and pharmacokinetics of oral DTX and demonstrated strong cytotoxicity against tumor cell lines.