Exploring the optimal chain length of modification module in disulfide bond bridged paclitaxel prodrug nanoassemblies for breast tumor treatment.

In the prodrug-based self-assembled nanoassemblies, prodrugs usually consist of drug modules, response modules, and modification modules. Modification modules play a critical role in regulating the nano-assembly ability of the prodrugs. Herein, we carried out a "fatty alcoholization" strategy and chose various lengths of aliphatic alcohol chains (AC) as modification modules to construct disulfide bond bridged paclitaxel (PTX) prodrug nanoassemblies. The PTX-AC prodrugs would self-assemble into nanoassemblies (PTX-AC PNs) with higher drug loading, stability, and tumor selectivity than commercial preparations. After comprehensive exploration, we found the chain length (AC12, AC16, AC20, AC24) of modification modules affected the assembly of PTX-AC PNs, further leading to disparate in vivo fate and antitumor efficacy. With the increase of the chain length of the modification modules (from AC12 to AC20), the assembly ability of the nanoassemblies was improved, attributed to the appropriate enhancement of hydrophobic force. When the chain length was further increased to AC24, the excessive hydrophobic force will lead to the aggregation of prodrugs and weaken the assembly ability. Therefore, PTX-AC20 PNs with proper chain length may solve the paradox of efficacy and tolerance in 4 T1 breast tumor owing to their optimal nano-assembly stability and modest redox-sensitivity. In short, this work highlighted the importance of screening optimal modification modules in developing prodrug nanoassemblies.

Dual role of triglyceride structures facilitates anti-tumor drug delivery: Both as a self-assembling module and a responsive module.

Small molecule prodrugs self-assembled nano-delivery systems with tumor responsive linkages are emerging as an effective platform. However, the heterogeneity of tumor microenvironment may limit the anti-tumor effect of prodrug nanomedicines with a single response module. Here, we chose disulfide bond as the response module and branched chain alcohol as the self-assembly modification module to construct a single-responsive prodrug. We also constructed a double-responsive paclitaxel prodrug combining triglyceride and disulfide bond, taking into account of the highly expressed lipase and glutathione levels in tumor cells. The results showed that the anti-tumor effect of single-responsive branched chain alcohol modified prodrug nanoparticles was inferior to triglyceride prodrug nanoparticles with dual response modules. The triglyceride structure can not only serve as a self-assembly modification module, but also serve as a response module for intelligent drug release in tumor. Such dual roles will facilitate the efficient delivery of small molecule self-assembled prodrugs to tumor sites.

Protective effect of walnut active peptide against dextran sulfate sodium-induced colitis in mice based on untargeted metabolomics.

Inflammatory bowel disease (IBD) is a chronic condition characterized by inflammation of the digestive tract, whose exact cause remains unknown, and its prevalence is on the rise. This study investigated the effects of a walnut-derived peptide LPLLR (LP-5) on intestinal inflammation and metabolism in IBD mice. Metabolomics revealed that LP-5 regulated the levels of metabolites, such as thalsimidine, fumagillin, and geniposide, and LP-5 could regulate several signaling pathways, such as protein digestion and absorption, aminoacyl-tRNA biosynthesis, and ABC transporters. Additionally, LP-5 alleviated dextran sulfate sodium (DSS)-induced colitis by modulating autophagy and inflammasome pathways. Western blotting demonstrated that LP-5 reduced the expressions of NLRP3, Caspase-1, ASC and IL-1ß, and increased the expressions of Beclin-1 and LC3-II/LC3-I, corresponding to activation of the AMPK/mTOR/ULK1 pathway. These findings suggested that LP-5 activated autophagy in vivo to suppress inflammation and modulate metabolic substances, highlighting potential implications for gut health and the development of functional foods containing LP-5.

Walnut-Derived Peptides Alleviate Learning and Memory Impairments in a Mice Model via Inhibition of Microglia Phagocytose Synapses.

Microglia phagocytose synapses have an important effect on the pathogenesis of neurological disorders. Here, we investigated the neuroprotective effects of the walnut-derived peptide, TWLPLPR(TW-7), against LPS-induced cognitive deficits in mice and explored the underlying C1q-mediated microglia phagocytose synapses mechanisms in LPS-treated HT22 cells. The MWM showed that TW-7 improved the learning and memory capacity of the LPS-injured mice. Both transmission electron microscopy and immunofluorescence analysis illustrated that synaptic density and morphology were increased while associated with the decreased colocalized synapses with C1q. Immunohistochemistry and immunofluorescence demonstrated that TW-7 effectively reduced the microglia phagocytosis of synapses. Subsequently, overexpression of C1q gene plasmid was used to verify the contribution of the TW-7 via the classical complement pathway-regulated mitochondrial function-mediated microglia phagocytose synapses in LPS-treated HT22 cells. These data suggested that TW-7 improved the learning and memory capability of LPS-induced cognitively impaired mice through a mechanism associated with the classical complement pathway-mediated microglia phagocytose synapse.

Human amniotic mesenchymal stem cell-islet organoids enhance the efficiency of islet engraftment in a mouse diabetes model.

AIMS: Despite islet transplantation has proved a great potential to become the standard therapy for type 1 diabetes mellitus (T1DM), this approach remains limited by ischemia, hypoxia, and poor revascularization in early post-transplant period as well as inflammation and life-long host immune rejection. Here, we investigate the potential and mechanism of human amniotic mesenchymal stem cells (hAMSCs)-islet organoid to improve the efficiency of islet engraftment in immunocompetent T1DM mice. MAIN METHODS: We generated the hAMSC-islet organoid structure through culturing the mixture of hAMSCs and islets on 3-dimensional-agarose microwells. Flow cytometry, whole-body fluorescent imaging, immunofluorescence, Calcein-AM/PI staining, ELISA, and qPCR were used to assess the potential and mechanism of shielding hAMSCs to improve the efficiency of islet transplantation. KEY FINDINGS: Transplant of hAMSC-islet organoids results in remarkably better glycemic control, an enhanced glucose tolerance, and a higher ß cell mass in vivo compared with control islets. Our results show that hAMSCs shielding provides an immune privileged microenvironment for islets and promotes graft revascularization in vivo. In addition, hAMSC-islet organoids show higher viability and reduced dysfunction after exposure to hypoxia and inflammatory cytokines in vitro. Finally, our results show that shielding with hAMSCs leads to the activation of PKA-CREB-IRS2-PI3K and PKA-PDX1 signaling pathways, up-regulation of SIL1 mRNA levels, and down-regulation of MT1 mRNA levels in ß cells, which ultimately promotes the synthesis, folding and secretion of insulin, respectively. SIGNIFICANCE: hAMSC-islet organoids can evidently increase the efficiency of islet engraftment and might develop into a promising alternative for the clinical treatment of T1DM.

Dual-modified starch micelles as nanocarriers for efficient encapsulation and controlled release of walnut-derived active peptides.

Hydrophilic and hydrophobic modified nanomicelles might be more conducive to passage of the gastrointestinal barrier than walnut peptide (WP). In this study, a novel double modified starch polymer, SB-CST-DCA, was synthesized by grafting sulfabetaine (SB) and deoxycholic acid (DCA) onto corn starch (CST) molecules through etherification and esterification. The modification mechanism was discussed to determine its chemical structure, morphological properties, and thermal stability. Peptide-loaded nanomicelles (SB-CST-DCA-WP) were prepared using WP as the core material. The encapsulation efficiency and peptide loading amount reached 76.90 ± 1.52% and 18.27 ± 0.53%, respectively, with good stability and pH-responsive release behavior observed to effectively control WP release and enhance its antioxidant activity. The composite exhibited safety, non-toxicity, and good blood compatibility at concentrations below 125 µg/mL. Duodenum was identified as the main absorption site with an absorption ratio of 41.16 ± 0.36%.

Fine-tuning the activation behaviors of ternary modular cabazitaxel prodrugs for efficient and on-target oral anti-cancer therapy.

The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of reducing substances (e.g., ascorbic acid, glutathione, uric acid and tea polyphenols) in the systemic circulation. This may lead to toxicity, particularly in oral prodrugs that require more frequent and high-dose treatments. Fine-tuning the activation kinetics of these prodrugs is a promising prospect for more efficient on-target cancer therapies. In this study, disulfide, steric disulfide, and ester bonds were used to bridge cabazitaxel (CTX) to an intestinal lymph vessel-directed triglyceride (TG) module. Then, synthetic prodrugs were efficiently incorporated into self-nanoemulsifying drug delivery system (corn oil and Maisine CC were used as the oil phase and Cremophor EL as the surfactant). All three prodrugs had excellent gastric stability and intestinal permeability. The oral bioavailability of the disulfide bond-based prodrugs (CTX-(C)S-(C)S-TG and CTX-S-S-TG) was 11.5- and 19.1-fold higher than that of the CTX solution, respectively, demonstrating good oral delivery efficiency. However, the excessive reduction sensitivity of the disulfide bond resulted in lower plasma stability and safety of CTX-S-S-TG than that of CTX-(C)S-(C)S-TG. Moreover, introducing steric hindrance into disulfide bonds could also modulate drug release and cytotoxicity, significantly improving the anti-tumor activity even compared to that of intravenous CTX solution at half dosage while minimizing off-target adverse effects. Our findings provide insights into the design and fine-tuning of different disulfide bond-based linkers, which may help identify oral prodrugs with more potent therapeutic efficacy and safety for cancer therapy.

The effect of lengths of branched-chain fatty alcohols on the efficacy and safety of docetaxel-prodrug nanoassemblies.

The self-assembly prodrugs are usually consisted of drug modules, activation modules, and assembly modules. Keeping the balance between efficacy and safety by selecting suitable modules remains a challenge for developing prodrug nanoassemblies. This study designed four docetaxel (DTX) prodrugs using disulfide bonds as activation modules and different lengths of branched-chain fatty alcohols as assembly modules (C16, C18, C20, and C24). The lengths of the assembly modules determined the self-assembly ability of prodrugs and affected the activation modules' sensitivity. The extension of the carbon chains improved the prodrugs' self-assembly ability and pharmacokinetic behavior while reducing the cytotoxicity and increased cumulative toxicity. The use of C20 can balance efficacy and safety. These results provide a great reference for the rational design of prodrug nanoassemblies.

Mechanism of Intestinal Epithelial Absorption and Electrophysiological Regulation of the Shrimp Peptide QMDDQ.

We investigated the absorption mechanism of the shrimp peptide QMDDQ in small intestines, explored its physiological function in inhibiting neuronal hyperactivity, and verified its entry into the brain in vivo to display functional activity. The everted rat sac model and a Caco-2 paracellular absorption monolayer model were used, indicating that QMDDQ has a good absorption capacity with an apparent permeability coefficient (Papp) > 1 × 10-6 cm/s and the absorption of QMDDQ was concentration-dependent. When the concentration of QMDDQ was 1 mM and the transport time was 180 min, the highest absorption concentration of QMDDQ was 41.17 ± 3.48 µM (P < 0.05). The myosin light-chain kinase (MLCK)-specific inhibitor ML-7 and activator MPA, Western blotting, and immunofluorescence results showed that QMDDQ absorption takes place by mediating the MLCK-p-MLCK-MLC signaling pathway, reversibly opening the zonula occludens-1 (ZO-1), occludin in tight junctions (TJs), upregulating claudin-2 expression, and reaching targets through blood to inhibit neuronal overactivity. Results of fluorescence imaging in vivo verified that QMDDQ could enter the brain 4 h after oral administration. The results provide a theoretical foundation for the mechanism of paracellular absorption of active peptides and a starting point for the development of functional foods for Alzheimer's disease intervention.

Walnut-Derived Peptide Improves Cognitive Impairment in Colitis Mice Induced by Dextran Sodium Sulfate via the Microbiota-Gut-Brain Axis (MGBA).

In this study, we investigated the protective mechanism of walnut-derived peptide LPLLR (LP-5) against cognitive impairment induced in a dextran sodium sulfate (DSS)-induced colitis mouse model, with emphasis on the microbiota-gut-brain axis (MGBA). The results revealed that LP-5 could improve the learning ability and memory of mice with cognitive impairment and mitigate colitis symptoms, including weight loss, bloody stools, colon shortening, and histopathological changes. Additionally, LP-5 protected the integrity of the intestinal barrier by promoting the expression of tight junction proteins (TJs) while attenuating colonic inflammation by suppressing proinflammatory cytokine and epithelial cell apoptosis. Western blotting indicated that LP-5 treatment suppressed the inflammatory NF-κB/MLCK/MLC signaling pathway activity. Furthermore, LP-5 ameliorated hippocampal neuron damage and protected blood-brain barrier (BBB) integrity by downregulating microglia marker protein Iba-1, increasing TJ protein expression, and restoring the deterioration of synaptic proteins. Importantly, 16S rRNA sequencing results indicated that LP-5 reshaped the abundance of a wide range of gut microbiota at the phylum and genus levels, with increased Prevotella and Akkermansia associated with tryptophan (TRP), 5-hydroxytryptamine (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA). These findings suggest that LP-5 could maintain intestinal barrier and BBB integrity, reverse gut dysbiosis, and improve learning and memory ability in colitis mice, providing novel insights into alterations of gut microbes in colitis and a potential new mechanism by which it causes cognitive impairment.

Molecular complexes of drug combinations: A review of cocrystals, salts, coamorphous systems and amorphous solid dispersions.

As the advancements in the medical technology and healthcare develop through the years, combinational therapy has evolved to be an important treatment modality in many disease settings, including cancer, cardiovascular disease and infectious diseases. In an effort to alleviate "pill burden" and improve patient compliance, fixed dose combinations (FDCs) have been developed to be used as effective therapeutics. Among all FDCs, the category of drug-drug molecular complexes has been proven an efficient methodology in designing and treating diseases, with many drugs being approved. Among all drug-drug molecular complexes, drug-drug cocrystals, salts, coamorphous systems and solid dispersions have been successfully developed and many have been approved by the FDA. In this review, we dwell deeply into the molecular mechanisms behind the different types of drug-drug molecular complexes, including the key functional groups involved in the intermolecular interactions, the applications of each category of molecular complexes, as well as the advantages and challenges thereof. This comprehensive review provides useful insights into the practical design and manufacture of drug-drug molecular complexes and points out the future direction for the development of new advantageous combinational therapies that benefit more patients.

Complement in Human Brain Health: Potential of Dietary Food in Relation to Neurodegenerative Diseases.

The complement pathway is a major component of the innate immune system, which is critical for recognizing and clearing pathogens that rapidly react to defend the body against external pathogens. Many components of this pathway are expressed throughout the brain and play a beneficial role in synaptic pruning in the developing central nervous system (CNS). However, excessive complement-mediated synaptic pruning in the aging or injured brain may play a contributing role in a wide range of neurodegenerative diseases. Complement Component 1q (C1q), an initiating recognition molecule of the classical complement pathway, can interact with a variety of ligands and perform a range of functions in physiological and pathophysiological conditions of the CNS. This review considers the function and immunomodulatory mechanisms of C1q; the emerging role of C1q on synaptic pruning in developing, aging, or pathological CNS; the relevance of C1q; the complement pathway to neurodegenerative diseases; and, finally, it summarizes the foods with beneficial effects in neurodegenerative diseases via C1q and complement pathway and highlights the need for further research to clarify these roles. This paper aims to provide references for the subsequent study of food functions related to C1q, complement, neurodegenerative diseases, and human health.

Recent advances in the metabolic engineering and physiological opportunities for microbial synthesis of L-aspartic acid family amino acids: A review.

L-aspartic acid, L-threonine, L-isoleucine, l-lysine, and L-methionine constitute the l-aspartate amino acids (AFAAs). Except for L-aspartic acid, these are essential amino acids that cannot be synthesized by humans or animals themselves. E. coli and C. glutamicum are the main model organisms for AFAA production. It is necessary to reconstitute microbial cell factories and the physiological state of industrial fermentation cells for in-depth research into strains with higher AFAA production levels and optimal growth states. Considering that the anabolic pathways of the AFAAs and engineering modifications have rarely been reviewed in the latest progress, this work reviews the central metabolic pathways of two strains and strategies for the metabolic engineering of AFAA synthetic pathways. The challenges posed by microbial physiology in AFAA production and possible strategies to address them, as well as future research directions for constructing strains with high AFAA production levels, are discussed in this review article.

Enhancing the SCC Resistance of the Anchor Steel with Microalloying in a Simulated Mine Environment.

This work explored a new idea for enhancing the resistance to stress corrosion cracking (SCC) of mining anchor steel through microalloying. Microalloyed anchor steels with Nb, Cu, Ni, Sb, and C were prepared through vacuum smelting and hot rolling. Electrochemical measurements, slow strain rate tensile (SSRT) tests, and fracture morphology observations were used to study the electrochemical and SCC behavior in the simulated mine environment. The results proved that the microstructure of microalloyed steels varies slightly. Adding Ni, Cu, and Sb can improve the mechanical properties of the anchor steel, while reducing C content decreases tensile strength as a result of loss of the solution-strengthening effect. The addition of Sb, Cu, Ni, and reducing the content of C enhances the resistance to corrosion and SCC by mitigating anodic dissolution (AD), while adding Nb improves SCC resistance by inhibiting hydrogen embrittlement (HE). The combined addition of 1% Ni, 0.5% Cu, 0.05% Nb, 0.1% Sb, and 0.5% C presented the highest SCC resistance, which is a promising prospect for the development of high-performance, low-alloy anchor steels. The combined addition of 1% Ni, 0.5% Cu, 0.05% Nb, and 0.1% Sb resulted in the inhibition of electrochemical reactions and corrosion. As a result of the synergistic effect of the microalloy, both AD and HE mechanisms were simultaneously inhibited, which greatly enhanced SCC resistance.

Purification, Identification, Chelation Mechanism, and Calcium Absorption Activity of a Novel Calcium-Binding Peptide from Peanut (Arachis hypogaea) Protein Hydrolysate.

A novel calcium-binding peptide was purified from peanut protein hydrolysate using gel filtration chromatography and identified using HPLC-MS/MS. Its amino acid sequence was determined as Phe-Pro-Pro-Asp-Val-Ala (FPPDVA, named as FA6) with the calcium-binding capacity of 15.67 ± 0.39 mg/g. Then, the calcium chelating characteristics of FPPDVA were investigated using ultraviolet-visible absorption spectroscopy, fluorescence spectroscopy, Fourier transform infrared spectroscopy, particle size, and zeta potential. The results showed that FPPDVA interacted with calcium ions, the chelation of calcium ions induced FPPDVA to fold and form a denser structure, the calcium-binding sites may mainly involve oxygen atoms from the carboxyl residues of Asp and Ala, and Phe possessed contact energy and carbonyl residues of Val. Microstructure analysis showed that FPPDVA-calcium chelate exhibited a regularly ordered and tightly aggregated sheets or block structures. Additionally, FPPDVA-calcium chelate had good gastrointestinal digestive stability and thermal stability. The results of everted rat intestinal sac and Caco-2 cell monolayer experiments showed that FPPDVA-calcium chelate could promote calcium absorption and transport through the Cav1.3 and TRPV6 calcium channels. These data suggest that FPPDVA-calcium chelate possesses the potential to be developed and applied as calcium supplement.

A review on the identification of transgenic oilseeds and oils.

Transgenic technology can increase the quantity and quality of vegetable oils worldwide. However, people are skeptical about the safety of transgenic oil-bearing crops and the oils they produce. In order to protect consumers' rights and avoid transgenic oils being adulterated or labeled as nontransgenic oils, the transgenic detection technology of oilseeds and oils needs careful consideration. This paper first summarized the current research status of transgenic technologies implemented at oil-bearing crops. Then, an inspection process was proposed to detect a large number of samples to be the subject rapidly, and various inspection strategies for transgenic oilseeds and oils were summarized according to the process sequence. The detection indicators included oil content, fatty acid, triglyceride, tocopherol, and nucleic acid. The detection technologies involved chromatography, spectroscopy, nuclear magnetic resonance, and polymerase chain reaction. It is hoped that this article can provide crucial technical reference and support for staff engaging in the supervision of transgenic food and for researchers developing fast and efficient monitoring methods in the future.

Bacterial synthetic biology: tools for novel drug discovery.

INTRODUCTION: Bacterial synthetic biology has provided powerful tools to revolutionize the drug discovery process. These tools can be harnessed to generate bacterial novel pharmaceutical compounds with enhanced bioactivity and selectivity or to create genetically modified microorganisms as living drugs. AREAS COVERED: This review provides a current overview of the state-of-the-art in bacterial synthetic biology tools for novel drug discovery. The authors discuss the application of these tools including bioinformatic tools, CRISPR tools, engineered bacterial transcriptional regulators, and synthetic biosensors for novel drug discovery. Additionally, the authors present the recent progress on reprogramming bacteriophages as living drugs to fight against antibiotic-resistant pathogens. EXPERT OPINION: The field of using bacterial synthetic biology tools for drug discovery is rapidly advancing. However, challenges remain in developing reliable and robust methods to engineer bacteria. Further advancements in synthetic biology hold promise to speed up drug discovery, facilitating the development of novel therapeutics against various diseases.

Synergistic Effect of Combined Walnut Peptide and Ginseng Extracts on Memory Improvement in C57BL/6 Mice and Potential Mechanism Exploration.

This work aimed to investigate whether there are synergistic effects between walnut peptide (WNP) and ginseng extracts (GSE) treatments to ameliorate the memory impairment caused by scopolamine (SCOP). The Morris water maze trial, hippocampal neuron morphology, neurotransmitters, and synaptic ultrastructure were examined, along with brain-derived neurotrophic factor (BDNF)-related signaling pathway proteins. The results of the Morris water maze trial demonstrated that the combined administration of WNP and GSE effectively alleviated memory impairment in C57BL/6 rats caused by SCOP. Improvement in the morphology of hippocampal neurons, dendritic spines, and synaptic plasticity and upregulation of neurotransmitters AChE, ACh, ChAT, Glu, DA, and 5-HT supported the memory improvement effects of WNP + GSE. In addition, compared with the model group, WNP + GSE significantly enhanced the protein levels of VAChT, Trx-1, and the CREB/BDNF/TrkB pathway in hippocampal and PC12 cells induced by SCOP (p < 0.05). Notably, WNP + GSE boosted memory via multiple pathways, not only the BDNF/TrkB/CREB target.

Mechanistic Insight of Polymer Effects on the Kinetic of Solution-Mediated Phase Transformation of Nitrofurantoin Anhydrate to Monohydrate.

PURPOSE: Nitrofurantoin is an effective antibacterial drug for the treatment of lower urinary tract infection. However, the anhydrate form can easily transform to the less soluble hydrate form (monohydrate) during dissolution, resulting in a reduction of dissolution rate and oral bioavailability. Therefore, inhibition of phase transformation is vital to stabilize the quality of drugs. METHODS: In this work, the potential of polyethylene glycol (PEG 8000), polyvinyl pyrrolidone (PVP K30), poloxamer 188 and hydroxypropyl methylcellulose (HPMC) to inhibit the hydration of nitrofurantoin during dissolution was investigated by experimental and simulation approaches. RESULTS: The rates of phase transformation were decreased in the presence of PEG 8000 and poloxamer 188, and PVP K30 and HPMC completely inhibited the phase transformation of anhydrate. The abundant hydrogen bond donor and acceptor groups of PVP and HPMC may easily establish intermolecular interactions with nitrofurantoin molecules, accounting for stronger inhibition of nucleation. Besides, the molecular dynamic simulation further indicated the formation of more extensive interactions between PVP K30 (or HPMC) and the (111) face of monohydrate, suggesting that the strong absorption of polymers on the surface and thus block the sites for incorporation of new growth. CONCLUSION: This study provides a mechanistic insight into the inhibition of nitrofurantoin hydration by polymeric additives, which helps design formulations and improve the physical stability of anhydrate.

Enhancing Oral Performance of Paclitaxel Lipid-Mimic Prodrug via Modulating Type of Fatty Acids.

Owing to the serious clinical side effects of intravenous Taxol, an oral chemotherapeutic strategy is expected to be promising for paclitaxel (PTX) delivery. However, its poor solubility and permeability, high first-pass metabolism, and gastrointestinal toxicity need to be overcome. A triglyceride (TG)-like prodrug strategy facilitates oral drug delivery by bypassing liver metabolism. However, the effect of fatty acids (FAs) in sn-1,3 on the oral absorption of prodrugs remains unclear. Herein, a series of TG-mimetic prodrugs of PTX is explored with different carbon chain lengths and degrees of unsaturation of FAs at the sn-1,3 position in an attempt to enhance oral antitumor effect and to guide the design of TG-like prodrugs. Interestingly, the different FA lengths exhibit great influence on in vitro intestinal digestion behavior, lymph transport efficiency, and up to fourfold differences in plasma pharmacokinetics. The prodrug with long-chain FAs shows a more effective antitumor effect, whereas the degree of unsaturation has a negligible impact. The findings illustrate how FAs structures affect the oral delivery efficiency of TG-like PTX prodrugs and thus provide a theoretical basis for their rational design.