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.

Hybrid adipocyte-derived exosome nano platform for potent chemo-phototherapy in targeted hepatocellular carcinoma.

The high prevalence and severity of hepatocellular carcinoma (HCC) present a significant menace to human health. Despite the significant advancements in nanotechnology-driven antineoplastic agents, there remains a conspicuous gap in the development of targeted chemotherapeutic agents specifically designed for HCC. Consequently, there is an urgent need to explore potent drug delivery systems for effective HCC treatment. Here we have exploited the interplay between HCC and adipocyte to engineer a hybrid adipocyte-derived exosome platform, serving as a versatile vehicle to specifically target HCC and exsert potent antitumor effect. A lipid-like prodrug of docetaxel (DSTG) with a reactive oxygen species (ROS)-cleavable linker, and a lipid-conjugated photosensitizer (PPLA), spontaneously co-assemble into nanoparticles, functioning as the lipid cores of the hybrid exosomes (HEMPs and NEMPs). These nanoparticles are further encapsuled within adipocyte-derived exosome membranes, enhancing their affinity towards HCC cancer cells. As such, cancer cell uptakes of hybrid exosomes are increased up to 5.73-fold compared to lipid core nanoparticles. Our in vitro and in vivo experiments have demonstrated that HEMPs not only enhance the bioactivity of the prodrug and extend its circulation in the bloodstream but also effectively inhibit tumor growth by selectively targeting hepatocellular carcinoma tumor cells. Self-facilitated synergistic drug release subsequently promoting antitumor efficacy, inducing significant inhibition of tumor growth with minimal side effects. Our findings herald a promising direction for the development of targeted HCC therapeutics.

Ferroptosis inducers: A new frontier in cancer therapy.

Ferroptosis represents a non-apoptotic form of programmed cell death characterized by iron-dependent lipid peroxidation. This cell death modality not only facilitates the direct elimination of cancer cells, but also enhances their susceptibility to other pharmacological anti-cancer agents. The burgeoning interest in ferroptosis has been driven by a growing body of evidence that underscores the efficiency and minimal toxicity of ferroptosis inducers. Traditional inducers, such as erastin and RSL3 have shown substantial promise in clinical applications due to their potent therapeutic effects. Their significant potential of these inducers has spurred the development of a variety of small molecule ferroptosis inducers. These novel inducers boast an enhanced structural variety, improved metabolic stability, the capability to initiate ferroptosis without triggering apoptosis, making them well-suited for in vivo use. Despite these advancements, challenges still remain, particularly concerning the drug delivery, tumor specificity, and circulation duration of these small molecules in vivo. Addressing these challenges, contemporary research has pivoted towards innovative delivery systems tailored for ferroptosis inducers to facilitate precise, targeted, and synegestic therapeutic delivery. This review scrutinizes the latest progress in small molecule ferroptosis inducers and nano drug delivery systems geared towards ferroptosis sensitization. Furthermore, it delineated the prospective therapeutic advantages and the existing hurdles in the development of ferroptosis inducers for malignant tumor treatment.

Emerging platinum(IV) prodrug nanotherapeutics: A new epoch for platinum-based cancer therapy.

Owing to the unique DNA damaging cytotoxicity, platinum (Pt)-based chemotherapy has long been the first-line choice for clinical oncology. Unfortunately, Pt drugs are restricted by the severe dose-dependent toxicity and drug resistance. Correspondingly, Pt(IV) prodrugs are developed with the aim to improve the antitumor performance of Pt drugs. However, as "free" molecules, Pt(IV) prodrugs are still subject to unsatisfactory in vivo destiny and antitumor efficacy. Recently, Pt(IV) prodrug nanotherapeutics, inheriting both the merits of Pt(IV) prodrugs and nanotherapeutics, have emerged and demonstrated the promise to address the underexploited dilemma of Pt-based cancer therapy. Herein, we summarize the latest fronts of emerging Pt(IV) prodrug nanotherapeutics. First, the basic outlines of Pt(IV) prodrug nanotherapeutics are overviewed. Afterwards, how versatile Pt(IV) prodrug nanotherapeutics overcome the multiple biological barriers of antitumor drug delivery is introduced in detail. Moreover, advanced combination therapies based on multimodal Pt(IV) prodrug nanotherapeutics are discussed with special emphasis on the synergistic mechanisms. Finally, prospects and challenges of Pt(IV) prodrug nanotherapeutics for future clinical translation are spotlighted.

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.

Incorporating a Lipophilic Disulfide-Bridged Linoleic Prodrug into a Self-Microemulsifying Drug Delivery System to Facilitate Oral Absorption of Paclitaxel.

The oral absorption of paclitaxel (PTX) is restricted by poor solubility in the gastrointestinal tract (GIT), low permeability, and high first-pass metabolism. Lipid carriers, such as a self-microemulsifying drug delivery system (SMEDDS), have been deemed as promising vehicles for promoting oral delivery of PTX. Herein, a lipophilic disulfide-bridged linoleic prodrug (PTX-S-S-LA) was synthesized and efficiently incorporated into SMEDDS to facilitate the oral absorption of PTX. This study mainly aims to evaluate the usefulness of the disulfide-bridged linoleic prodrug incorporated with SMEDDS and provides a new strategy for efficient oral delivery of PTX. The prodrug SMEDDS showed a markedly higher drug loading efficiency (3-fold) compared to that of parent PTX. PTX-S-S-LA SMEDDS significantly increased the drug partition (about 1.9-fold) in the intestinal micellar aqueous phase compared to PTX in the in vitro lipolysis study. Additionally, the gastrointestinal (GI) biodistribution study demonstrated that SMEDDS could enhance the GI biological adhesion and go through the lymphatic system to transport. Moreover, it was found that the reduction-sensitive prodrug (PTX-S-S-LA) has good stability in the GIT, leading to an improved antitumor efficiency without significant GI toxicity. Overall, the PTX-linoleic prodrug (PTX-S-S-LA) in combination with SMEDDS provides a promising way to enable effective oral delivery of PTX.

Tumor-on-a-chip model for advancement of anti-cancer nano drug delivery system.

Despite explosive growth in the development of nano-drug delivery systems (NDDS) targeting tumors in the last few decades, clinical translation rates are low owing to the lack of efficient models for evaluating and predicting responses. Microfluidics-based tumor-on-a-chip (TOC) systems provide a promising approach to address these challenges. The integrated engineered platforms can recapitulate complex in vivo tumor features at a microscale level, such as the tumor microenvironment, three-dimensional tissue structure, and dynamic culture conditions, thus improving the correlation between results derived from preclinical and clinical trials in evaluating anticancer nanomedicines. The specific focus of this review is to describe recent advances in TOCs for the evaluation of nanomedicine, categorized into six sections based on the drug delivery process: circulation behavior after infusion, endothelial and matrix barriers, tumor uptake, therapeutic efficacy, safety, and resistance. We also discuss current issues and future directions for an end-use perspective of TOCs.

Long chain triglyceride-lipid formulation promotes the oral absorption of the lipidic prodrugs through coincident intestinal behaviors.

Oral administration of chemotherapy agents, such as docetaxel (DTX), is expected to reduce side effects significantly and increase dosing frequency. However, they often suffer from poor oral bioavailability, impeding their oral application. Dietary lipids such as triglycerides favor lymphatic transport nor vein system, bypassing the first-pass metabolism. Inspired by this concept, we developed a triglyceride-like prodrug of DTX (named as OATG) and explored the effect of lipid types on the OATG oral delivery. The plasma profile in rats revealed that long chain triglyceride (LCT)-based lipid formulations (LBLF) were more promising for OATG delivery than medium chain triglyceride (MCT) ones. The OATG LBLF elicited a markedly enhanced absorption compared with oral Taxotere or DTX LBLF, resulting in relative bioavailability 6.11 or 2.47-fold higher, respectively. The coincident intestinal behaviors of lipid excipients and TG-like prodrug facilitate the oral absorption of the prodrug. The effectiveness of the prodrug formulation was also examined in beagles with absolute bioavailability up to 41.08%, in sharp contrast to that of control DTX group (8%). Besides, the OATG oral formulation could be schedule-intensively administrated with no hypersensitivity, gastrointestinal and hematological toxicity. The current strategy provides an effective lipid formulation and a promising chance for chemotherapy at home.

Artificial tumor microenvironment regulated by first hemorrhage for enhanced tumor targeting and then occlusion for synergistic bioactivation of hypoxia-sensitive platesomes.

The unique characteristics of the tumor microenvironment (TME) could be exploited to develop antitumor nanomedicine strategies. However, in many cases, the actual therapeutic effect is far from reaching our expectations due to the notable tumor heterogeneity. Given the amplified characteristics of TME regulated by vascular disrupting agents (VDAs), nanomedicines may achieve unexpected improved efficacy. Herein, we fabricate platelet membrane-fusogenic liposomes (PML/DP&PPa), namely "platesomes", which actively load the hypoxia-activated pro-prodrug DMG-PR104A (DP) and physically encapsulate the photosensitizer pyropheophorbide a (PPa). Considering the different stages of tumor vascular collapse and shutdown induced by a VDA combretastatin-A4 phosphate (CA4P), PML/DP&PPa is injected 3 h after intraperitoneal administration of CA4P. First, CA4P-mediated tumor hemorrhage amplifies the enhanced permeation and retention (EPR) effect, and the platesome-biological targeting further promotes the tumor accumulation of PML/DP&PPa. Besides, CA4P-induced vascular occlusion inhibits oxygen supply, followed by photodynamic therapy-caused acute tumor hypoxia. This prolonged extreme hypoxia contributes to the complete activation of DP and then high inhibitory effect on tumor growth and metastasis. Thus, such a combining strategy of artificially-regulated TME and bio-inspired platesomes pronouncedly improves tumor drug delivery and boosts tumor hypoxia-selective activation, and provides a preferable solution to high-efficiency cancer therapy.

A novel fixed-combination timolol-netarsudil-latanoprost ophthalmic solution for the treatment of glaucoma and ocular hypertension.

Currently commercial fixed-concomitant three agents have multiple problems such as multiple dosing administration, poor efficacy and side effects. Once-daily fixed-combination timolol-netarsudil-latanoprost ophthalmic solution (FC-TNL) has the ability to treat glaucoma by lowering the intraocular pressure (IOP) with great efficacy and improving patient compliance. However, the commercialized netarsudil dimesylate precipitated when the pH of the solution was above 5.4, or when maleic acid, the salt of commercial timolol maleate, was mixed with netarsudil dimesylate. Consequently, the homologous salt engineering strategy was used to make netarsudil dimesylate soluble in pH 4.8-5.2 solution by synthesizing timolol mesylate. Next, the morphology of timolol mesylate was observed by scanning electron microscopy, differential scanning calorimetry, thermogravimetric analysis, and powder X-ray diffraction. The prepared FC-TNL showed good stability during refrigeration storage. Additionally, FC-TNL exerted no influence on the intraocular penetration of each active compounds in the pharmacokinetic study. Importantly, once-daily FC-TNL exerted potent IOP-lowering effect and protective effect on retinal ganglion cells. The FC-TNL was stable, safe and effective, being a promising glaucoma therapeutic.

Triglyceride-Mimetic Structure-Gated Prodrug Nanoparticles for Smart Cancer Therapy.

Off-target drug release and insufficient drug delivery are the main obstacles for effective anticancer chemotherapy. Prodrug-based self-assembled nanoparticles bioactivated under tumor-specific conditions are one of the effective strategies to achieve on-demand drug release and effective tumor accumulation. Herein, stimuli-activable prodrugs are designed yielding smart tumor delivery by combination of the triglyceride-mimic (TG-mimetic) prodrug structure and disulfide bond. Surprisingly, these prodrugs can self-assemble into uniform nanoparticles (NPs) with a high drug loading (over 40%) and accumulate in tumor sites specifically. The super hydrophobic TG structure can act as a gate that senses lipase to selectively control over NP dissociation and affect the glutathione-triggered prodrug activation. In addition, the impacts of the double bonds in the prodrug NPs on parent drug release and the following cytotoxicity, pharmacokinetics, and antitumor efficiency are further demonstrated. Our findings highlight the promising potential of TG-mimetic structure-gated prodrug nanoparticles for tumor-specific drug delivery.

Probing the new strategy for the oral formulations of taxanes: changing the method with the situation.

The first-generation taxanes (including paclitaxel and docetaxel) are widely used for the treatment of various cancers in clinical settings. In the past decade, a series of new-generation taxanes have been developed which are effective in the inhibition of tumor resistance. However, intravenous (i.v.) infusion is still the only route of administration, and may result in serious adverse reactions with respect to the utilization of Cremophor EL or Tween-80 as solvent. Besides, the dosing schedule is also limited. Therefore, oral administration of taxanes is urgently needed to avoid the adverse reactionss and increase dosing frequency. In this review, we first outlined the discovery and development of taxane-based anticancer agents. Furthermore, we summarized the research progress on the oral formulations of taxanes and proposed some thoughts on the future development of oral taxane formulations.

A solvent-assisted active loading technology to prepare gambogic acid and all-trans retinoic acid co-encapsulated liposomes for synergistic anticancer therapy.

Liposomal drug delivery has become an established technology platform to deliver dual drugs to produce synergistic effects and reduce the adverse effects of traditional chemotherapy. Gambogic acid (GA) and retinoic acid (RA) are both effective anticancer components, but their low water-solubility (gambogic acid < 0.0050 mg/mL, retinoic acid 0.0048 < mg/mL) makes it difficult to load both drugs into the liposomes actively using the conventional method. We have successfully used solvent-assisted active loading technology (SALT) to load the insoluble drugs into the internal water phase via water-miscible organic solvent. Gambogic acid and retinoic acid co-encapsulated liposomes (weight ratio of GA to RA = 1:2, GRL) exhibited the strongest synergistic effect; combination index (CI) was 0.614 in 4T1 cells. Our studies demonstrated that GRL had uniform droplet size of about 130 nm, high stability, and controlled release behavior. GRL outperformed gambogic acid and retinoic acid solution (GRS) in pharmacokinetic profiles for a longer half-life and increased AUC. Comparing to GRS, GL, and RL, GRL showed increased cytotoxicity and apoptosis in 4T1 cells and showed the strongest anti-tumor ability in the in vivo anti-tumor efficacy. Overall, the SALT was a promising method to active loading poorly soluble drugs into liposomes, and the results showed GRL possessed a great potential for use in synergistic anticancer therapy.

Efficient Intestinal Digestion and On Site Tumor-Bioactivation are the Two Important Determinants for Chylomicron-Mediated Lymph-Targeting Triglyceride-Mimetic Docetaxel Oral Prodrugs.

The oral absorption of chemotherapeutical drugs is restricted by poor solubility and permeability, high first-pass metabolism, and gastrointestinal toxicity. Intestinal lymphatic transport of lipophilic prodrugs is a promising strategy to improve the oral delivery efficiency of anticancer drugs via entrapment into a lipid formulation and to avoid first-pass metabolism. However, several basic principles have still not been clarified, such as intestinal digestibility and stability and on-site tumor bioactivation. Herein, triglyceride-mimetic prodrugs of docetaxel (DTX) are designed by conjugating them to the sn-2 position of triglyceride (TG) through different linkage bonds. The role of intestinal digestion in oral absorption of TG-like prodrugs is then investigated by introducing significant steric-hindrance α-substituents into the prodrugs. It is surprisingly found that poor intestinal digestion leads to an unsatisfactory bioavailability but efficient intestinal digestion of TG-like prodrugs with a less steric-hindrance linkage (DTX-S-S-TG) facilitating oral absorption. Moreover, it is found that the TG-like reduction-sensitive prodrug (DTX-S-S-TG) has good stability during intestinal transport and blood circulation, and on-demand release of docetaxel at the tumor site, leading to a significantly improved antitumor efficiency with negligible gastrointestinal toxicity. In summary, the chylomicron-mediated lymph-targeting triglyceride-mimetic oral prodrug approach provides a good foundation for the development of oral chemotherapeutical formulations.

Monocarboxylate Transporter 1 in Brain Diseases and Cancers.

BACKGROUND: Monocarboxylate Transporter 1 (MCT1), an important membrane transport protein, mediates the translocation of monocarboxylates together with protons across biological membranes. Due to its pathological significance, MCT1 plays an important role in the progression of some diseases, such as brain diseases and cancers. METHODS: We summarize the general description of MCT1 and provide a comprehensive understanding of the role of MCT1 in brain diseases and cancers. Furthermore, this review discusses the opportunities and challenges of MCT1- targeting drug-delivery systems in the treatment of brain diseases and cancers. RESULTS: In the brain, loss of MCT1 function is associated with pathologies of degeneration and injury of the nervous system. In tumors, MCT1 regulates the activity of signaling pathways and controls the exchange of monocarboxylates in aerobic glycolysis to affect tumor metabolism, proliferation and invasion. Meanwhile, MCT1 also acts as a good biomarker for the prediction and diagnosis of cancer progressions. CONCLUSION: MCT1 is an attractive transporter in brain diseases and cancers. Moreover, the development of MCT1- based small molecule drugs and MCT1 inhibitors in the clinic is promising. This review systematically summarizes the basic characteristics of MCT1 and its role in brain diseases and cancers, laying the foundation for further research on MCT1.

Dipeptide-modified nanoparticles to facilitate oral docetaxel delivery: new insights into PepT1-mediated targeting strategy.

Oligopeptide transporter 1 (PepT1) has been a striking prodrug-designing target. However, the underlying mechanism of PepT1 as a target to facilitate the oral absorption of nanoparticles (NPs) remains unclear. Herein, we modify Poly (lactic-co-glycolic acid) (PLGA) NPs with the conjugates of dipeptides (L-valine-valine, L-valine-phenylalanine) and polyoxyethylene (PEG Mw: 1000, 2000) stearate to facilitate oral delivery of docetaxel (DTX) to investigate the oral absorption mechanism and regulatory effects on PepT1 of the dipeptide-modified NPs. The cellular uptake of the dipeptide-modified NPs is more efficient than that of the unmodified NPs in the stably transfected hPepT1- Hela cells and Caco-2 cells, suggesting the involvement of PepT1 in the endocytosis of NPs. The internalization of the dipeptide-modified NPs is proved to be a proton-dependent process. Moreover, the L-valine-valine modified NPs with shorter PEG chain exhibit distinct advantages in terms of intestinal permeability and oral absorption, resulting in significantly improved oral bioavailability of DTX. In summary, PepT1 could serve as a desirable target for oral nanoparticulate drug delivery and the dipeptide-modified NPs represent a promising nanoplatform to facilitate oral delivery of hydrophobic drugs with low bioavailability.