Research on the loading and release kinetics of the vincristine sulfate liposomes and its anti-breast cancer activity.

Vincristine (VCR), as a cytotoxic drug, is used clinically to treat acute lymphatic leukemia and breast cancer, and commonly used clinically as vincristine sulfate (VCRS). However, its clinical use is limited by unpredictable pharmacologic characteristics, a narrow therapeutic index, and neurotoxicity. The pH gradient method was used for active drug loading of VCRS, and the process route mainly includes the preparation of blank liposomes and drug-loaded liposomes. VCRS liposomes had suitable particle size, high encapsulation efficiency and good stability. The loading and release kinetics of VCRS liposomes were explored. By calculating the changes of encapsulation efficiency with time at different temperatures, it was confirmed that the drug-loading process of liposomes exhibited a first-order kinetic feature, and the activation energy required for the reaction was determined as 20.6 kcal/mol. The release behavior at different pH was also investigated, and it was demonstrated that the release behavior conformed to the first-order model, suggesting that the release mechanism of VCRS was simple transmembrane diffusion. VCRS liposomes also enhanced in vitro and in vivo antitumor activity. Thus, VCRS liposomes showed great potential for VCRS delivery, and the loading and release kinetics were well researched to provide a reference for investigating active drug loading liposomes.

Effect of mPEG-PLGA on Drug Crystallinity and Release of Long-Acting Injection Microspheres: In Vitro and In Vivo Perspectives.

PURPOSE: Traditional progesterone (PRG) injections require long-term administration, leading to poor patient compliance. The emergence of long-acting injectable microspheres extends the release period to several days or even months. However, these microspheres often face challenges such as burst release and incomplete drug release. This study aims to regulate drug release by altering the crystallinity of the drug during the release process from the microspheres. METHODS: This research incorporates methoxy poly(ethylene glycol)-b-poly(lactide-co-glycolide) (mPEG-PLGA) into poly(lactide-co-glycolide) (PLGA) microspheres to enhance their hydrophilicity, thus regulating the release rate and drug morphology during release. This modification aims to address the issues of burst and incomplete release in traditional PLGA microspheres. PRG was used as the model drug. PRG/mPEG-PLGA/PLGA microspheres (PmPPMs) were prepared via an emulsification-solvent evaporation method. Scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC) were employed to investigate the presence of PRG in PmPPMs and its physical state changes during release. RESULTS: The addition of mPEG-PLGA altered the crystallinity of the drug within the microspheres at different release stages. The crystallinity correlated positively with the amount of mPEG-PLGA incorporated; the greater the amount, the faster the drug release from the formulation. The bioavailability and muscular irritation of the long-acting injectable were assessed through pharmacokinetic and muscle irritation studies in Sprague-Dawley (SD) rats. The results indicated that PmPPMs containing mPEG-PLGA achieved low burst release and sustained release over 7 days, with minimal irritation and self-healing within this period. PmPPMs with 5% mPEG-PLGA showed a relative bioavailability (Frel) of 146.88%. IN CONCLUSION: In summary, adding an appropriate amount of mPEG to PLGA microspheres can alter the drug release process and enhance bioavailability.

Dual-Targeted Self-Adjuvant Heterocyclic Lipidoid@Polyester Hybrid Nanovaccines for Boosting Cancer Immunotherapy.

Tumor vaccines have demonstrated a modest response rate, primarily attributed to their inefficient delivery to dendritic cells (DCs), low cross-presentation, DC-intrinsic immunosuppressive signals, and an immunosuppressive tumor microenvironment (TME). Here, draining lymph node (DLN)-targeted and tumor-targeted nanovaccines were proposed to address these limitations, and heterocyclic lipidoid (A18) and polyester (BR647) were synthesized to achieve dual-targeted cancer immunotherapy. Meanwhile, oligo hyaluronic acid (HA) and DMG-PEG2000-Mannose were incorporated to prepare dual-targeted nanovaccines encapsulated with STAT3 siRNA and model antigens. The nanovaccines were designed to target the DLN and the tumor, facilitating the delivery of cargo into the cytoplasm. These dual-targeted nanovaccines improved antigen presentation and DC maturation, activated the stimulator of interferon genes (STING) pathway, enhanced the pro-apoptotic effect, and stimulated antitumor immune responses. Additionally, these dual-targeted nanovaccines overcame immunosuppressive TME, reduced immunosuppressive cells, and promoted the polarization of tumor-associated neutrophils from N2 to N1. Among the four dual-targeted nanovaccines that induced robust antitumor responses, the heterocyclic lipidoid@polyester hybrid nanovaccines (MALO@HBNS) demonstrated the most promising results. Furthermore, a combination strategy involving MALO@HBNS and an anti-PD-L1 antibody exhibited an immensely powerful anticancer role. This work introduced a dual-targeted nanovaccine platform for antitumor treatment, suggesting its potential combination with an immune checkpoint blockade as a comprehensive anticancer strategy.

Eudragit L100-coated nintedanib nanocrystals improve oral bioavailability by reducing drug particle size and maintaining drug supersaturation.

The aim of this study was to prepare nintedanib nanocrystals (BIBF-NCs) to lower the solubility of the drug in the stomach, maintain the supersaturation of the drug in the intestine, and improve the oral absorption of nintedanib (BIBF). In this study, BIBF-NCs were prepared by acid solubilization and alkaline precipitation following nano granding method, with a particle size of 290.80 nm and a zeta potential of -49.13 mV. Subsequently, Nintedanib enteric-coated nanocrystals (BIBF-NCs@L100) were obtained by coating with Eudragit L100. The microscopic morphology, crystalline characteristics, stability, and in vitro dissolution of BIBF-NCs and BIBF-NCs@L100 were also studied. In addition, the in vivo pharmacokinetic behaviors of Samples prepared according to the prescription process of commercially available soft capsules (soft capsules), BIBF-NCs, and BIBF-NCs@L100 were further investigated. The results showed that the oral bioavailability of BIBF-NCs and BIBF-NCs@L100 were increased by 1.43 and 2.58 times, compared with that of the soft capsules. BIBF-NCs@L100 effectively reduced the release of BIBF in the formulation in the stomach, allowing more drug to reach the intestine in the form of nanocrystals, maintaining the supersaturation in the intestine, thereby improving the oral bioavailability of the drug.

Preparation and in vitro/in vivo evaluation of a pantoprazole sodium drug-resin liquid delayed release suspension.

A drug-resin liquid delayed-release suspension of pantoprazole sodium (PAZ-Na) was prepared to improve the effectiveness, convenience and safety of peptic ulcer treatment in children, the elderly and patients with dysphagia. Pantoprazole sodium drug-resin complexes (PAZ-Na-DRC) were prepared using the bath method. The fluidized bed coating method is used to coat it and then add excipients to make a dry suspension prepared before use. The parameters of the in vitro release experimental conditions were optimized and the drug release curve showed delayed release. Rats were given commercial PAZ-Na enteric-coated pellet capsules and the PAZ-Na delayed release suspension via intragastric administration. The results showed that the Tmax of the PAZ-Na delayed release suspension was increased from 2h to 4h compared with the PAZ-Na enteric-coated pellet capsules. Similarly, the Cmax was reduced from 6.162µg/mL to 3.244µg/mL with the concentration-time curve is very gentle compared with the commercial drug capsules. After oral administration, the relative bioavailability of PAZ-Na delayed release suspension (AUC0-24 of 19.578 µg•h•mL-1) compared with the commercial drug (AUC0-24 of 17.388 µg•h•mL-1) was 112.67%. The findings showed that the PAZ-Na delayed release suspension for oral administration was successfully formulated with highly improved pharmacokinetic indices.

Development and in vitro/in vivo evaluation of famotidine hydrochloride bioadhesive sustained release suspension.

To develop a new kind of famotidine-resin microcapsule for gastric adhesion sustained release by screening out suitable excipients and designing reasonable prescriptions to improve patient drug activities to achieve the expected therapeutic effect. The famotidine drug resin was prepared using the water bath method with carbomer 934 used as coating material. Microcapsules were prepared using the emulsified solvent coating method and appropriate excipients were used to prepare famotidine sustained release suspension. Pharmacokinetics of the developed microcapsules were studied in the gastrointestinal tract of rats. The self-made sustained-release suspension of famotidine hydrochloride effectively reduced the blood concentration and prolonged the action time. The relative bioavailability of the self-made suspension of the famotidine hydrochloride to the commercially available famotidine hydrochloride was 146.44%, with an average retention time of about 5h longer, which indicated that the new suspension had acceptable adhesion properties. The findings showed that the newly developed famotidine-resin microcapsule increased the bioavailability of the drug with a significant sustained-release property.

Enhanced localized therapeutic precision: A face-to-face folate-targeted Cu2+-mediated nanotherapy with thermosensitive sustained-release system.

Safe and effective Cu2+ supplementation in local lesion is crucial for minimizing toxicity of DSF-based chemotherapy. Targeted delivery of Cu2+ appears more promising. Intraperitoneal chemotherapy for peritoneal carcinoma (PC) establishes "face-to-face" contact between targeted nanocarriers and tumor tissue. Herein, this study developed a biodegradable, injectable thermosensitive hydrogel that coencapsulating DSF submicroemulsion (DSF-SE) and folate-modified liposome loading glycyrrhizic acid-Cu (FCDL). FCDL acted as 'beneficial horse' to target the tumor-localized folate receptor, thus liberating Cu2+ in tumor nidus. The prepared FCDL and DSF-SE were found with uniform sizes (160.2 nm, 175.4 nm), low surface charge (-25.77 mV, -16.40 mV) and high encapsulation efficiency (97.93 %, 90.08 %). In vitro drug release profile of FCDL, DSF-SE and FCDL＆DSF-SE@G followed a sustained release pattern. And the release behavior of Cu2+ from FCDL was pH-related, i.e., Cu2+ was released faster under acidic condition. When FCDL and DSF-SE were loaded into an PLGA-PEG-PLGA-based hydrogel system, FCDL＆DSF-SE@G was formed to ensure separated delivery of Cu2+ and DSF in space but synchronized release over time. The rheology experiment showed a satisfactory gelling temperature of 32.7 °C. In vitro cytotoxicity study demonstrated that FCDL＆DSF-SE@G significantly lowered the IC50 of free Cu2+/DSF, Cu2+/DSF hydrogel and non-targeted analogue by almost 70 %, 65 % and 32 %, respectively. Accordingly, in tumor-bearing mice, FCDL＆DSF-SE@G augmented the tumor inhibition rates for the same formulations by 352 %, 145 % and 44 %, respectively. The main mechanism was attributed to higher uptake of FCDL and DSF-SE, resulting in increased Cu(DDTC)2 formation, ROS production and cell apoptosis. In conclusion, this targeted nanotherapy approach with dual-nanocarriers loaded hydrogel system, with its focus on face-to-face contact between nanocarriers and tumor tissues in the peritoneal cavity, holds significant promise for intraperitoneal chemotherapy in PC.

Effect of hydroxyethyl starch on drug stability and release of semaglutide in PLGA microspheres.

The degradation of peptide drugs limits the application of peptide drug microspheres. Structural changes of peptides at the water-oil interface and the destruction of their spatial structure in the complex microenvironment during polymer degradation can affect drug release and in vivo biological activity. This study demonstrates that adding hydroxyethyl starch (HES) to the internal aqueous phase (W1) significantly enhances the stability of semaglutide and optimizes its release behavior in PLGA microspheres. The results showed that this improvement was due to a spontaneous exothermic reaction (ΔH = -132.20 kJ mol-1) facilitated by hydrogen bonds. Incorporating HES into the internal aqueous phase using the water-in-oil-in-water (W1/O/W2) emulsion method yielded PLGA microspheres with a high encapsulation rate of 94.38 %. Moreover, microspheres with HES demonstrated well-controlled drug release over 44 days, unlike the slower and incomplete release in microspheres without HES. The optimized h-MG2 formulation achieved a more complete drug release (83.23 %) and prevented 30.65 % of drug loss compared to the HES-free microspheres within the same period. Additionally, the optimized semaglutide microspheres provided nearly three weeks of glycemic control with adequate safety. In conclusion, adding HES to the internal aqueous phase improved the in-situ drug stability and release behavior of semaglutide-loaded PLGA microspheres, effectively increasing the peptide drug payload in PLGA microspheres.

Improving the prediction performance of leaf water content by coupling multi-source data with machine learning in rice (Oryza sativa L.).

BACKGROUND: Leaf water content (LWC) significantly affects rice growth and development. Real-time monitoring of rice leaf water status is essential to obtain high yield and water use efficiency of rice plants with precise irrigation regimes in rice fields. Hyperspectral remote sensing technology is widely used in monitoring crop water status because of its rapid, nondestructive, and real-time characteristics. Recently, multi-source data have been attempted to integrate into a monitored model of crop water status based on spectral indices. However, there are fewer studies using spectral index model coupled with multi-source data for monitoring LWC in rice plants. Therefore, 2-year field experiments were conducted with three irrigation regimes using four rice cultivars in this study. The multi-source data, including canopy ecological factors and physiological parameters, were incorporated into the vegetation index to accurately predict LWC in rice plants. RESULTS: The results presented that the model accuracy of rice LWC estimation after combining data from multiple sources improved by 6-44% compared to the accuracy of a single spectral index normalized difference index (ND). Additionally, the optimal prediction accuracy of rice LWC was produced using a machine algorithm of gradient boosted decision tree (GBDT) based on the combination of ND(1287,1673) and crop water stress index (CWSI) (R2 = 0.86, RMSE = 0.01). CONCLUSIONS: The machine learning estimation model constructed based on multi-source data fully utilizes the spectral information and considers the environmental changes in the crop canopy after introducing multi-source data parameters, thus improving the performance of spectral technology for monitoring rice LWC. The findings may be helpful to the water status diagnosis and accurate irrigation management of rice plants.

An adaptive drug-releasing contact lens for personalized treatment of ocular infections and injuries.

This research introduces an innovative solution to address the challenges of bacterial keratitis and alkali burns. Current treatments for bacterial keratitis and alkali burns rely on the frequent use of antibiotics and anti-inflammatory eye drops. However, these approaches suffer from poor bioavailability and fluctuating concentrations, leading to limited efficacy and potential drug resistance. Our approach presents an adaptive drug-releasing contact lens responsive to reactive oxygen species (ROS) at ocular inflammation sites, synchronously releasing Levofloxacin and Diclofenac. During storage, minimal drug release occurred, but over 7 days of wear, the lens maintained a continuous, customizable drug release rate based on disease severity. This contact lens had strong antibacterial activity and biofilm prevention, effectively treating bacterial keratitis. When combined with autologous serum, this hydrophilic, flexible lens aids corneal epithelial regeneration, reducing irritation and promoting healing. In summary, this ROS-responsive drug-releasing contact lens combines antibacterial and anti-inflammatory effects, offering a promising solution for bacterial keratitis and alkali burns.

Construction and in vitro/in vivo evaluation of menantine hydrochloride oral liquid sustained-release drug delivery system.

OBJECTIVE: The purpose of the present study was to formulate a menantine hydrochloride (MH) sustained-release suspension. METHODS: Menantine hydrochloride drug resin complex (MH-DRC) was prepared with strong acid cation exchange resin as carrier using water bath method. The MH-DRC was characterized using scanning electron microscopy, X-ray diffraction and infrared spectroscopy. The MH-coated microcapsule (MH-CM) with optimized formulation was further dispersed in a suitable medium to obtain a sustained-release suspension. The rats were given both the MH sustained-release suspension and the commercial MH sustained-release capsule by intragastric administration. The plasma concentration-time curves and related pharmacokinetic parameters were also investigated using a non-atrioventricular model. RESULTS: MH and ion-exchange resin were ionically bonded. AmberliteIRP®69 had a higher affinity for MH at the initial concentration of 5 mg·mL-1 and a reaction temperature of 25.0 ± 0.5 °C. In vitro drug release profile showed that both the drug resin complex and the coated microcapsules had a certain level of sustained-release effect. The t1/2 of MH sustained-release suspension was extended from 68.44 h to 72.79 h with the peak blood concentration being decreased to 3.56 µg·mL-1 and the Tmax extended to 12 h compared with the commercial MH sustained-release capsule. The concentration-time curve of the self-made MH sustained-release suspension was flattened and the average relative bioavailability (Fr) was 116.65% compared with the commercial MH sustained-release capsules. CONCLUSIONS: The findings showed that the MH sustained-release suspension was successfully formulated with acceptable pharmacokinetic indices for effective treatment of Alzheimer's disease.

Novel solid self-emulsifying drug delivery system to enhance oral bioavailability of cabazitaxel.

In this study, a novel cabazitaxel solid self-emulsifying drug delivery system (CTX S-SEDDS) was developed by solvent evaporation and liquid-solid compression technology, which overcame the limitations of the traditional SEDDS and improved the oral bioavailability. From the results of solubility, pseudo-ternary phase diagram, and single-factor analysis, Tween 80 (surfactant), Tricaprylin (oil), and Glyceryl monooleate (oil) with the ratio of 30:55:15 showed optimized particle size (140.87 nm), short emulsification and high cabazitaxel (CTX) loading capacity (50 mg·g-1). Based on the liquid-solid compression mathematical model, Syloid XDP3050 was determined as carrier material and Syloid 244FP as coating material. The prepared CTX S-SEDDS showed excellent flowability, tabletability, and reconstitution property. In vivo pharmacokinetics in rats demonstrated the absolute bioavailability of CTX S-SEDDS (17.27 %) was significantly enhanced compared with CTX solution (1.69 %), which was close to that of CTX-SEDSS (20.48 %). Lymphatic absorption was verified by in vitro imaging to be an important absorption route for self-emulsifying preparations. These results suggested that CTX S-SEDDS could enhance oral bioavailability of poorly water-soluble drug cabazitaxel while avoiding SEDDS limitations and harnessing the dual advantages of solid and liquid preparations.

Synthesis of the DEF-Ring Spirocyclic Core of Cyclopamine.

A stereoselective synthesis of the DEF-ring spirocyclic core of cyclopamine was accomplished using commercially available materials. The key steps in the synthesis were (i) the enantioselective vinylogous Mannich reaction, followed by lactamization to generate the piperidine F ring, and (ii) intramolecular oxidative dearomative spiroetherification to construct the DEF-ring spirocyclic core of cyclopamine. We found that the stereochemistry of the spirocyclization was controlled by the configuration of the methyl group (C-20) in the substrate.

Intramuscular injection of palmitic acid-conjugated Exendin-4 loaded multivesicular liposomes for long-acting and improving in-situ stability.

BACKGROUND: Exendin-4 (Ex4) is a promising drug for diabetes mellitus with a half-life of 2.4 h in human bodies. Besides, the Ex4 formulations currently employed in the clinic or under development have problems pertaining to stability. In this study, palmitic acid-modified Ex4 (Pal-Ex4) was prepared and purified to extend the half-life of Ex4. In addition, Pal-Ex4-MVLs were further designed and optimized as a long-acting delivery system for intramuscular injection. METHODS: Pal-Ex4 was encapsulated within multivesicular liposomes (MVLs) via a two-step double emulsification process. The formulated products were then assessed for their vesicle size, encapsulation efficiency, and in vitro and in vivo. RESULTS: Pal-Ex4-MVLs with a notable encapsulation efficiency of 99.18% were successfully prepared. Pal-Ex4-MVLs, administered via a single intramuscular injection in Sprague-Dawley rats, sustained stable plasma concentrations for 168 h, presenting extended half-life (77.28 ± 12.919 h) and enhanced relative bioavailability (664.18%). MVLs protected Ex4 through providing stable retention and slow release. This approach considerably improved the in-situ stability of the drug for intramuscular administration. CONCLUSIONS: The combination of palmitic acid modification process with MVLs provides dual protection for Ex4 and can be a promising strategy for other hydrophilic protein/polypeptide-loaded sustained-release delivery systems with high drug bioactivity.

Activate the endogenous Cu2+ switch for Zn(DDC)2 liposomes conversion: Providing a safer and less toxic alternative in cancer therapy.

The ancient anti-alcohol drug disulfiram (DSF) has gained widespread attention for its highly effective anti-tumor effects in cancer treatment. Our previous studies have developed liposome of Cu (DDC)2 to overcome the limitations, like the poor water solubility. However, Cu (DDC)2 liposomes still have shown difficulties in severe hemolytic reactions at high doses and systemic toxicity, which have limited their clinical use. Therefore, this study aims to exploratively investigate the feasibility of using DSF or DDC in combination also can chelate Zn2+ to form zinc diethyldithiocarbamate (Zn (DDC)2). Furthermore, this study prepared stable and homogeneous Zn (DDC)2 liposomes, which were able to be released in the tumor microenvironment (TME). The released Zn (DDC)2 was converted to Cu (DDC)2 with the help of endogenous Cu2+-switch enriched in the TME, which has a higher stability constant compared with Zn (DDC)2. In other words, the Cu2+-switch is activated at the tumor site, completing the conversion of the less cytotoxic Zn (DDC)2 to the more cytotoxic Cu (DDC)2 for effective tumor therapy so that the Zn (DDC)2 liposomes in vivo achieved the comparable therapeutic efficacy and provided a safer alternative to Cu (DDC)2 liposomes in cancer therapy.

Asymmetric Synthesis of Cyclopamine, a Hedgehog (Hh) Signaling Pathway Inhibitor.

Cyclopamine is a teratogenic steroidal alkaloid, which inhibits the Hedgehog (Hh) signaling pathway by targeting the Smoothened (Smo) receptor. Suppression of Hh signaling with synthetic small molecules has been pursued as a therapeutic approach for the treatment of cancer. We report herein the asymmetric synthesis of cyclopamine based on a two-stage relay strategy. Stage-I: total synthesis of veratramine through a convergent approach, wherein a crucial photoinduced excited-state Nazarov reaction was applied to construct the basic [6-6-5-6] skeleton of C-nor-D-homo-steroid. Stage-II: conversion of veratramine to cyclopamine was achieved through a sequence of chemo-selective redox manipulations.

Design of carboxymethylcellulose-conjugated polymeric prodrug micelles for enhanced in vivo performance of docetaxel.

Docetaxel (DTX) has become one of the most important cytotoxic drugs to treat cancer; nevertheless, its poor hydrophilicity and non-specific distribution of DTX lead to detrimental side effects. In this article, we devised carboxymethylcellulose (CMC)-conjugated polymeric prodrug micelles (mPEG-CMC-DTX PMs) for DTX delivery. The ester-bonded polymeric prodrug, mPEG-CMC-DTX, was synthesized and exhibited the capacity for self-assembling into polymeric micelles. The CMC is profusely substituted and acetylated to promote the coupling rate of DTX. Covalent binding of DTX and CMC through an ester bond can be hydrolyzed to dissociate the bond under the action of esterase in the tumor. The mPEG-CMC-DTX PMs displayed promoted drug loading (>50 %, wt), commendable stability, and sustained release behavior in vitro. The gradual release of the prodrug amplified the selectivity of cytotoxicity between normal cells and tumor cells, mitigating the systemic toxicity of mPEG-CMC-DTX PMs and enabling dose intensification. Notably, mPEG-CMC-DTX PMs demonstrated a superior antitumor efficacy and low systemic toxicity due to the elevated tolerance dosage (even at 40 mg/kg DTX). In summation, mPEG-CMC-DTX PMs harmonized the antitumor efficacy and toxicity of DTX. In essence, innovative perspectives for the rational design of CMC-conjugated polymeric prodrug micelles for the delivery of potently toxic drugs were proffered.

Research on the preparation process of the cytarabine/daunorubicin dual-encapsulation liposome and its physicochemical properties and performances in vitro/vivo.

As the only Food and Drug Administration (FDA)-approved dual-encapsulation liposome injection for treating Acute myeloid leukemia (AML), CPX-351 outperforms the standard chemotherapy treatment "DA 7 + 3″ in terms of clinical effectiveness. Although research on dual-loaded liposomes has increased in recent years, little attention has been paid to their preparation, which can affect their quality, efficacy, and safety. This study explored various preparation processes to create the cytarabine/daunorubicin co-loaded liposome (the Cyt/Daun liposome) and eventually settled on two methods: the sequential loading approach, thin film hydration-extrusion-copper ion gradient, and the simultaneous encapsulation technique, copper ion gradient-concentration gradient. Different preparation methods resulted in different particle sizes and encapsulation efficiencies; the two aforementioned preparation processes generated dual-loaded liposomes with comparable physicochemical properties. The sequential encapsulation technique was selected for the subsequent research owing to its higher encapsulation efficiency prior to purification; the prepared Cyt/Daun liposomes had small and uniform particle size (108.6 ± 1.02 nm, Polydispersity index (PDI) 0.139 ± 0.01), negative charge (-(60.2 ± 1.15) mV), high drug encapsulation efficiency (Cyt 88.2 ± 0.24 %, Duan 94.2 ± 0.45 %) and good plasma stability. To improve its storage stability, the Cyt/Daun liposome was lyophilized (-40 °C for 4 h, maintained for 130 min, and dried for 1200 min) using sucrose-raffinose (mass ratio 7:3; glycolipid ratio 4:1, w/w) as a lyoprotectant. The lyophilized liposomes were purple cakes, redissolved rapidly with insignificant alterations in particle size and encapsulation efficiency, and possessed well storage stability. The pharmacokinetic and tissue distribution studies demonstrated that the Cyt/Daun liposome could achieve long circulation and maintain synergic proportions of drugs within 24 h, increasing the accumulation of drugs at tumor sites. Furthermore, the in vitro/in vivo pharmacodynamic studies confirmed its good anti-tumor activity and safety.

Intratumoral injection of norcantharidin liposome emulsion hybrid delivery system amplifies the cancer-fighting effects of oral sorafenib against hepatocellular carcinoma.

Interventional therapies are increasingly used in clinical trials for hepatocellular carcinoma (HCC). Sorafenib is the front-line remedy for HCC, however, chemoresistance occurs immutably and affects the effectiveness of treatment. In a previous study, a norcantharidin liposome emulsion hybrid (NLEH) delivery system for HCC was developed. This study aims to examine the therapeutic effects of the combination of intratumoral injection of NLEH and sorafenib in treating HCC. Sorafenib combined with NLEH activated the apoptosis pathway by synergistically upregulating caspase-9, promoting cytotoxicity, apoptosis (64.57%), and G2/M cell cycle arrest (48.96%). Norcantharidin could alleviate sorafenib resistance by counteracting sorafenib-induced phosphorylation of Akt. Additionally, intratumoral injection of NLEH exhibited a sustained accumulation in the tumor within 24 h and didn't distribute to other major organs. Intratumoral injection of NLEH in combination with oral sorafenib displayed the most potent tumor growth inhibitory effect (77.91%) in vivo. H&E staining results and the indicators of the renal and liver function tests demonstrated the safety of this combination therapy. Overall, these results showed that intratumoral injection of NLEH in combination with oral sorafenib treatment represented a rational potential therapeutic option for HCC.

Dual-responsive PEG-lipid polyester nanoparticles for siRNA and vaccine delivery elicit anti-cancer immune responses by modulating tumor microenvironment.

Cancer vaccine-based immunotherapy has great potential; however, the vaccines have been hindered by the immunosuppressive tumor microenvironment (TME). In this study, dual-responsive PEG-lipid polyester nanoparticles (PEG BR647-NPs) for tumor-targeted delivery were proposed. PEG BR647-NPs containing the model tumor-associated antigen (TAA) OVA and the signal transduction and activator of transcription 3 (STAT3) siRNA were delivered to the tumor. The PEG BR647-NPs were internalized by tumor-associated dendritic cells (TADCs), where the TAA and siRNA were released into the cytoplasm via the endo/lysosome escape effect. The released OVA was presented by the major histocompatibility complex class I to activate T cells, and the released STAT3 siRNA acted to relieve TADC dysfunction, promote TADC maturation, improve antigen-presenting ability, and enhance anticancer T cell immunity. Meanwhile, the PEG BR647-NPs were ingested by tumor cells, killing them by the pro-apoptosis effect of STAT3 siRNA. Moreover, PEG BR647-NPs could reduce the proportion of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in tumors and abrogate immunosuppression. The integration of relieved TADC dysfunction, promoted TADC maturation, enhanced antigen cross-presentation, abrogated immunosuppression, and improved pro-apoptosis effect boosted the vaccination for tumor immunotherapy. Thus, PEG BR647-NPs efficiently delivered the vaccine and STAT3 siRNA to the tumor and modulated immunosuppressive TME, thus providing better antitumor effects.