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.

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.

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.

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.

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.

Human Serum Albumin Nanoparticles as a Carrier of 20(S)-Protopanaxadiol via Intramuscular Injection to Alleviate Cyclophosphamide-Induced Myelosuppression.

Myelosuppression is a prevalent and potentially life-threatening side effect during chemotherapy. As the main active component of ginseng, 20(S)-protopanaxadiol (PPD) is capable of relieving myelosuppression by restoring hematopoiesis and immunity. In this study, PPD was encapsulated in human albumin nanoparticles (PPD-HSA NPs) by nanoparticle albumin-bound (Nab) technology for intramuscular injection to optimize its pharmacokinetic properties and promote recovery of myelosuppression. The prepared PPD-HSA NPs had a particle size of about 280 nm with a narrow size distribution. PPD dispersed as an amorphous state within the PPD-HSA NPs, and the NPs exhibited in vitro sustained release behavior. PPD-HSA NPs showed a favorable pharmacokinetic profile with high absolute bioavailability, probably due to the fact that NPs entered into the blood circulation via lymphatic circulation and were eliminated slowly. In vivo distribution experiments demonstrated that PPD-HSA NPs were mainly distributed in the liver and spleen, but a strong fluorescence signal was also found in the inguinal lymph node, indicating drug absorption via a lymph route. The myelosuppressive model was established using cyclophosphamide as the inducer. Pharmacodynamic studies confirmed that PPD-HSA NPs were effective in promoting the level of white blood cells. Moreover, the neutrophil and lymphocyte counts were significantly higher in the PPD-HSA NPs group compared with the control group. This preliminary investigation revealed that PPD-HSA NPs via intramuscular administration may be an effective intervention strategy to alleviate myelosuppression.

pH-Activatable copper-axitinib coordinated multifunctional nanoparticles for synergistic chemo-chemodynamic therapy against aggressive cancers.

Chemodynamic therapy (CDT) is an emerging oncological treatment that eliminates tumor cells by generating lethal hydroxyl radicals (˙OH) through Fenton or Fenton-like reactions within tumors. However, the effectiveness of CDT is limited by the overexpression of glutathione (GSH) and low reaction efficiency in the tumor microenvironment (TME). To address these challenges and enhance tumor treatment, we developed a novel pH-activatable metal ion-drug coordinated nanoparticle (Cu-AXB NPs) system, incorporating a CDT agent (Cu2+) and a chemotherapeutic agent (axitinib, AXB). The obtained Cu-AXB NPs exhibited exceptional characteristics, including ultrahigh drug loading capacity (87.55%) and an average size of 180 nm. These nanoparticles also demonstrated excellent plasma stability and pH-responsive drug release, enabling prolonged circulation in the bloodstream and targeted therapy at weakly acidic tumor sites. Upon release, AXB acted as a chemotherapeutic agent, effectively eliminating tumor cells, while Cu2+ ions were reduced to Cu+ by GSH, further generating toxic ˙OH with hydrogen peroxide (H2O2) for CDT through a Fenton-like reaction. Additionally, the Cu-AXB NPs efficiently disrupted the copper metabolic balance and increased the intracellular Cu content, further amplifying the therapeutic impact of CDT. In vitro studies assessing cytotoxicity and apoptosis confirmed the superior tumor cell-killing efficacy of the Cu-AXB NPs. This enhanced efficacy can be attributed to the synergistic effect of CDT and chemotherapy. Moreover, the Cu-AXB NPs exhibited excellent tumor targeting capabilities, resulting in significant tumor inhibition (77.53% inhibition) while maintaining favorable biocompatibility in tumor-bearing mice. In conclusion, this study presents a promising and safe strategy for cancer therapy by combining CDT with chemotherapy, offering a potential breakthrough in the field of oncology.

FRET-based analysis on the structural stability of polymeric micelles: Another key attribute beyond PEG coverage and particle size affecting the blood clearance.

Various attributes of micelles, such as PEG density and particle size, are considered to be related to blood clearance. The structural stability of micelles is another key attribute that will affect the in vivo fate. This study employed fluorescence resonance energy transfer (FRET) analysis to guide the preparation of polymeric micelles with different structural stability. Micelles prepared using copolymers with longer hydrophobic blocks showed higher structural stability; emulsification was a better method than nanoprecipitation to prepare stable micelles. The fast chain exchange kinetics and the high-water content of micellar cores explained the low structural stability of those micelles. Moreover, this study highlighted the importance of structural stability that affected blood clearance in concert with PEG length and particle size. One-third of the small and stable micelles were detected in the blood 24 h after injection. While unstable micelles would be cleared from the circulation within 4 h. Notably, there would be a threshold of structural stability. Micelles with structural stability below this threshold were quickly cleared even if they possessed a longer PEG length and a smaller size. In contrast, higher structural stability allowed polymeric micelles to maintain higher integrity in vivo and enhance tumor accumulation and anti-tumor efficacy. In conclusion, this study systematically analyzed the importance of the structural stability of micelles on the in vivo fate.

Enzyme/pH dual stimuli-responsive nanoplatform co-deliver disulfiram and doxorubicin for effective treatment of breast cancer lung metastasis.

OBJECTIVES: Metastasis is still one of the main obstacles in the treatment of breast cancer. This study aimed to develop disulfiram (DSF) and doxorubicin (DOX) co-loaded nanoparticles (DSF-DOX NPs) with enzyme/pH dual stimuli-responsive characteristics to inhibit breast cancer metastasis. METHODS: DSF-DOX NPs were prepared using the amphiphilic poly(ε-caprolactone)-b-poly(L-glutamic acid)-g-methoxy poly(ethylene glycol) (PCL-b-PGlu-g-mPEG) copolymer by a classical dialysis method. In vitro release tests, in vitro cytotoxicity assay, and anti-metastasis studies were conducted to evaluate pH/enzyme sensitivity and therapeutic effect of DSF-DOX NPs. RESULTS: The specific pH and enzyme stimuli-responsiveness of DSF-DO NPs can be attributed to the transformation of secondary structure and the degradation of amide bonds in the PGlu segment, respectively. This accelerated drug release significantly increased the cytotoxicity to 4T1 cells. Compared with the control group, the DSF-DOX NPs showed a strong inhibition of in vitro metastasis with a wound healing rate of 36.50% and a migration rate of 18.39%. Impressively, in vivo anti-metastasis results indicated that the metastasis of 4T1 cells was almost completely suppressed by DSF-DOX NPs. CONCLUSION: DSF-DOX NPs with controllable tumor site delivery of DOX and DSF were a prospectively potential strategy for metastatic breast cancer treatment.

Recent advances in nanoscale metal-organic frameworks for cancer chemodynamic therapy.

Chemodynamic therapy (CDT), a novel therapeutic approach based on Fenton (Fenton-like) reaction, has been widely employed for tumor therapy. This approach utilizes Fe, Cu, or other metal ions (Mn, Zn, Co, or Mo) to react with the excess hydrogen peroxide (H2O2) in tumor microenvironments (TME), and form highly cytotoxic hydroxyl radical (˙OH) to kill cancer cells. Recently, nanoscale metal-organic frameworks (nMOFs) have attracted considerable attention as promising CDT agents with the rapid development of cancer CDT. This review focuses on summarizing the latest advances (2020-2022) on the design of nMOFs as nanomedicine for CDT or combination therapy of CDT and other therapies. The future development and challenges of CDT are also proposed based on recent progress. Our group hopes that this review will enlighten the research and development of nMOFs for CDT.

Progress and prospects of polysaccharide-based nanocarriers for oral delivery of proteins/peptides.

The oral route has long been recognized as the most preferred route for drug delivery as it offers high patient compliance and requires minimal expertise. Unlike small molecule drugs, the harsh environment of the gastrointestinal tract and low permeability across the intestinal epithelium make oral delivery extremely ineffective for macromolecules. Accordingly, delivery systems that are rationally constructed with suitable materials to overcome barriers to oral delivery are exceptionally promising. Among the most ideal materials are polysaccharides. Depending on the interaction between polysaccharides and proteins, the thermodynamic loading and release of proteins in the aqueous phase can be realized. Specific polysaccharides (dextran, chitosan, alginate, cellulose, etc.) endow systems with functional properties, including muco-adhesiveness, pH-responsiveness, and prevention of enzymatic degradation. Furthermore, multiple groups in polysaccharides can be modified, which gives them a variety of properties and enables them to suit specific needs. This review provides an overview of different types of polysaccharide-based nanocarriers based on different kinds of interaction forces and the influencing factors in the construction of polysaccharide-based nanocarriers. Strategies of polysaccharide-based nanocarriers to improve the bioavailability of orally administered proteins/peptides were described. Additionally, current restrictions and future trends of polysaccharide-based nanocarriers for oral delivery of proteins/peptides were also covered.

Self-Assembly of a Linear-Dendritic Polymer Containing Cisplatin and Norcantharidin into Raspberry-like Multimicelle Clusters for the Efficient Chemotherapy of Liver Cancer.

Combination chemotherapy has been proved to be an effective strategy in the clinic, and nanoformulations have drawn much attention in the field of drug delivery. However, conventional nanocarriers suffer from shortcomings such as inefficient coloading and undesired molar ratios of the combined drugs, preleakage of cargos during systemic circulation, and lack of cancer-selective drug release. To achieve tumor-specific codelivery of cisplatin (CDDP) and norcantharidin (NCTD) for synergistic treatment of liver cancer, a novel linear-dendritic polymer, termed as G1(PPDC)x, was designed and synthesized, where a prodrug consisting of cisplatin (CDDP) and norcantharidin (NCTD) was conjugated to PEG2000 via ester bonds to fabricate linear polymer-drug conjugates, and the conjugates were subsequently grafted to the terminal hydroxyls of a dendritic polycarbonate core. Benefiting from the hydrogen bond interactions, G1(PPDC)x could spontaneously self-assemble into a unique type of raspberry-like multimicelle clusters in solution (G1(PPDC)x-PMs). G1(PPDC)x-PMs possessed an optimal synergistic ratio of CDDP and NCTD, without obvious premature release or disassembly in biological environments. Intriguingly, upon extravasation into the interstitial tumor tissues, G1(PPDC)x-PMs (132 nm in diameter) could disassemble and reassemble into smaller micelles (40 nm in diameter) in response to the mildly acidic tumor microenvironment, which would enhance the deep tumor penetration and cellular accumulation of drugs. In vivo delivery of G1(PPDC)x-PMs led to a significantly prolonged blood circulation half-life, which is beneficial to achieve sufficient tumor accumulation through the enhanced permeability and retention (EPR) effect. G1(PPDC)x-PMs displayed the best antitumor activity in H22 tumor-bearing mice with a tumor inhibition rate of 78.87%. Meanwhile, G1(PPDC)x-PMs alleviated both myelosuppression toxicities of CDDP and vascular irritation of NCTD. Our results demonstrated that G1(PPDC)x-PMs could serve as an effective drug delivery system for codelivery of CDDP and NCTD to treat liver cancer efficiently.

The treatment of hepatocellular carcinoma with SP94 modified asymmetrical bilayer lipid-encapsulated Cu(DDC)2 nanoparticles facilitating Cu accumulation in the tumor.

BACKGROUND: Copper diethyldithiocarbamate (Cu(DDC)2) has been demonstrated to possess excellent antitumor activity. However, the extremely poor water solubility of Cu(DDC)2 bring difficulty for its formulation research. In this study, we aim to develop a novel nanocarrier for Cu(DDC)2 delivery to overcome this obstacle and enhance antitumor activity. METHODS: The SP94 modified asymmetrical bilayer lipid-encapsulated Cu(DDC)2 nanoparticles (DCDP) was established by combining the method of inverse microemulsion aggregation and thin-film dispersion. In vitro cellular assays and in vivo tumor-xenograft experiments were conducted to evaluate the tumor chemotherapeutic effect of DCDP. And the vital role of copper ions played in DSF or DDC (DSF/DDC)-based cancer chemotherapy was also explored. RESULTS: DCDP with an encapsulation efficiency (EE%) of 74.0% were successfully prepared. SP94 modification facilitated cellular intake for DCDP, and promoted apoptosis to repress tumor cell proliferation (IC50, 200 nM). And DCDP effectively inhibited tumor growth with a high tumor inhibition rate of 74.84%. Furthermore, Cu(DDC)2 was found to facilitate the copper ion accumulation in tumor tissues, which is beneficial to therapy with high potency. CONCLUSION: DCDP exhibited high-efficient tumor chemotherapeutic efficacy and provided a novel strategy for investigating the anticancer mechanism of Cu(DDC)2.

Progesterone Phospholipid Gel for Intramuscular Administration Prepared by In Situ-Phase Separation.

Long-term daily injection of progesterone for the treatment of threatened abortion can be a source of considerable pain to patients. To reduce the frequency of injections and improve patient compliance, a novel injectable phospholipid-based phase separation gel (PPSG) was prepared using small molecular materials such as phospholipids, medium-chain triglycerides (MCTs), and ethanol. Progesterone was loaded into PPSGs to promote rapid gel formation in situ via a sol-gel transformation mechanism, thereby achieving a sustained controlled release. Furthermore, progesterone was distributed in the oil-water interface layer and within the oil phase. Solvent exchange drives phase transitions, and phospholipid vesicle formation and rupture are likely to promote drug release and gel degradation. At a drug loading of 140 mg/mL, a progesterone release of up to 60% could be reached within 9 days according to the release curve in vitro. Pharmacokinetic studies demonstrated that the progesterone-loaded PPSGs released the drug continuously for over 7 days, the half-life was eight times higher than that of progesterone oil solution, and relative bioavailability of up to 184.90% was obtained. Collectively, the sustained release properties for hydrophobic cargos would effectively enhance patient compliance. Moreover, PPSGs are promising drug delivery systems that have high market value and biosafety given the readily accessible and safe excipients.

Norcantharidin liposome emulsion hybrid delivery system enhances PD-1/PD-L1 immunotherapy by agonizing the non-canonical NF-κB pathway.

PD-1/L1 checkpoint blockade has gained approval in terms of treating patients suffering from hepatocellular carcinoma (HCC). It should be noted that the PD-1/L1 inhibitor (α-PD-1/L1) has a low overall response rate when used as a single agent. Accordingly, the combination of α-PD-1/L1 and a series of therapies to further increase the response rate has become a major research direction. In our previous study, we developed a novel norcantharidin (NCTD) liposome emulsion hybrid delivery system (NE) with enhanced anticancer activity and reduced toxicity. In this study, NE was combined with α-PD-1/L1 for treating HCC. The combination therapy exhibited an enhanced antitumor activity, which led to the up-regulated expression levels of white blood cells, interleukin 12 (IL-12), interferon γ (IFN-γ), PD-L1, as well as CD8. Furthermore, the combination of NE and α-PD-1 achieved the optimal efficiency. NCTD-based chemotherapy is capable of synergizing with α-PD-1/L1 while enhancing checkpoint immunotherapy. It follows a mechanism that NCTD agonizes the non-canonical NF-κB pathway of dendritic cells for better activating CD8+T cells. Furthermore, NCTD may enhance antitumor immunity due to the leukogenic effect. In brief, new therapeutic regimens were provided for anti-HCC treatment by integrating NE to PD-1/L1 immunotherapy.

S/O/W microparticles prepared with hydroxyethyl starch-based emulsifier showed reduced macrophage affinity.

The intramuscular administration of long-acting injectable microparticles elicits a local macrophage uptake resulting in decreased bioavailability. Herein, we developed a ginkgolide B (GB) loaded Solid/Oil/Water (S/O/W) solid lipid microparticles (SLMs) which were modified by hydroxyethyl starch (HES) or poly(ethylene glycol) (PEG) with different surface densities to investigate the influence of surface properties on the cellular uptake and systemic drug exposure. The spherical SLMs with a mean particle size of 10 µm were prepared by melt emulsification and post-insertion method, showing controlled release profile with less than 10 % of GB released in first 2 h. HES-SLMs resulted in lowest degree of RAW264.7 macrophage uptake in vitro and a higher systemic drug exposure in rats than PEG coating SLMs, indicting the capability of thick HES layer of SLMs in evading cellular uptake and sustained GB release. Overall, HES modified SLMs possess a great potential as intramuscular injected drug delivery system to improved bioavailability.