The Remarkable Anti-Breast Cancer Efficacy and Anti-Metastasis by Multifunctional Nanoparticles Co-Loading Squamocin, R848 and IR 780.

Background: Breast cancer is a heterogeneous disease globally accounting for approximately 1 million new cases annually. Chemotherapy remains the main therapeutic option, but the antitumor efficacy needs to be improved. Methods: Two multifunctional nanoparticles were developed in this paper using oleic acid and mPEG2k-PCL2k as the drug carriers. Squamocin (Squ) was employed as a chemotherapeutic agent. Resiquimod (R848) or ginsenoside Rh2 was co-encapsulated in the nanoparticles to remold the immunosuppressive tumor microenvironment, and IR780 was coloaded as a photosensitizer to realize photothermal therapy. Results: The obtained Squ-R848-IR780 nanoparticles and Squ-Rh2-IR780 nanoparticles were uniformly spherical and approximately (162.200 ± 2.800) nm and (157.300 ± 1.1590) nm, respectively, in average diameter, with good encapsulation efficiency (above 85% for each drug), excellent stability in various physiological media and high photothermal conversion efficiency (24.10% and 22.58%, respectively). After intravenous administration, both nanoparticles quickly accumulated in the tumor and effectively enhanced the local temperature of the tumor to over 45 °C when irradiated by an 808 nm laser. At a low dose of 0.1 mg/kg, Squ nanoparticles treatment alone displayed a tumor inhibition rate of 55.28%, pulmonary metastasis inhibition rate of 59.47% and a mean survival time of 38 days, which were all higher than those of PTX injection (8 mg/kg) (43.64%, 25 days and 37.25%), indicating that Squ was a potent and effective antitumor agent. Both multifunctional nanoparticles, Squ-Rh2-IR780 nanoparticles and Squ-R848-IR780 nanoparticles, demonstrated even better therapeutic efficacy, with tumor inhibition rates of 90.02% and 97.28%, pulmonary metastasis inhibition rates of 95.42% and 98.09, and mean survival times of 46 days and 52 days, respectively. Conclusion: The multifunctional nanoparticles coloaded with squamocin, R848 and IR 780 achieved extraordinary therapeutic efficacy and excellent antimetastasis activity and are thus promising in the future treatment of breast tumors and probably other tumors.

Nanoparticle-Mediated Synergistic Chemoimmunotherapy for Cancer Treatment.

Until now, there has been a lack of effective strategies for cancer treatment. Immunotherapy has high potential in treating several cancers but its efficacy is limited as a monotherapy. Chemoimmunotherapy (CIT) holds promise to be widely used in cancer treatment. Therefore, identifying their involvement and potential synergy in CIT approaches is decisive. Nano-based drug delivery systems (NDDSs) are ideal delivery systems because they can simultaneously target immune cells and cancer cells, promoting drug accumulation, and reducing the toxicity of the drug. In this review, we first introduce five current immunotherapies, including immune checkpoint blocking (ICB), adoptive cell transfer therapy (ACT), cancer vaccines, oncolytic virus therapy (OVT) and cytokine therapy. Subsequently, the immunomodulatory effects of chemotherapy by inducing immunogenic cell death (ICD), promoting tumor killer cell infiltration, down-regulating immunosuppressive cells, and inhibiting immune checkpoints have been described. Finally, the NDDSs-mediated collaborative drug delivery systems have been introduced in detail, and the development of NDDSs-mediated CIT nanoparticles has been prospected.

Simple preparation and greatly improved oral bioavailability: The supersaturated drug delivery system of quercetin based on PVP K30.

Quercetin, as a representative flavonoid, is widely present in daily diet and has been developed as a dietary supplement due to its beneficial physiological activities. However, the application of quercetin is limited due to its poor water solubility and extensive metabolism. So far, the nano-drug delivery systems designed to improve its bioavailability generally have the shortcomings of low drug loading content and difficulty in industrial production. In order to tackle these problems, quercetin supersaturated drug delivery system (QSDDS) was successfully prepared using solvent method, for which PVP K30 was employed as a crystallization and precipitation inhibitor to maintain the supersaturated state of quercetin in aqueous system. The obtained QSDDS, with a relative high drug loading content of 13%, could quickly disperse in water and form colloidal system with the mean particle size of about 200 nm, meanwhile induce the generation of supersaturated quercetin solution more than 12 h. In vivo pharmacokinetic study proved that QSDDS achieved a high absolute bioavailability of 36.05%, 10 times as that of physical quercetin suspension, which was dose-dependent with higher bioavailability at higher dose. Considering the simple preparation method, QSDDS provided a feasible strategy and a simple way to improve oral absorption of insoluble flavonoids.

Ochratoxin A: Overview of Prevention, Removal, and Detoxification Methods.

Ochratoxins are the secondary metabolites of Penicillium and Aspergillus, among which ochratoxin A (OTA) is the most toxic molecule. OTA is widely found in food and agricultural products. Due to its severe nephrotoxicity, immunotoxicity, neurotoxicity, and teratogenic mutagenesis, it is essential to develop effective, economical, and environmentally friendly methods for OTA decontamination and detoxification. This review mainly summarizes the application of technology in OTA prevention, removal, and detoxification from physical, chemical, and biological aspects, depending on the properties of OTA, and describes the advantages and disadvantages of each method from an objective perspective. Overall, biological methods have the greatest potential to degrade OTA. This review provides some ideas for searching for new strains and degrading enzymes.

A γ-Glutamyl Transpeptidase (GGT)-Triggered Charge Reversal Drug-Delivery System for Cervical Cancer Treatment: In Vitro and In Vivo Investigation.

Neutral/negatively charged nanoparticles are beneficial to reduce plasma protein adsorption and prolong their blood circulation time, while positively charged nanoparticles easily transverse the blood vessel endothelium into a tumor and easily penetrate the depth of the tumor via transcytosis. Γ-Glutamyl transpeptidase (GGT) is overexpressed on the external surface of endothelial cells of tumor blood vessels and metabolically active tumor cells. Nanocarriers modified by molecules containing γ-glutamyl moieties (such as glutathione, G-SH) can maintain a neutral/negative charge in the blood, as well as can be easily hydrolyzed by the GGT enzymes to expose the cationic surface at the tumor site, thus achieving good tumor accumulation via charge reversal. In this study, DSPE-PEG2000-GSH (DPG) was synthesized and used as a stabilizer to generate paclitaxel (PTX) nanosuspensions for the treatment of Hela cervical cancer (GGT-positive). The obtained drug-delivery system (PTX-DPG nanoparticles) was 164.6 ± 3.1 nm in diameter with a zeta potential of -9.85 ± 1.03 mV and a high drug-loaded content of 41.45 ± 0.7%. PTX-DPG NPs maintained their negative surface charge in a low concentration of GGT enzyme (0.05 U/mL), whereas they showed a significant charge-reversal property in the high-concentration solution of GGT enzyme (10 U/mL). After intravenous administration, PTX-DPG NPs mainly accumulated more in the tumor than in the liver, achieved good tumor-targetability, and significantly improved anti-tumor efficacy (68.48% vs. 24.07%, tumor inhibition rate, p < 0.05 in contrast to free PTX). This kind of GGT-triggered charge-reversal nanoparticle is promising to be a novel anti-tumor agent for the effective treatment of such GGT-positive cancers as cervical cancer.

Ginsenoside Rb1 stabilized and paclitaxel / protopanaxadiol co-loaded nanoparticles for synergistic treatment of breast tumor.

Ginsenosides are the major and key components for ginseng to exert its wide and beneficial therapeutic efficacy in clinic. Meanwhile, many ginsenosides and their metabolites showed in vitro an in vivo anti-tumor activity, among which ginsenoside Rb1 has attracted much attention due to its good solubility and amphipathy. In this study, the self-assembly behavior of Rb1 was investigated and the Rb1 nano-assembly could further stabilize or encapsulated hydrophobic drugs such as protopanaxadiol (PPD) and paclitaxel (PTX) to form nanoparticles, based on which, a natural nanoscale drug delivery system, ginsenoside Rb1 stabilized and PTX/PPD co-loaded nanoparticles (GPP NPs) were prepared. The resultant GPP NPs exhibited a small particle size of 126.2 nm, a narrow size distribution (PDI=0.145), and a zeta potential of -27.3 mV. PTX loading content was 11.06% with an encapsulation efficiency of 93.86%. GPP NPs were spherical and stable in normal saline, 5% glucose, PBS, plasma, or on-shelf storage for 7 days. Both PTX and PPD existed in an amorphous state in GPP NPs and were released in a sustained pattern. GPP NPs showed 10-fold higher in vitro anti-tumor activity of than PTX injections. In the in vivo experiment, GPP NPs achieved a much higher tumor inhibition rate than PTX injections (64.95% vs 43.17%, P < 0.01) and certain tumor target ability. In conclusion, GPP NPs had significantly enhanced anti-tumor efficacy and improved tumor microenvironment, thus were promising to be developed into a novel anti-tumor agent for the treatment of breast tumor.

Effects of different conformations of polylysine on the anti-tumor efficacy of methotrexate nanoparticles.

Drug delivery systems require that carrier materials have good biocompatibility, degradability, and constructability. Poly(amino acids), a substance with a distinctive secondary structure, not only have the basic features of the carrier materials but also have several reactive functional groups in the side chain, which can be employed as drug carriers to deliver anticancer drugs. The conformation of isomers of drug carriers has some influence on the preparation, morphology, and efficacy of nanoparticles. In this study, two isomers of polylysine, including ε-polylysine (ε-PL) and α-polylysine (α-PL), were used as drug carriers to entrap methotrexate (MTX) and construct nano-drug delivery systems. ε-PL/MTX nanoparticles with the morphology of helical nanorods presented a small particle size (115.0 nm), and relative high drug loading content (57.8 %). The anticancer effect of ε-PL/MTX nanoparticles was 1.3-fold and 2.6-fold stronger than that of α-PL/MTX nanoparticles in vivo and in vitro, respectively. ε-PL is an ideal drug carrier with potential clinical application prospects.

Mitochondrial-Targeted Triphenylphosphonium-Hydroxycamptothecin Conjugate and Its Nano-Formulations for Breast Cancer Therapy: In Vitro and In Vivo Investigation.

Mitochondria are involved in various stages of cancer cell diffusion and metastasis. Therefore, targeting tumor mitochondria with antineoplastic medicines to cause mitochondria to initiate apoptosis may be an effective strategy for cancer therapy. Here, in order to enhance the anti-tumor efficacy of the antineoplastic agent hydroxycamptothecin (HCPT), the mitochondrial targeting ligand 4-(carboxybutyl) triphenylphosphine bromide (TPP) was attached to HCPT by an ester linkage. The resultant TPP-HCPT (TH) conjugate could self-assemble into nano-aggregates, with a mean particle size of 203.2 nm and a polydispersity index (PDI) value of 0.312. The TH conjugate could also co-assembly with mPEG3000-PLGA5000 into nanoparticles (TH-NPs), with a mean diameter of 86.41 nm, a PDI value of 0.256 and a zeta potential of -0.125 mV. In contrast to HCPT injections, TH aggregates displayed enhanced cellular uptake, mitochondria-targetability and cytotoxicity against 4T1 cells, while TH-NPs showed even better improvement than TH aggregates. In the in vivo study, TH aggregates displayed higher anti-tumor efficacy in 4T1 tumor-bearing mice than HCPT injections (tumor inhibition rate, 55.71% vs. 69.17%), and TH-NPs displayed more superior anti-tumor effects (tumor inhibition rate, 80.02%). In conclusion, our research demonstrated that the TPP-HCPT conjugate and its nano-formulations, including TH aggregates and TH-NPs, may be a promising mitochondria-targeting anticancer medicine for cancer therapy. As far as we know, this is the first report in which TPP and HCPT have been conjugated directly for this aim.

A Celastrol Drug Delivery System Based on PEG Derivatives: The Structural Effects of Nanocarriers.

The therapeutic efficacy of nanoscale drug delivery systems is related to particle size, zeta potential, morphology, and other physicochemical properties. The structure and composition of nanocarriers may affect their physicochemical properties. To systematically evaluate these characteristics, three analogues, namely polyethylene glycol (PEG), PEG-conjugated octadecylamine (PEG-C18), and tri(ethylene glycol) (TEG), were explored as nanocarriers to entrap celastrol (CSL) via the injection-combined dialysis method. CSL nanoparticles were successfully prepared as orange milky solutions, which revealed a similar particle size of approximately 120 nm, with narrow distribution and a negative zeta potential of -20 mV. All these CSL nanoparticles exhibited good storage stability and media stability but presented different drug-loading capacities (DLCs), release profiles, cytotoxicity, and hemolytic activity. For DLCs, PEG-C18/CSL exhibited better CSL entrapment capacity. Regarding the release profiles, TEG/CSL showed the lowest release rate, PEG-C18/CSL presented a moderate release rate, and PEG/CSL exhibited a relatively fast release rate. Based on the different release rates, PEG-C18/CSL and TEG/CSL showed higher degrees of cytotoxicity than PEG/CSL. Furthermore, TEG/CSL showed the lowest membrane toxicity, and its hemolytic rate was below 20%. These results suggest that the structural effects of nanocarriers can affect the interactions between nanocarriers and drugs, resulting in different release profiles and antitumor activity.

Combined Photothermal Therapy and Lycium barbarum Polysaccharide for Topical Administration to Improve the Efficacy of Doxorubicin in the Treatment of Breast Cancer.

In order to improve the efficacy of doxorubicin in the treatment of breast cancer, we constructed a drug delivery system combined with local administration of Lycium barbarum polysaccharides (LBP) and photothermal-material polypyrrole nanoparticles (PPY NPs). In vitro cytotoxicity experiments showed that the inhibitory effect of DOX + LBP + PPY NPs on 4T1 cells under NIR (near infrared) laser was eight times that of DOX at the same concentration (64% vs. 8%). In vivo antitumor experiments showed that the tumor inhibition rate of LBP + DOX + PPY NPs + NIR reached 87.86%. The results of the H&E staining and biochemical assays showed that the systemic toxicity of LBP + DOX + PPY NPs + NIR group was reduced, and liver damage was significantly lower in the combined topical administration group (ALT 54 ± 14.44 vs. 28 ± 3.56; AST 158 ± 16.39 vs. 111 ± 20.85) (p < 0.05). The results of the Elisa assay showed that LBP + DOX + PPY NPs + NIR can enhance efficacy and reduce toxicity (IL-10, IFN-γ, TNF-α, IgA, ROS). In conclusion, LBP + DOX + PPY NPs combined with photothermal therapy can improve the therapeutic effect of DOX on breast cancer and reduce its toxic side effects.

Hydrophilic Natural Polylysine as Drug Nanocarrier for Preparation of Helical Delivery System.

Polypeptide materials have clear secondary structure and biodegradability, which can be further modified and functionalized, so that they can be employed as therapeutic agents in clinical applications. PEGylation of polylysine (PEG-PLL) is a kind of safe and effective nanocarrier that is utilized for gene and drug delivery. However, PEG-PLL needs to be produced through chemical synthesis, which is expensive and difficult to obtain. We hope to simplify the nanocarrier and use hydrophilic natural polylysine (PLL) to develop a high-efficacy delivery system. To evaluate the possibility of PLL as nanocarriers, methotrexate (MTX) is selected as a model drug and PEG-PLL is utilized as control nanocarriers. The experimental results showed that PLL is an ideal polypeptide to prepare MTX-loaded PLL nanoparticles (PLL/MTX NPs). Compared with PEG-PLL as nanocarriers, PLL/MTX NPs showed higher drug-loading content (58.9%) and smaller particle sizes (113.7 nm). Moreover, the shape of PLL/MTX NPs was a unique helical nanorod. The PLL/MTX NPs had good storage stability, media stability, and sustained release effect. Animal research demonstrated that PLL/MTX NPs could improve the anti-tumor activity of MTX, the antitumor efficacy is enhanced 1.9-fold and 1.2-fold compared with MTX injection and PEG-PLL/MTX NPs, respectively. To sum up, natural polymer PLL is an ideal nano drug delivery carrier which has potential clinical applications.

Poly(methacrylate citric acid) as a Dual Functional Carrier for Tumor Therapy.

Owing to its pH-sensitive property and chelating Cu2+ effect, poly(methacrylate citric acid) (PCA) can be utilized as a dual functional nanocarrier to construct a nanodelivery system. Negatively charged carboxyl groups can interact with positively charged antineoplastic drugs through electrostatic interaction to form stable drug nanoparticles (NPs). Through drug experimental screening, doxorubicin (DOX) was selected as the model drug, PCA/DOX NPs with a diameter of 84 nm were prepared, and the drug-loading content was 68.3%. PCA/DOX NPs maintained good stability and a sustained release profile. Cell experiments presented that PCA/DOX NPs could inhibit effectively the growth of 4T1 cells; the IC50 value was decreased by approximately 15-fold after incubation for 72 h. The cytotoxicity toward H9C2 was decreased significantly. Moreover, based on its ability to efficiently adsorb copper ions, PCA showed good vascular growth inhibition effect in vitro. Furthermore, animal experiments showed that PCA/DOX NPs presented stronger anticancer effects than DOX; the tumor inhibition rate was increased by 1.5-fold. Myocardial toxicity experiments also confirmed that PCA reduced the cardiotoxicity of DOX. In summary, PCA/DOX NPs show good antitumor efficacy and low toxicity, and have good potential for clinical application.

A simple but efficient tumor-targeted nanoparticle delivery system constructed by oleic acid.

Oleic acid (OA) is a kind of monounsaturated omega-3 fatty acid that abounds in plants and animals which can induce apoptosis and has broad-spectrum inhibitory activity against a variety of tumor cell lines. However, OA is quite insoluble and thus inconvenient to be efficiently delivered in vivo. In this work, OA was fabricated into nanoparticles to generate OA elastic nanoparticles (OA-ENPs) with a particle size of 185.6 nm and good stability in various physiological media. OA-ENPs alone achieved a high tumor inhibition rate of 60.3% without significant side effect. More surprisingly, the resultant OA-ENPs displayed dose-dependent tumor targetability. Low dose of OA-ENPs (10 mg/kg) mainly distributed in the liver after intravenous injection, while high dose of OA-ENPs mainly distributed in tumor. At the high dose of 90 mg/kg, OA-ENPs accumulation in tumor reached nearly twice as that in the liver. Here we provide a simple but effective way to achieve excellent tumor targetability without the need of any surface modification of nanoparticles.

Improved Therapeutic Efficacy of CBD with Good Tolerance in the Treatment of Breast Cancer through Nanoencapsulation and in Combination with 20(S)-Protopanaxadiol (PPD).

Cannabidiol (CBD), a nonpsychoactive major component derived from Cannabis sativa, widely used in neurodegenerative diseases, has now been proven to have growth inhibitory effects on many tumor cell lines, including breast tumors. Meanwhile CBD can effectively alleviate cancer-associated pain, anxiety, and depression, especially tumor cachexia, thus it is very promising as an anti-tumor drug with unique advantages. 20(S)-Protopanaxadiol (PPD) derived from the best-known tonic Chinese herbal medicine Ginseng was designed to be co-loaded with CBD into liposomes to examine their synergistic tumor-inhibitory effect. The CBD-PPD co-loading liposomes (CP-liposomes) presented a mean particle size of 138.8 nm. Further glycosyl-modified CP-liposomes (GMCP-liposomes) were prepared by the incorporation of n-Dodecyl ß-D-maltoside (Mal) into the liposomal bilayer with glucose residue anchored on the surface to act as a ligand targeting the GLUT1 receptor highly expressed on tumor cells. In vivo studies on murine breast tumor (4T1 cells)-bearing BALB/c mice demonstrated good dose dependent anti-tumor efficacy of CP-liposomes. A high tumor inhibition rate (TIR) of 82.2% was achieved with good tolerance. However, glycosylation modification failed to significantly enhance TIR of CP-liposomes. In summary, combined therapy with PPD proved to be a promising strategy for CBD to be developed into a novel antitumor drug, with characteristics of effectiveness, good tolerance, and the potential to overcome tumor cachexia.

Hydrophilic Poly(glutamic acid)-Based Nanodrug Delivery System: Structural Influence and Antitumor Efficacy.

Poly(amino acids) have advanced characteristics, including unique secondary structure, enzyme degradability, good biocompatibility, and stimuli responsibility, and are suitable as drug delivery nanocarriers for tumor therapy. The isoform structure of poly(amino acids) plays an important role in their antitumor efficacy and should be researched in detail. In this study, two kinds of pH-sensitive isoforms, including α-poly(glutamic acid) (α-PGA) and γ-PGA, were selected and used as nanocarriers to prepare a nanodrug delivery system. According to the preparation results, α-PGA can be used as an ideal drug carrier. Selecting doxorubicin (DOX) as the model drug, an α-PGA/DOX nanoparticle (α-PGA/DOX NPs) with a particle size of 110.4 nm was prepared, and the drug-loading content was 66.2%. α-PGA/DOX NPs presented obvious sustained and pH-dependent release characteristics. The IC50 value of α-PGA/DOX NPs was 1.06 ± 0.77 µg mL-1, decreasing by approximately 8.5 fold in vitro against 4T1 cells after incubation for 48 h. Moreover, α-PGA/DOX NPs enhanced antitumor efficacy in vivo, the tumor inhibition rate was 67.4%, increasing 1.5 fold over DOX injection. α-PGA/DOX NPs also reduced the systemic toxicity and cardiotoxicity of DOX. In sum, α-PGA is a biosafe nanodrug delivery carrier with potential clinical application prospects.

Optimization of Naringenin Nanoparticles to Improve the Antitussive Effects on Post-Infectious Cough.

Naringenin (NRG) is a natural compound with several biological activities; however, its bioavailability is limited owing to poor aqueous solubility. In this study, NRG nanoparticles (NPs) were prepared using the wet media milling method. To obtain NRG NPs with a small particle size and high drug-loading content, the preparation conditions, including stirring time, temperature, stirring speed, and milling media amount, were optimized. The NRG (30 mg) and D-α-tocopherol polyethylene glycol succinate (10 mg) were wet-milled in deionized water (2 mL) with 10 g of zirconia beads via stirring at 50 °C for 2 h at a stirring speed of 300 rpm. As a result, the NRG NPs, with sheet-like morphology and a diameter of approximately 182.2 nm, were successfully prepared. The NRG NPs were stable in the gastrointestinal system and were released effectively after entering the blood circulation. In vivo experiments indicated that the NRG NPs have good antitussive effects. The cough inhibition rate after the administration of the NRG NPs was 66.7%, cough frequency was three times lower, and the potential period was 1.8 times longer than that in the blank model group. In addition, the enzyme biomarkers and histological analysis results revealed that the NRG NPs can effectively regulate the inflammatory and oxidative stress response. In conclusion, the NRG NPs exhibited good oral bioavailability and promoted antitussive and anti-inflammatory effects.

Enhanced Solubility and Antitumor Activity of Annona Squamosa Seed Oil via Nanoparticles Stabilized with TPGS: Preparation and In Vitro and In Vivo Evaluation.

Annona squamosa seed oil (ASSO), which is a waste product in the extraction of annonaceous acetogenins (ACGs), displays good antitumor activity against a variety of tumor cells. However, ASSO is insoluble and has low bioavailability. In order to improve the solubility and application value of ASSO, the seed oil nanoparticles (ASSO-NPs) were successfully prepared only using TPGS as a stabilizer. ASSO-NPs obtained were spherical with a uniform size (less than 200 nm). ASSO-NPs showed the good storage stability at 25 ± 2 °C and were suitable for both oral administration and intravenous injection. The antitumor study in vitro and in vivo demonstrated more enhanced antitumor efficacy of ASSO-NPs than free ASSO. The ASSO-NPs group (15 mg/kg) had the highest tumor inhibition rate (TIR) of 69.8%, greater than the ASSO solution (52.7%, 135 mg/kg, p < 0.05) in 4T1 tumor-bearing mice. The in vivo biodistribution data displayed that the fluorescence intensity of ASSO/DiR-NPs in tumor was similar to that in liver in the presence of the reticuloendothelial system. Besides, the relative tumor-targeting index (RTTI) of (ACGs + ASSO)-NPs was 1.47-fold that of ACGs delivered alone, and there is great potential in ASSO-NPs as tumor-targeted delivery vehicles. In this study, ASSO-NPs were firstly prepared by a very simple method with fewer excipients, which improved the solubility and antitumor activity of the ASSO, displaying a good prospect in the in vivo delivery of natural bioactive compounds.

Enhanced tumor accumulation and therapeutic efficacy of liposomal drugs through over-threshold dosing.

BACKGROUND: Most intravenously administered drug-loaded nanoparticles are taken up by liver Kupffer cells, and only a small portion can accumulate at the tumor, resulting in an unsatisfactory therapeutic efficacy and side effects for chemotherapeutic agents. Tumor-targeted drug delivery proves to be the best way to solve this problem; however, the complex synthesis, or surface modification process, together with the astonishing high cost make its clinical translation nearly impossible. METHODS: Referring to Ouyang's work and over-threshold dosing theory in general, blank PEGylated liposomes (PEG-Lipo) were prepared and used as tumor delivery enhancers to determine whether they could significantly enhance the tumor accumulation and in vivo antitumor efficacy of co-injected liposomal ACGs (PEG-ACGs-Lipo), a naturally resourced chemotherapeutic. Here, the phospholipid dose was used as an indicator of the number of liposomes particles with similar particle sizes, and the liposomes was labelled with DiR, a near-red fluorescent probe, to trace their in vivo biodistribution. Two mouse models, 4T1-bearing and U87-bearing, were employed for in vivo examination. RESULTS: PEG-Lipo and PEG-ACGs-Lipo had similar diameters. At a low-threshold dose (12 mg/kg equivalent phospholipids), PEG-Lipo was mainly distributed in the liver rather than in the tumor, with the relative tumor targeting index (RTTI) being ~ 0.38 at 72 h after administration. When over-threshold was administered (50 mg/kg or 80 mg/kg of equivalent phospholipids), a much higher and quicker drug accumulation in tumors and a much lower drug accumulation in the liver were observed, with the RTTI increasing to ~ 0.9. The in vivo antitumor study in 4T1 tumor-bearing mice showed that, compared to PEG-ACGs-Lipo alone (2.25 mg/kg phospholipids), the co-injection of a large dose of blank PEG-Lipo (50 mg/kg of phospholipids) significantly reduced the tumor volume of the mice by 22.6% (P < 0.05) and enhanced the RTTI from 0.41 to 1.34. The intravenous injection of a low drug loading content (LDLC) of liposomal ACGs (the same dose of ACGs at 50 mg/kg of equivalent phospholipids) achieved a similar tumor inhibition rate (TIR) to that of co-injection. In the U87 MG tumor-bearing mouse model, co-injection of the enhancer also significantly promoted the TIR (83.32% vs. 66.80%, P < 0.05) and survival time of PEG-ACGs-Lipo. CONCLUSION: An over-threshold dosing strategy proved to be a simple and feasible way to enhance the tumor delivery and antitumor efficacy of nanomedicines and was benefited to benefit their clinical result, especially for liposomal drugs.

Preparation of Naringenin Nanosuspension and Its Antitussive and Expectorant Effects.

Naringenin (NRG) is a natural flavonoid compound abundantly present in citrus fruits and has the potential to treat respiratory disorders. However, the clinical therapeutic effect of NRG is limited by its low bioavailability due to poor solubility. To enhance the solubility, naringenin nanosuspensions (NRG-NSps) were prepared by applying tocopherol polyethylene glycol succinate (TPGS) as the nanocarrier via the media-milling method. The particle size, morphology, and drug-loading content of NRG-NSps were examined, and the stability was evaluated by detecting particle size changes in different physiological media. NRG-NSps exhibited a flaky appearance with a mean diameter of 216.9 nm, and the drug-loading content was 66.7%. NRG-NSps exhibited good storage stability and media stability. NRG-NSps presented a sustainable release profile, and the cumulative drug-release rate approached approximately 95% within 7 d. NRG-NSps improved the antitussive effect significantly compared with the original NRG, the cough frequency was decreased from 22 to 15 times, and the cough incubation period was prolonged from 85.3 to 121.6 s. Besides, NRG-NSps also enhanced expectorant effects significantly, and phenol red secretion was increased from 1.02 to 1.45 µg/mL. These results indicate that NRG-NSps could enhance the bioavailability of NRG significantly and possess a potential clinical application.

Photothermal combined with intratumoral injection of annonaceous acetogenin nanoparticles for breast cancer therapy.

ACGs (annonaceous acetogenins) possess excellent antitumor activity, but their serious accompanying toxicity has prevented their application in the clinic. To address this problem, we therefore constructed an intratumoral drug delivery system integrating chemotherapy and photothermal therapy. The PEGylation of polydopamine nanoparticles (PDA-PEG NPs) possessed an excellent biocompatibility with size of 70.96 ± 2.55 nm, thus can be used as good photothermal materials in the body. Moreover, PDA-PEG NPs can kill half of cancer cells under NIR (near-infrared) laser irradiation, and the survival rate of 4T1 cells is only 1% when ACG NPs and PDA-PEG NPs are combined. In vivo distribution studies showed that the 0.1 mg/kg ACGs NPs + PDA-PEG NPs + NIR group had the highest tumor inhibition rate, which was significantly superior to that of the 0.1 mg/kg ACGs NPs intratumoral injection group (82.65% vs. 59.08%). Altogether, the combination of PDA-PEG NPs + NIR with chemotherapy drugs may provide a feasible and effective strategy for the treatment of superficial tumors.