Development of nanoscale drug delivery systems of dihydroartemisinin for cancer therapy: A review

Dihydroartemisinin (DHA), a first-line antimalarial drug, has demonstrated great anticancer effects in many types of tumors, including liver cancer, glioblastoma, and pancreatic cancer. Due to its abilities to induce programmed cell death (PCD; apoptosis, autophagy and ferroptosis), inhibit tumor metastasis and angiogenesis, and modulate the tumor microenvironment, DHA could become an antineoplastic agent in the foreseeable future. However, the therapeutic efficacy of DHA is compromised owing to its inherent disadvantages, including poor stability, low aqueous solubility, and short plasma half-life. To overcome these drawbacks, nanoscale drug delivery systems (NDDSs), such as polymeric nanoparticles (NPs), liposomes, and metal-organic frameworks (MOFs), have been introduced to maximize the therapeutic efficacy of DHA in either single-drug or multidrug therapy. Based on the beneficial properties of NDDSs, including enhanced stability and solubility of the drug, prolonged circulation time and selective accumulation in tumors, the outcomes of DHA-loaded NDDSs for cancer therapy are significantly improved compared to those of free DHA. This review first summarizes the current understanding of the anticancer mechanisms of DHA and then provides an overview of DHA-including nanomedicines, aiming to provide inspiration for further application of DHA as an anticancer drug.     

A horsefly saliva antigen 5-like protein containing RTS motif is an angiogenesis inhibitor

The Ag5 proteins are the most abundant and immunogenic proteins in the venom secretory ducts of stinging insects. An antigen 5-like protein (named tabRTS) composed of 221 amino acid residues was purified and characterized from the salivary glands of the horsefly, Tabanus yao (Diptera, Tabanidae). Its cDNA was cloned from the cDNA library of the horsefly's salivary gland. TabRTS containing the SCP domain (Sc7 family of extracellular protein domain) was found in insect antigen 5 proteins. More interestingly, there is an Arg-Thr-Ser (RTS) disintegrin motif at the C-terminus of tabRTS. The RTS motif is positioned in a loop bracketed by cysteine residues as those found in RTS-disintegrins of Crotalidae and Viperidae snake venoms, which act as angiogenesis inhibitors. Endothelial Cell Tube formation assay in vitro and chicken chorioallantoic membrane (CAM) angiogenesis assay in vivo were performed as to investigate the effect of tabRTS on angiogenesis. It was found that tabRTS could significantly inhibit angiogenesis in vitro and in vivo. Anti-α₁β₁ monoclonal antibody could dose-dependently inhibit the anti-angiogenic activity of tabRTS. This result indicated that tabRTS possibly targets the α₁β₁ integrin to exert the anti-angiogenic activity as snake venom RTS-/KTS-disintegrins do. The current work revealed the first angiogenesis inhibitor protein containing RTS motif from invertebrates, a possible novel type of RTS-disintegrin.     

Dual-targeting delivery system for bone cancer: synthesis and preliminary biological evaluation

Chemotherapy in treatment of malignant tumors has many side effects due to the poor physiochemical properties and the toxicity to normal tissues. The dual-targeting drug delivery system combining two high-affinity ligands can target anticancer drug primary to the diseased tissue, then to the tumor, which provides both greater efficacy of treatment and less harm to normal tissues. In this paper, a novel dual-targeting moiety RGD₇ (R-G-D-D-D-D-D-D-D; Nonapeptide for bone cancer combining D₆ peptide as bone target moiety and RGD peptide as tumors target moiety was contracted. A series of bone and/or tumor targeting conjugates have been synthesized in a convergent approach and well characterized by nuclear magnetic resonance (NMR) and mass spectrometry (MS) techniques. The hydroxyapatite (HAP) binding, water solubility, the drug release and the distribution in vivo were evaluated. All the conjugates were water-soluble and able to release the parent drugs in vitro. The bone-targeting property of the dual-targeting delivery system was enhanced from the results of the HAP binding and the distribution in vivo. The experiment for verifying tumor targeting property was underway. These results provided an effective entry to the development of a new dual-targeting delivery system for bone cancer.     

Curcumin-docetaxel co-loaded nanosuspension for enhanced anti-breast cancer activity

ABSTRACT

Purpose: A curcumin-docetaxel co-loaded nanosuspension with increased anti-breast cancer activity was developed. Curcumin is a potential anticancer agent with p-glycoprotein (p-gp) inhibiting activity may be co-administered with docetaxel as a nanosuspension to enhance its anticancer effect by increasing the oral bioavailability and decreasing drug efflux.

Methods: Nanosuspensions of curcumin and docetaxel were prepared by precipitation-homozenisation technique and evaluated for particle size, polydispersity, zeta potential and drug release. The in vitro MTT assay was conducted using MCF-7 for anti-breast cancer activity. The in vivo biodistribution by radiolabeling and tumor inhibition study was conducted in mice.

Results: Homogenous nanosuspensions of 80 ± 20 nm were obtained with increased solubility. The drugs as nanosuspensions showed higher cytotoxicity on MCF-7 cell line compared to their suspensions due to the increased in vitro cellular uptake. Due to this increased solubility, sensitization of tumor cells and inhibition of p-gp the in-vivo results showed greater tumor inhibition rate of up to 70% in MCF-7 treated mice. Histopathological results showed higher apoptotic activity and reduced level of angiogenesis.

Conclusions: The in vitro and in vivo study of the nanosuspensions has shown that Co-administration of Curcumin as a p-gp inhibitor with docetaxel may have the potential to increase the anti-breast cancer efficacy of both drugs.     

A nanoparticulate drug-delivery system for glaucocalyxin A: formulation,characterization, increased in vitro,and vivo antitumor activity

Glaucocalyxin A (GLA) is a phytochemical component with multiple pharmacological activities; however, glaucocalyxin A's wider use has been restricted by its poor solubility. In this study, GLA nanosuspensions were prepared with precipitation-combined ultrasonication and were characterized by dynamic light scattering (DLS), transmission electron microscope (TEM), and differential scanning calorimetry (DSC). The GLA nanosuspensions were spherical with a smooth surface and a small size of 143?nm, the drug payload achieved 8.95%, and the maximum GLA concentration reached 1?mg/mL. The lyophilized powders for the GLA nanosuspensions were amorphous and displayed a biphasic drug release pattern with an initial burst release and a consequent sustained release. In contrast to the free drug solution, GLA nanosuspensions showed higher in vitro antitumor activity against HepG2 cells (IC₅₀ value of 1.793 versus 2.884?μg/mL at 24?h, p?<?0.01). Meanwhile, nanosuspensions displayed better anticancer efficacy than free GLA on H22 bearing mice (54.11% versus 36.02% tumor inhibition rate). These results indicate that GLA nanosuspensions have great potential for the treatment of hepatic cancer.     

Advances in polymeric micelles for drug delivery and tumor targeting

A plethora of formulation techniques have been reported in the literature for targeting drugs to specific sites. Polymeric micelles (PMs) can be targeted to tumor sites by passive as well as active mechanisms. Some inherent properties of PMs, including size in the nanorange, stability in plasma, longevity in vivo, and pathological characteristics of tumor allow PMs to be targeted to the tumor site by a passive mechanism called the enhanced permeability and retention effect. PMs formed from an amphiphilic block copolymer are suitable for encapsulation of poorly water-soluble, hydrophobic anticancer drugs. Other characteristics of PMs such as separate functionality at the outer shell are useful for targeting the anticancer drug to tumor by active mechanisms. PMs can be conjugated with many ligands such as antibody fragments, epidermal growth factors, α₂-glycoprotein, transferrin, and folate to target micelles to cancer cells. Application of heat or ultrasound are the alternative methods to enhance drug accumulation in tumoral cells. Targeting using micelles can also be directed toward tumor angiogenesis, which is a potentially promising target for anticancer drugs. PMs have been used for the delivery of many anticancer agents in preclinical and clinical studies. This review summarizes recently available information regarding targeting of anticancer drugs to the tumor site using PMs.From the Clinical EditorThis review summarizes recent developments related to targeted anticancer drug delivery to tumor sites using polymeric micelles via active and passive mechanisms. Polymeric micelles can be conjugated with diverse ligands such as antibodies fragments, epidermal growth factors, α2-glycoprotein, transferrin, folate to target micelles to cancer cells.     

Synthesis and in vivo anticancer and antiangiogenic effects of novel thioxothiazolidin-4-one derivatives against transplantable mouse tumor

A series of novel thioxothiazolidin-4-one derivatives 5(a–g) were synthesized by the coupling of different amines containing aliphatic, substituted aromatic, and heterocyclic moieties, such as oxadiazol, pyrazole, isoxazole, and piperazine with 2-(5-(4-chlorophenyl)furan-2-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid. All compounds were characterized by ¹H NMR, LCMS, FTIR and elemental analysis. In this study, we investigated the possibility that these novel thioxothiazolidin-4-one derivatives 5(a–g) inhibits tumor growth and tumor induced angiogenesis using mouse Ehrlich Ascites Tumor (EAT) as a model system. Our results demonstrated that the compounds significantly reduced ascites tumor volume, cell number, and increased the life span of EAT-bearing mice. In addition, the compounds manifested strong antiangiogenic effects and suppressed tumor induced endothelial proliferation in the mice peritoneum. From our findings, it is noted that the derivatives 5(a–e) may be possible candidates for anticancer therapy with the ability to inhibit tumor angiogenesis and tumor cell proliferation.     

Mechanochemical preparation of triptolide-loaded self-micelle solid dispersion with enhanced oral bioavailability and improved anti-tumor activity

Triptolide (TP), a compound isolated from a Chinese medicinal herb, possesses potent anti-tumor, immunosuppressive, and anti-inflammatory properties, but was clinically limited due to its poor solubility, bioavailability, and toxicity. Considering the environment-friendly, low-cost mechanochemical techniques and potential dissolution enhancement ability of Na₂GA, an amorphous solid dispersion (Na₂GA&TP-BM) consisting of TP and Na₂GA were well-prepared to address these issues. The performance of Na₂GA&TP-BM was improved through ball milling, such as from crystalline state to an amorphous solid dispersion, suitable nano micelle size and surface potential, and increased solubility. This change had a significant improvement of pharmacokinetic behavior in mice and could be able to extend the blood circulation time of the antitumor drug. Moreover, in vitro and in vivo anti-tumor study showed that Na₂GA&TP-BM displayed more potent cytotoxicity to tumor cells. The work illustrated an environment-friendly and safe preparation of the TP formulation, which was promising to enhance the oral bioavailability and antitumor ability of TP, might be considered for efficient anticancer therapy.     

Cimetidine: An anticancer drug?

Cimetidine, H₂ receptor antagonists, is commonly prescribed for gastric and duodenal ulcer disease. Additionally, cimetidine has been shown to have anticancer effects. This review describes the mechanism of antitumor action of cimetidine including its ability to interfere with tumor cell adhesion, angiogenesis and proliferation; its effect on the immune system; as well as inhibition of postoperative immunosuppression. Its anticancer effect is also compared to that of the other H₂ receptor antagonists as well as outcomes of cimetidine in clinical studies in cancer patients.     

Near-infrared light-activated IR780-loaded liposomes for anti-tumor angiogenesis and Photothermal therapy

Tumor angiogenesis is a key step in the process of tumor development, and antitumor angiogenesis has a profound influence on tumor growth. Herein we report a dual-function drug delivery system comprising a Near-infrared (NIR) dye and an anti-angiogenic drug within liposomes (Lip-IR780-Sunitinib) for enhanced antitumor therapy. The hydrophobic NIR dye IR780 was loaded into the liposome phospholipid bilayer, and the bilayer would be disrupted by laser irradiation so that anti-angiogenic drug sunitinib release would be activated remotely at the tumor site. The released hydrophilic sunitinib could potentially target multiple VEGF receptors on the tumor endothelial cell surface to inhibit angiogenesis. Meanwhile, IR780-loaded liposomes kill the cancer cells by photothermal therapy. Lip-IR780-Sunitinib exhibited enhanced anti-tumor and anti-angiogenic effects in vitro and in vivo. This system facilitates easy and controlled release of cargos to achieve anti-tumor angiogenesis and photothermal therapy.     

Encapsulation of Poorly Soluble Drugs in Polymer-Drug Conjugates: Effect of Dual-Drug Nanoformulations on Cancer Therapy

Purpose

Current cancer chemotherapy is gradually shifting to the application of drug combinations that prevent development of drug resistance. Many anticancer drugs have poor solubility and limited oral bioavailability. Using an innovative approach, we developed dual-drug nanoformulations of a polymeric nanogel conjugate with anticancer 5-FU nucleoside analog, floxuridine (FLOX), and the second anticancer drugs, paclitaxel (PCL), or a geldanamycin analog, 17-AAG, for combination therapy.

Methods

PCL or 17-AAG had been encapsulated in the cholesteryl-polyvinyl alcohol-floxuridine nanogel (CPVA-FLOX) by simple solution mixing and sonication. Dual nanodrugs formed particles with diameter 180 nm and either drug content (5–20%) that were stable and could be administered orally. Their cytotoxicity in human and mouse cancer cells was determined by MTT assay, and cellular target inhibition – by Western blot analysis. Tumor growth inhibition was evaluated using an orthotopic mouse mammary 4T1 cancer model.

Results

CPVA-FLOX was more potent than free drug in cancer models including drug-resistant ones; while dual nanodrugs demonstrated a significant synergy (CPVA-FLOX/PCL), or showed no significant synergy (CPVA-FLOX/17-AAG) compared to free drugs (PCL or 17-AAG). Dual nanodrug CPVA-FLOX/17-AAG effect on its cellular target (HSP70) was similar to 17-AAG alone. In animal model, however, both dual nanodrugs effectively inhibited tumor growth compared to CPVA-FLOX after oral administration.

Conclusion

Oral dual-drug nanoformulations of poorly-soluble drugs proved to be a highly efficient combination anticancer therapy in preclinical studies.     

Development and optimization of curcumin analog nano-bilosomes using 21.31 full factorial design for anti-tumor profiles improvement in human hepatocellular carcinoma: in-vitro evaluation,in-vivo safety assay

Curcumin (CU) is a natural polyphenolic phytoingredient. CU has anti-inflammatory, anti-oxidant, and anticancer activities. The poor solubility, bioavailability, and stability of CU diminish its clinical application. Hence, structural modification of CU is highly recommended. The CU analog; 3,5-bis(4-bromobenzylidene)-1-propanoylpiperidin-4-one (PIP) exhibited high stability, safety, and more potent antiproliferative activity against hepatocellular carcinoma. In the present study, nano-bilosomes (BLs) were formulated to augment PIP delivery and enhance its solubility. A 2¹.3¹ full factorial design was adopted to prepare the synthesized PIP-loaded BLs. Optimized F4 showed a biphasic release pattern extended over 24 h, with EE%, ZP, and PS of 90.21 ± 1.0%, −27.05 ± 1.08 mV, and 111.68 ± 1.4 nm. PIP-loaded BLs were tested for safety against a non-cancerous cell line (Wi-38) and for anticancer activity against the Huh-7 human hepatocellular carcinoma cells and compared to the standard anticancer drug doxorubicin (Dox). The anticancer selectivity index of PIP-loaded BLs recorded 420.55 against Huh-7 liver cancer cells, markedly higher than a CU suspension (18.959) or the Dox (20.82). The antiproliferative activity of nano-encapsulated PIP was roughly equivalent to Dox. PIP-loaded BLs, showed enhanced drug solubility, and enhanced anticancer effect, with lower toxicity and higher selectivity against Huh-7 liver cancer cells, compared to the parent CU.     

Increasing antitumor activity in vivo by enhancing acridine dimer solubility with salt preparations

The potent activities of many anticancer agents have been demonstrated by in vitro assays. However, their poor solubility may result in diminishing anticancer activities in vivo. Previously, we synthesized a series of bisacridine derivatives shown to be potent in cytotoxicity and DNA intercalating activity in vitro. Initially, the compound 1, (N-(6-chloro-2-methoxy-acridin-9-yl)-N′-[3-(6-chloro-2-methoxy-acridin-9-ylamino)-propyl]-propane-1,3-diamine), is insoluble in polar solvent and does not reveal antihuman COLO 205 solid-tumor activity in vivo. To enhance its solubility, three salt forms (CH₃COOH, CH₃SO₃H, and CF₃COOH) of compound 1 were synthesized and their solubility was found to be greatly improved compared with that of the free base. Among these salts, the compound 1 · (tris)acetate salt has shown good solubility in H₂O and 2.5% Cremophor (v/v) and demonstrated anti-COLO205 solid-tumor activity in vivo.     

Solubility Prediction of Satranidazole in Aqueous N,N-dimethylformamide Mixtures Using Extended Hildebrand Solubility Approach

The solubility of satranidazole in several water–N,N-dimethylformamide mixtures was analysed in terms of solute–solvent interactions and data were treated on the basis of extended Hildebrand solubility approach. The solubility profile of satranidazole in water–N,N-dimethylformamide mixtures shows a curve with a solubility maxima well above the ideal solubility of drug. This is attributed to solvation of the drug with the water–N,N-dimethylformamide mixture, and indicates that the solute–solvent interaction energy (W) is larger than the geometric mean (δ₁δ₂) of regular solution theory. The new approach provides an accurate prediction of solubility once the interaction energy (W) is obtained. In this case, the energy term is regressed against a polynomial in δ₁ of the binary solvent mixture. A quartic expression of W in terms of solvent solubility parameter was found for predicting the mole fraction solubility of satranidazole in the studied mixtures. The method has potential usefulness in preformulation and formulation studies during which solubility prediction is important for drug design.     

Ligand-modified homologous targeted cancer cell membrane biomimetic nanostructured lipid carriers for glioma therapy

The main treatment measure currently used for glioma treatment is chemotherapy; the biological barrier of solid tumors hinders the deep penetration of nanomedicines and limits anticancer therapy. Furthermore, the poor solubility of many chemotherapeutic drugs limits the efficacy of antitumor drugs. Therefore, improving the solubility of chemotherapeutic agents and drug delivery to tumor tissues through the blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB) are major challenges in glioma treatment. Nanostructured lipid carriers (NLCs) have high drug loading capacity, high stability, and high in vivo safety; moreover, they can effectively improve the solubility of insoluble drugs. Therefore, in this study, we used solvent volatilization and ultrasonic melting methods to prepare dihydroartemisinin nanostructured lipid carrier (DHA-NLC). We further used the glioma C6 cancer cell (CC) membrane to encapsulate DHA-NLC owing to the homologous targeting mechanism of the CC membrane; however, the targeting ability of the CC membrane was weak. We accordingly used targeting ligands for modification, and developed a bionanostructured lipid carrier with BBB and BBTB penetration and tumor targeting abilities. The results showed that DHA-loaded NGR/CCNLC (asparagine–glycine–arginine, NGR) was highly targeted, could penetrate the BBB and BBTB, and showed good anti-tumor effects both in vitro and in vivo, which could effectively prolong the survival time of tumor-bearing mice. Thus, the use of DHA-loaded NGR/CCNLC is an effective strategy for glioma treatment and has the potential to treat glioma.     

山慈菇抗乳腺癌的作用机制研究进展

在中国乳腺癌已经成为上升幅度最快的恶性肿瘤,占女性死亡率的首位。目前化学药治疗乳腺癌存在不良反应大、耐药、容易侵袭及转移等缺点。山慈菇作为传统的中蒙医常用抗癌药,不仅能抑制肿瘤细胞的生长增殖、诱导凋亡、干扰侵袭及迁移,还能抗血管生成,目前已经广泛应用于临床。将近些年来山慈菇抗乳腺癌的作用机制进行综述,为山慈菇进一步应用于临床提供参考。     

Enhancement of solubility and dissolution of Coenzyme Q10 using solid dispersion formulation

This study aimed to develop a stable solid dispersion of Coenzyme Q₁₀ (CoQ₁₀) with high aqueous solubility and dissolution rate. Among various carriers screened, poloxamer 407 was most effective to form a superior solid dispersion of CoQ₁₀ having significantly enhanced solubility. Particularly, solid dispersion of CoQ₁₀ with poloxamer 407 in the weight ratio of 1:5 prepared by melting method enhanced the solubility of CoQ₁₀ to the greatest extent. However, it exhibited poor stability and hence Aerosil^® 200 (colloidal silicon dioxide) was incorporated into the solid dispersion as an adsorbent to inhibit the recrystallization process. The solid dispersion of CoQ₁₀, poloxamer 407 and Aerosil^® 200 in the weight ratio of 1:5:6 exhibited improved stability with no significant change in solubility during the 1-month stability test. Moreover, the solid dispersion formulation containing Aerosil^® 200 significantly enhanced the extent of drug release (approx. 75% release) as well as the dissolution rate of CoQ₁₀. In conclusion, the present study has developed the stable solid dispersion formulation of CoQ₁₀ with poloxamer 407 and Aerosil^® 200 for the enhanced solubility and dissolution of CoQ₁₀, which could also offer some additional advantages including ease of preparation, good flowability and cost-effectiveness.     

Angiogenesis: new targets for the development of anticancer chemotherapies

Angiogenesis is the process by which new blood vessels are formed from preexisting microvasculature. To ensure an adequate blood supply, tumor cells release angiogenic factors that are capable of promoting nearby blood vessels to extend vascular branches to the tumor. In addition, larger tumors have been shown to release angiogeneic inhibitory factors that prevent blood vessels from sending branches to smaller, more distant tumors that compete for oxygen and nutrients. Angiogenesis is a complex multistep biochemical process, and offers several potential molecular targets for non-cytotoxic anticancer therapies. Strategies for exploiting tumor angiogenesis for novel cancer drug discovery include: (i) inhibition of proteolytic enzymes that breakdown the extracellular matrix surrounding existing capillaries; (ii) inhibition of endothelial cell migration; (iii) inhibition of endothelial cell proliferation; (iv) enhancement of tumor endothelial cell apoptosis. There is also a host of miscellaneous agents that inhibit angiogenesis for which the specific mechanisms are not clear. Several methods have been developed for measuring antiangiogenic activity both in vitro and in vivo. Although there has been intensive research efforts focused at the phenomena of angiogenesis, as well as the search for antiangiogenic agents for more than two decades, many questions remain unanswered with regard to the overall biochemical mechanisms of the angiogenesis process and the potential therapeutic utility of angiogenic inhibitors. Nevertheless potent angiogenic inhibitors capable of blocking tumor growth have been discovered, and appear to have potential for development into novel anticancer therapeutics. However there are still hurdles to be overcome before these inhibitors become mainstream therapies.     

雄黄抗癌作用的研究进展

中药雄黄在我国传统医学中应用历史悠久,近年来在肿瘤的治疗中发挥着越来越大的作用,本文介绍雄黄抗癌作用的研究与进展,包括治疗研究、作用机理、不良反应及其新剂型—纳米雄黄的研发等,并对雄黄抗癌作用的未来进行展望。     

Advances in oral delivery of anti-cancer prodrugs

ABSTRACT

Introduction: Most anticancer drugs have poor aqueous solubility and low permeability across the gastrointestinal tract. Furthermore, extensive efflux by P-glycoproteins (P-gp) in the small intestine also limits the efficient delivery of anticancer drugs via oral route.

Area covered: This review explores the prodrug strategy for oral delivery of anticancer drugs. Different categories of oral anticancer prodrugs along with recent clinical studies have been comprehensively reviewed here. Furthermore, novel anticancer prodrugs such as polymer-prodrugs and lipid-prodrugs have been discussed in detail. Finally, various nanocarrier-based approaches employed for oral delivery of anticancer prodrugs have also been discussed.

Expert opinion: Premature degradation of anticancer prodrugs in the gastrointestinal tract could lead to variable pharmacokinetics and undesired toxicity. Despite their increased aqueous solubility, the oral bioavailability of several anticancer prodrugs are limited by their poor permeability across the gastrointestinal tract. These limitations can be overcome by the use of functional excipients (polymers, lipids, amino acids/dipeptides), which are specifically absorbed via transporters and receptor-mediated endocytosis. Oral delivery of anticancer prodrugs using nanocarrier-based drug delivery system is a recent development; however it should be justified based on the comparative advantages of encapsulating prodrug in a nanocarrier versus the use of anticancer prodrug molecule itself.