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Despite current progress in the development of targeted therapies for cancer treatment, there is a lack in convenient therapeutics for colorectal cancer (CRC). Lactoferrin nanoparticles (Lf NPs) are a promising drug delivery system in cancer therapy. However, numerous obstacles impede their oral delivery, including instability against stomach enzymes and premature uptake during passage through the small intestine. Microencapsulation of Lf NPs offer a great solution for these obstacles. It can protect Lf NPs and their drug payloads from degradation in the upper gastrointestinal tract (GIT), reduce burst drug release, and improve the release profile of the encapsulated NPs triggered by stimuli in the colon. Here, we developed nanoparticle-in-microparticle delivery systems (NIMDs) for the oral delivery of docetaxel (DTX) and atorvastatin (ATR). The NPs were obtained by dual conjugation of DTX and ATR into the Lf backbone, which was further microencapsulated into calcium-crosslinked microparticles using polysaccharide–protein hybrid copolymers. The NIMDs showed no detectable drug release in the upper GIT compared to NPs. Furthermore, sustained release of the NPs from the NIMDs in rat cecal content was observed. Moreover, the in vivo study demonstrated the superiority of the NIMDs over NPs in CRC treatment by suppressing p-AKT, p-ERK1/2, and NF-κB. This study provides the proof of concept for using NIMDs to enhance the effect of protein NPs in CRC treatment.

Herein, both strategies of synergistic drug combination together with dual active tumor targeting were combined for effective therapy of hepatocellular carcinoma (HCC). Therefore, based on the tumor sensitizing action, the herbal quercetin (QRC) was co-delivered with the targeted therapeutic drug sorafenib (SFB), preformulated as phospholipid complex, via protein shell-oily core nanocapsules (NCs). Inspired by the targeting action of lactoferrin (LF) via binding to LF receptors overexpressed by HCC cells, LF shell was electrostatically deposited onto the drug-loaded oily core to elaborate LF shell-oily core NCs. For dual tumor targeting, lactobionic acid (LA) or glycyrrhetinic acid (GA) was individually coupled to LF shell for binding to asialoglycoprotein and GA receptors on liver cancer cells, respectively. Compared to LF and GA/LF NCs, the dual-targeted LA/LF-NCs showed higher internalization into HepG2 cells with 2-fold reduction in half-maximal inhibitory concentration compared to free combination therapy after 48 h. Moreover, dual-targeted LF-NCs showed powerful in vivo antitumor efficacy. It was revealed as significant downregulation of the mRNA expression levels of nuclear factor-kappa B and tumor necrosis factor α as well as suppression of Ki-67 protein expression level in diethylnitrosamine (DEN)-induced HCC mice (P< 0.05). Furthermore, dual-targeted LF-NCs attenuated the liver toxicity induced by DEN in animal models. Overall, this study proposes dual-targeted LF-NCs for combined delivery of SFB and QRC as a potential therapeutic HCC strategy.

In this study, promising approaches of dual-targeted micelles and drug–polymer conjugation were combined to enable injection of poorly soluble anticancer drugs together with site-specific drug release. Ursodeoxycholic acid (UDCA) as a hepatoprotective agent was grafted to maltodextrin (MD) via carbodiimide coupling to develop amphiphilic maltodextrin-ursodeoxycholic acid (MDCA)-based micelles. Sulfasalazine (SSZ), as a novel anticancer agent, was conjugated via a tumor-cleavable ester bond to MD backbone to obtain tumor-specific release, whereas resveratrol (RSV) was physically entrapped within the hydrophobic micellar core. For maximal tumor-targeting, both folic acid (FA) and lactobionic acid (LA) were coupled to the surface of micelles to obtain dual-targeted micelles. The decrease of critical micelle concentration (CMC) from 0.012 to 0.006 mg/mL declares the significance of a dual hydrophobicized core of micelles by both UDCA and SSZ. The dual-targeted micelles showed a great hemocompatibility, as well as enhanced cytotoxicity and internalization into HepG-2 liver cancer cells via binding to overexpressed folate and asialoglycoprotein receptors. In vivo, the micelles demonstrated superior antitumor effects revealed as reduction in the liver/body weight ratio, inhibition of angiogenesis, and enhanced apoptosis. Overall, combined strategies of dual active targeted micelles with bioresponsive drug conjugation could be utilized as a promising approach for tumor-targeted drug delivery.

Background: Micellization provides numerous merits for the delivery of water insoluble anti-cancer therapeutic agents including a nanosized ‘core–shell’ drug delivery system. Recently, hydrophobically-modified polysaccharides and proteins are attracting much attention as micelle forming polymers to entrap poorly soluble anti-cancer drugs. Method: By virtue of their small size, the self-assembled micelles can passively target tumor tissues via enhanced permeation and retention effect (EPR). Moreover, the amphiphilic micelles can be exploited for active-targeted drug delivery by attaching specific targeting ligands to the outer micellar hydrophilic surface. Results: Here, we review the conjugation techniques, drug loading methods, physicochemical characteristics of the most important amphiphilic polysaccharides and proteins used as anti-cancer drug delivery systems. Attention focuses on the mechanisms of tumor-targeting and enhanced anti-tumor efficacy of the encapsulated drugs. This review will highlight the remarkable advances of hydrophobized polysaccharide and protein micelles and their potential applications as anti-cancer drug delivery nanosystems. Conclusion: Micellar nanocarriers fabricated from amphiphilic natural polymers hold great promise as vehicles for anti-cancer drugs.

Protein nanocarriers possess unique merits including minimal cytotoxicity, numerous renewable sources, and high drug-binding capability. In opposition to delivery carriers utilizing hydrophilic animal proteins, hydrophobic plant proteins (e.g, zein) have great tendency in fabricating controlled-release particulate carriers without additional chemical modification to stiffen them, which in turn evades the use of toxic chemical crosslinkers. Moreover, zein is related to a class of alcohol-soluble prolamins and generally recognized as safe (GRAS) carrier for drug delivery. Various techniques have been adopted to fabricate zein-based nanoparticulate systems including phase separation coacervation, spray-drying, supercritical anti-solvent approach, electrospinning and self-assembly. This manuscript reviews the recent advances in the zein-based colloidal nano-carrier systems such as nanospheres, nanocapsules, micelles and nanofibers with a special focus on their physicochemical characteristics and drug delivery applications.

Flutamide (FLT) is the only presently recommended drug for monotherapy of benign prostatic hypertrophy. It is known for its poor solubility and slow dissolution. In this study nine different formulae of liquisolid systems (LS) were prepared using Polyethyleneglycol 400 as a liquid vehicle, Avicel® PH 102 and Aerosil 200 as the carrier and the coating material, respectively. Hydrophilic polymers (PVP, HPMC and PEG 2000) were added at a 10 w/w concentration to improve LS properties. Thermal analysis showed complete absence of drug crystallinity in the prepared LS that indicates successful FLT solubilization. The prepared systems were tested for their micromeritic properties (angle of repose, Carrs index and Hausners ratio). The results showed that all the formulae had acceptable values of the angle of repose except formulae F2 (42.0) and F3 (43.50) indicating reasonable flow properties of the LS systems. Compressed into tablets, formula F8 showed the fastest drug release with about 69 of the drug released after the first 5 minutes and almost all the drug released after one hour. Directly compressed FLT tablets showed very slow release with only 5 and 30 of the drug released after 5 and 120 minutes, respectively.

The solubilization and amorphization of the poorly water soluble nonsteroidal anti-inflammatory drug, Etodolac (ETD) with a hydrophilic polymer, low molecular weight chitosan (CHT), have been investigated. Phase solubility studies were carried out to obtain an insight on the nature of a possible interaction between ETD and CHT in solution. Binary systems of varying drug polymer ratios were prepared using different techniques namely physical mixing, cogrinding and kneading. Drug-polymer interactions were investigated in solid state by differential scanning calorimetry, powder X-ray diffractometry and scanning electron microscopy. The results obtained indicated loss of drug crystallinity. Dissolution rate studies revealed that the drug dissolution was improved with increasing the polymer concentration in the mixture in the following order kneading> co-grinding> physical mixing > pure drug. The prepared capsules containing the binary mixture prepared by kneading in the drug-polymer ratio of 1:19 were coated with guar gum (a film coating material) and their dissolution rates were tested in comparison with commercial capsules present in the Egyptian market. A coating of 10 layers of guar gum prevented the release of etodolac in the acidic pH and permitted its release in colonic environment.

The unmet medical needs related to liver fibrosis and its incurable effects bring to an urgent necessity to find new treatment strategies from which, nutra-pharmaceuticals and nanotechnology are attracting a considerable interest. The natural flavonoid, quercetin and the essential oil of fennel were proposed for their proven antifibrotic activity. They were successfully loaded in lipid nanocapsules, which were furtherly coated with hyaluronic acid for enhanced CD44active targeting potential. Thorough in vitro optimization produced monodisperse nanocapsules (particle size; 36.78 nm and PDI <0.2). Coating with hyaluronic acid not only sustain quercetin release but also, induce an efficient time dependent accumulation in a highly CD44 expressing cell line, HepG2, opposite to the uncoated nanocapsules. lipid nanocapsules coated with hyaluronic acid and loaded with both quercetin and fennel oil proved a promising synergistic antifibrotic efficiency on rats with CCL4-induced liver fibrosis. In vivo results revealed a significant improvement in liver function tests along with a significant reduction in liver fibrosis markers. Based on the significant downregulation in both liver oxidative stress parameters and hepatic proinflammatory cytokines, mechanism of action can be elucidated to be through antioxidant enzymes activation and inhibition of inflammatory mediators. Concerning toxicity, no reported hematological, hepato-or nephrotoxicity with all formulations, guaranteeing their safety. Hence, tried combination holds a promising treatment to liver fibrosis.