Development of Polysaccharide-Based Colon Targeted Drug Delivery Systems for the Treatment of Amoebiasis

ABSTRACT

The main focus of this study is to develop colon targeted drug delivery systems for metronidazole (MTZ). Tablets were prepared using various polysaccharides or indigenously developed graft copolymer of methacrylic acid with guar gum (GG) as a carrier. Various polysaccharides such as GG, xanthan gum, pectin, carrageenan, β-cyclodextrin (CD) or methacrylic acid-g-guar (MAA-g-GG) gum have been selected and evaluated. The prepared tablets were tested in vitro for their suitability as colon-specific drug delivery systems. To further improve the colon specificity, some selected tablet formulations were enteric coated with Eudragit-L 100 to give protection in an acidic environment. Drug release studies were performed in simulated gastric fluid (SGF) for 2 hr followed by simulated intestinal fluid (SIF) at pH 7.4. The dissolution data demonstrate that the rate of drug release is dependent upon the nature and concentration of polysaccharide/polymer used in the formulations. Uncoated tablets containing xanthan gum or mixture of xanthan gum with graft copolymer showed 30–40% drug release during the initial 4–5 hr, whereas for tablets containing GG with the graft copolymer, it was 70%. After enteric coating, the release was drastically reduced to 18–24%. The other polysaccharides were unable to protect drug release under similar conditions. Preparations with xanthan gum as a matrix showed the time-dependent release behavior. Further, in vitro release was performed in the dissolution media with rat caecal contents. Results indicated an enhanced release when compared to formulations studied in dissolution media without rat caecal contents, because of microbial degradation or polymer solubilization. The nature of drug transport was found to be non-Fickian in case of uncoated formulations, whereas for the coated formulations, it was found to be super-Case-II. Statistical analyses of release data indicated that MTZ release is significantly affected by the nature of the polysaccharide used and enteric coating of the tablet. Differential scanning calorimetry indicated the presence of crystalline nature of drug in the formulations.     

Aptamer‐Directed Synthesis of Multifunctional Lanthanide‐Doped Porous Nanoprobes for Targeted Imaging and Drug Delivery

Multifunctional lanthanide‐doped porous nanoparticles are prepared via a facile one‐step solvothermal route by employing aptamers as the biotemplate. The nanoparticles feature excellent aqueous dispersibility and biospecific properties and could work as effective nanoprobes for targeted imaging and drug delivery. With aptamer being in principle available for any kind of target, this synthetic strategy may open the door to a new generation of nanoprobes for bioapplications such as time‐resolved biodetection, multimode bioimaging/biolabeling, and targeted cancer therapy.     

Activatable Protein Nanoparticles for Targeted Delivery of Therapeutic Peptides

Clinical translation of therapeutic peptides, particularly those that require penetration of the cell membrane or are cytolytic, is a major challenge. A novel approach based on a complementary mechanism, which has been widely used for guided synthesis of DNA or RNA nanoparticles, for de novo design of activatable protein nanoparticles (APNPs) for targeted delivery of therapeutic peptides is described. APNPs are formed through self‐assembly of three independent polypeptides based on pairwise coiled‐coil dimerization. They are capable of long circulation in the blood and can be engineered to target diseases. Peptides to be delivered are incorporated into APNPs and released into the disease microenvironment by locally enriched proteases. It is demonstrated that APNPs mediate efficient delivery of NR2B9c, a neuroprotective peptide that functions after cell penetration, and melittin, a cytolytic peptide that perturbs the lipid bilayer, for effective treatment of stroke and cancer, respectively. Due to their robust properties, simple design, and economic costs, APNPs have great potential to serve as a versatile platform for controlled delivery of therapeutic peptides.     

Targeted Delivery of siRNA‐Generating DNA Nanocassettes Using Multifunctional Nanoparticles

Molecular therapy using a small interfering RNA (siRNA) has shown promise in the development of novel therapeutics. Various formulations have been used for in vivo delivery of siRNAs. However, the stability of short double‐stranded RNA molecules in the blood and efficiency of siRNA delivery into target organs or tissues following systemic administration have been the major issues that limit applications of siRNA in human patients. In this study, multifunctional siRNA delivery nanoparticles are developed that combine imaging capability of nanoparticles with urokinase plasminogen activator receptor‐targeted delivery of siRNA expressing DNA nanocassettes. This theranostic nanoparticle platform consists of a nanoparticle conjugated with targeting ligands and double‐stranded DNA nanocassettes containing a U6 promoter and a shRNA gene for in vivo siRNA expression. Targeted delivery and gene silencing efficiency of firefly luciferase siRNA nanogenerators are demonstrated in tumor cells and in animal tumor models. Delivery of survivin siRNA expressing nanocassettes into tumor cells induces apoptotic cell death and sensitizes cells to chemotherapy drugs. The ability of expression of siRNAs from multiple nanocassettes conjugated to a single nanoparticle following receptor‐mediated internalization should enhance the therapeutic effect of the siRNA‐mediated cancer therapy.     

Protein-Precoated Surface of Metal-Organic Framework Nanoparticles for Targeted Delivery

Metal-organic framework (MOF) nanoparticles have recently emerged as a promising vehicle for drug delivery with high porosity and feasibility. However, employing a MOF-based drug delivery system remains a challenge due to the difficulty in controlling interfaces of particles in a biological environment. In this paper, protein corona-blocked Zr₆-based MOF (PCN-224) nanoparticles are presented for targeted cancer therapy with high efficiency. The unmodified PCN-224 surface is precoated with glutathione transferase (GST)-fused targetable affibody (GST-Afb) proteins via simple mixing conjugations instead of chemical modifications that can induce the impairment of proteins. GST-Afb proteins are shown to stably protect the surface of PCN-224 particles in a specific orientation with GST adsorbed onto the porous surface and the GST-linked Afb posed outward, minimizing the unwanted interfacial interactions of particles with external biological proteins. The Afb-directed cell-specific targeting ability of particles and consequent induction of cell death is demonstrated both in vitro and in vivo by using two kinds of Afb, which targets the surface membrane receptor, human epidermal growth factor receptor 2 (HER2) or epidermal growth factor receptor (EGFR). This study provides insight into the way of regulating the protein-adhesive surface of MOF nanoparticles and designing a more effective MOF-hosted targeted delivery system.     

Surface Modifications for Improved Delivery and Function of Therapeutic Bacteria

Live therapeutic bacteria (LTBs) hold promise to treat microbiome‐related diseases. However, few approaches to improve the colonization of LTBs in the gastrointestinal tract exist, despite colonization being a prerequisite for efficacy of many LTBs. Here, a modular platform to rapidly modify the surface of LTBs to enable receptor‐specific interactions with target surfaces is reported. Inspired by bacterial adhesins that facilitate colonization, synthetic adhesins (SAs) are developed for LTBs in the form of antibodies conjugated to their surface. The SA platform is nontoxic, does not alter LTB growth kinetics, and can be used with any antibody or bacterial strain combination. By improving adhesion, SA‐modified bacteria demonstrate enhanced in vitro pathogen exclusion from cell monolayers. In vivo kinetics of SA‐modified LTBs is tracked in the feces and intestines of treated mice, demonstrating that SA‐modified bacteria alter short‐term intestinal transit and improve LTB colonization and pharmacokinetics. This platform enables rapid formation of an intestinal niche, leading to an increased maximum concentration and a 20% improvement in total LTB exposure. This work is the first application of traditional pharmacokinetic analysis to design and evaluate LTB drug delivery systems and provides a platform toward controlling adhesion, colonization, and efficacy of LTBs.     

Biodegradable Microalgae‐Based Carriers for Targeted Delivery and Imaging‐Guided Therapy toward Lung Metastasis of Breast Cancer

High delivery efficiency, prolonged drug release, and low systemic toxicity are effective weapons for drug delivery systems to win the battle against metastatic breast cancer. Herein, it is shown that Spirulina platensis (S. platensis) can be used as natural carriers to construct a drug‐loaded system for targeted delivery and fluorescence imaging‐guided chemotherapy on lung metastasis of breast cancer. The chemotherapeutic doxorubicin (DOX) is loaded into S. platensis (SP) via only one facile step to fabricate the DOX‐loaded SP (SP@DOX), which exhibits ultrahigh drug loading efficiency and PH‐responsive drug sustained release. The rich chlorophyll endows SP@DOX excellent fluorescence imaging capability for noninvasive tracking and real‐time monitoring in vivo. Moreover, the micrometer‐sized and spiral‐shaped SP carriers enable the as‐prepared SP@DOX to passively target the lungs and result in a significantly enhanced therapeutic efficacy on lung metastasis of 4T1 breast cancer. Finally, the undelivered carriers can be biodegraded through renal clearance without notable toxicity. The SP@DOX described here presents a novel biohybrid strategy for targeted drug delivery and effective treatment on cancer metastasis.     

Modular Metal–Organic Polyhedra Superassembly: From Molecular‐Level Design to Targeted Drug Delivery

Targeted drug delivery remains at the forefront of biomedical research but remains a challenge to date. Herein, the first superassembly of nanosized metal–organic polyhedra (MOP) and their biomimetic coatings of lipid bilayers are described to synergistically combine the advantages of micelles and supramolecular coordination cages for targeted drug delivery. The superassembly technique affords unique hydrophobic features that endow individual MOP to act as nanobuilding blocks and enable their superassembly into larger and well‐defined nanocarriers with homogeneous sizes over a broad range of diameters. Various cargos are controllably loaded into the MOP with high payloads, and the nanocages are then superassembled to form multidrug delivery systems. Additionally, functional nanoparticles are introduced into the superassemblies via a one‐pot process for versatile bioapplications. The MOP superassemblies are surface‐engineered with epidermal growth factor receptors and can be targeted to cancer cells. In vivo studies indicated the assemblies to have a substantial circulation half‐life of 5.6 h and to undergo renal clearance—characteristics needed for nanomedicines.