Month: December 2020

Self-nanoemulsifying drug delivery systems as novel approach for pDNA drug delivery

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It was the aim of this study to investigate a novel strategy for oral gene delivery utilizing a self-nanoemulsifying drug delivery system (SNEDDS). After hydrophobic ion pairing a plasmid was incorporated into SNEDDS. The mean droplet size of resulting nanoemulsions was determined to be between 45.8 and 47.5 nm. A concentration dependent cytotoxicity of the formulations was found on HEK-293 cells via MTT assay. Degradation studies via DNase I showed that incorporation into SNEDDS led to significantly, up to 8-fold prolonged resistant time against enzymatic digestion compared to naked pDNA and pDNA–lipid complexes. Transfection studies carried out revealed a significantly improved transfection compared to naked pDNA. Further, no decrease in transfection efficiency compared to transfection using Lipofectin® transfection reagent was observed. (International Journal of Pharmaceutics. Volume 487, Issues 1–2, 20 June 2015, Pages 25-31.)

Impact of different hydrophobic ion pairs of octreotide on its oral bioavailability in pigs

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The objective of this study was to investigate the impact of different hydrophobic ion pairs (HIP) on the oral bioavailability of the model drug octreotide in pigs.

Octreotide was ion paired with the anionic surfactants deoxycholatedecanoate and docusate differing in lipophilicity. These hydrophobic ion pairs were incorporated in self-emulsifying drug delivery systems (SEDDS) based on BrijO10, octyldodecanol, propylene glycol and ethanol in a concentration of 5 mg/ml. SEDDS were characterized regarding size distribution, zeta potential, stability towards lipase, log DSEDDS/release medium and mucus diffusion behavior. The oral bioavailability of octreotide was evaluated in pigs via LC-MS/MS analyses.

Most efficient ion pairing was achieved at a molar ratio of 1:3 (peptide: surfactant). SEDDS containing the octreotide-deoxycholate, -decanoate and -docusate ion pair exhibited a mean droplet size of 152 nm, 112 nm and 191 nm and a zeta potential of − 3.7, − 4.6 and − 5.7 mV, respectively. They were completely stable towards degradation by lipase and showed a log DSEDDS/release medium of 1.7, 1.8 and 2.7, respectively. The diffusion coefficient of these SEDDS was in the range of 0.03, 0.11 and 0.17 × 10− 9 cm2/s, respectively. In vivo studies with these HIPs showed no improvement in the oral bioavailability in case of octreotide-decanoate. In contrast, octreotide-deoxycholate and octreotide-docusate SEDDS resulted in a 17.9-fold and 4.2-fold higher bioavailability vs. control.

According to these results, hydrophobic ion pairing could be identified as a key parameter for SEDDS to achieve high oral bioavailability. (Journal of Controlled Release. Volume 273, 10 March 2018, Pages 21-29.)

Perspectives on Biologically Active Camptothecin Derivatives

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Camptothecins (CPTs) are cytotoxic natural alkaloids that specifically target DNA topoisomerase I. Research on CPTs has undergone a significant evolution from the initial discovery of CPT in the late 1960s through the study of synthetic small molecule derivatives to investigation of macromolecular constructs and formulations. Over the past years, intensive medicinal chemistry efforts have generated numerous CPT derivatives. Three derivatives, topotecan, irinotecan, and belotecan, are currently prescribed as anticancer drugs, and several related compounds are now in clinical trials. Interest in other biological effects, besides anticancer activity, of CPTs is also growing exponentially, as indicated by the large number of publications on the subject during the last decades. Therefore, the main focus of the present review is to provide an ample but condensed overview on various biological activities of CPT derivatives, in addition to continued up-to-date coverage of anticancer effects.


Camptothecin (CPT) is a pentacyclic alkaloid isolated by Wall et al. in the early 1960s from the Chinese tree Camptotheca acuminata. This compound attracted immediate interest as a potential cancer chemotherapeutic agent due to its impressive activity against leukemias and various solid tumors in experimental systems. Due to CPT’s negligible water solubility, clinical trials were initiated using the water-soluble sodium salt of CPT in the early 1970s. The trials were suspended in the 1970s due to lower efficacy of 2, accompanied by unpredictable and severe levels of toxicity, including hemorrhagic cystitis and myelotoxicity. Interest in CPT then subsided for over a decade. Revived attention resulted from the breakthrough discovery of DNA topoisomerase I (Topo I) as a therapeutic target for CPT. This discovery put CPT back on the frontlines of anticancer drug development in the late 1980s. Accordingly, CPT’s total synthesis, mechanism of action, structure–activity relationship (SAR), analog synthesis as well as pharmacology, formulation, drug delivery, preclinical studies and clinical trials have been studied extensively. Recent interesting research approaches include using prodrug concepts and drug delivery systems for CPT.
As the result of these renewed research efforts, three CPT analogues, topotecan (TPT), irinotecan (CPT-11), and belotecan (CKD-602), received governmental approval for the clinical treatment of ovarian, small-cell lung, and refractory colorectal cancers. Three additional water-soluble analogues, exatecan (DX-8951f) lurtotecan (GG-211), and sinotecan, are currently under clinical evaluation. (Med Res Rev. 2015 Jul; 35(4): 753–789.)

Polymer–drug conjugates: recent advances and future perspectives

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Polymer–drug conjugates (PDC) have exhibited clinical and commercial success in the field of drug delivery. A polymeric backbone, linker, targeting moiety, and drug constitute the building blocks of PDCs. Current attention is focusing on natural polymeric carriers, in particular the concept of graft copolymers, such as a combination of polymers and polysaccharides, to explore dual benefits such as combined vehicles and targeting moieties. Polymer heterogeneity, synthesis of PDCs, broad molecular weight distribution, conjugate variability, immunogenicity of polymers, safety, stability, and stringent regulatory approval are the major obstacles to the successful transition of PDCs to the clinic. In this review, we discuss natural and synthetic PDCs combined with computational modeling for diverse pharmaceutical and biomedical applications. (Drug Discovery Today. Volume 25, Issue 9, September 2020, Pages 1718-1726.)

Natural product-derived phytochemicals as potential agents against coronaviruses: A review

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Coronaviruses are responsible for a growing economic, social and mortality burden, as the causative agent of diseases such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), avian infectious bronchitis virus (IBV) and COVID-19. However, there is a lack of effective antiviral agents for many coronavirus strains. Naturally existing compounds provide a wealth of chemical diversity, including antiviral activity, and thus may have utility as therapeutic agents against coronaviral infections. The PubMed database was searched for papers including the keywords coronavirus, SARS or MERS, as well as traditional medicine, herbal, remedy or plants, with 55 primary research articles identified. The overwhelming majority of publications focussed on polar compounds. Compounds that show promise for the inhibition of coronavirus in humans include scutellarein, silvestrol, tryptanthrin, saikosaponin B2, quercetin, myricetin, caffeic acid, psoralidin, isobavachalcone, and lectins such as griffithsin. Other compounds such as lycorine may be suitable if a therapeutic level of antiviral activity can be achieved without exceeding toxic plasma concentrations. It was noted that the most promising small molecules identified as coronavirus inhibitors contained a conjugated fused ring structure with the majority being classified as being polyphenols.

Coronaviruses (CoVs) belong to the family Coronaviridae, subfamily Coronavirinae and are large (genome size 26−32 kb; Wu et al., 2020a), enveloped, positive-sense single-stranded ribonucleic acid (RNA) viruses that can infect both animals and humans. Based on their genotypic and serological characteristics, the viruses are subdivided into four genera: Alpha-, Beta-, Gamma-, and Deltacoronavirus (Chu et al., 2020; Lu et al., 2015). At present, all identified CoVs that are capable of infecting humans belong to the first two genera. These include the alphacoronaviruses (αCoVs) HCoV-NL63 (Human CoV-NL63) and HCoV-229E and the betacoronaviruses (βCoVs) HCoV-OC43 (Human CoV-OC43), HKU1 (Human CoV), SARS-CoV (Severe Acute Respiratory Syndrome CoV), and MERS-CoV (Middle Eastern Respiratory Syndrome CoV) (Lu et al., 2015). In the past two decades there have been three epidemics caused by the betaCoVs, namely SARS in 2002−03, MERS in 2012 and COVID-19, first identified in 2019. (Virus Res. 2020 Jul 15;284:197989. )

A Novel Antimicrobial-Phytochemical Conjugate With Antimicrobial Activity Against Streptococcus uberis, Enterococcus faecium, and Enterococcus faecalis

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Antimicrobial resistance is one of the major threats to human and animal health. An effective strategy to reduce and/or delay antimicrobial resistance is to use combination therapies. Research in our laboratory has been focused on combination therapies of antimicrobials and phytochemicals and development of antimicrobial-phytochemical conjugates. In this study, we report the synthesis and antimicrobial activity of a novel sulfamethoxazole-gallic acid conjugate compound (Hybrid 1). Hybrid 1 not only showed much stronger activity than sulfamethoxazole towards Streptococcus uberis 19436, Enterococcus faecium 700221, and Enterococcus faecalis 29212, which were purchased from American Type Culture Collection (ATCC), but also exhibited a promising antimicrobial effect against two E. faecalis clinical isolates, one of which was multidrug-resistant. Further studies are warranted to establish the in vivo antimicrobial activity for Hybrid 1 and develop more potent sulfamethoxazole-gallic acid-based antimicrobial conjugates using hybrid 1 as a lead compound. (Front Pharmacol. 2019 Nov 28;10:1405.)

A Phytochemical-Based Copolymer Derived from Coriolus versicolor Polysaccharopeptides for Gene Delivery

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Coriolus versicolor is an herb widely used for cancer treatment in traditional Chinese medicine. Its active ingredients, polysaccharopeptides (PSP), have been used for adjuvant therapies in cancer treatment. This study conjugates Coriolus versicolor PSP with poly(ethylenimine) (PEI) to generate a PSP-PEI copolymer for gene transfer. After PEI conjugation, both the pH buffering capacity and DNA compaction ability of PSP are significantly increased. Compared with that of PSP, the transfection efficiency of PSP-PEI is 10 to 20-fold higher in vitro. This is a proof-of-concept study reporting the direct use of bioactive phytochemicals from traditional Chinese medicine for gene vector development. The promising performance of PSP-PEI raises the possibility that bioactive herbal ingredients can be further developed as a multi-therapeutic gene carrier for tackling cancers.

C. versicolor PSP are water-soluble substances having a dark brown colour and characteristic odour. Their polysaccharide moieties are highly complex, consisting of glucose molecules linked with different sugar units (e.g., galactose, mannose, arabinose, and xylose); whereas the peptide moieties contain a large amount of aspartic acid and glutamic acid, with acidic and neutral amino acids (such as leucine, glycine, alanine, threonine, serine, glutamic acid, valine and aspartic acid) accounting for 70% of all kinds of amino acids present. PEI is a cationic aziridine polymer that exists as a polycation showing high pH buffering capacity over a broad range of pH values. Previous studies have revealed that the transfection efficiency and cytotoxicity of PEI are positively related to the molecular weight of PEI. As the aim of PEI incorporation in this study is to enhance the positive charge density of PSP, LMW PEI (e.g., PEI 0.8K) is adopted because it can serve the purpose and is less toxic than its high-molecular-weight counterparts. During synthesis, 1,1′-carbonyldiimidazole (CDI), which activates the hydroxyl groups of PSP to form active imidazolyl carbamate intermediates, is used as a coupling agent. The intermediates are subsequently attacked by the primary amine groups of PEI to form PSP-PEI, with imidazole being released as a byproduct. (Molecules. 2018 Sep 6;23(9):2273.)

Novel cosmeceuticals from plants—An industry guided review

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Novel cosmeceutical ingredients from plant sources are in huge demand by the personal care products manufacturing industry due to the growing consumer awareness about healthy products with natural ingredients. The advancements in the understanding of the skin physiology and ageing resulted in the identification of novel biochemical targets of skin health, chemical manipulation of which has the potential to regain and/or remain in a healthy state. Plants are the chief source of such phytochemicals which can alter or bring back the original healthy skin and external appearance. A number of plants have been used by the industry to create novel cosmeceutical formulations with specific objectives such as sun protection, anti-ageing, anti-wrinkling, anti-oxidant, anti-allergy. Plants growing in adverse environmental climates are being explored, evaluated and converted into novel products by the cosmeceutical industry. The current review aims at the novel plant sources which are utilized by the various industry leaders in the business and their scientific rationale for their cosmeceutical applications. Around 68 plant sources used by the industry belonging to the six major plant families, Asteraceae, Lamiaceae, Fabaceae, Poaceae, Malvaceae and Rosaceae are reviewed scientifically for their cosmeceutical claims. (Journal of Applied Research on Medicinal and Aromatic Plants. Volume 7, December 2017, Pages 1-26.)