Month: December 2020

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

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

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

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.)