Exosome-drug conjugates delivery: a promising strategy for ameliorating the pharmacokinetic profile of artesunate.

Artesunate (ATS) is considered the most widely employed artemisnin derivative in the treatment of Plasmodium falciparum malaria. However, poor solubility and low bioavailability of ATS limit its further clinical application. Herein, we developed a new strategy based on the exosome (exo) - drug conjugation (EDC) using the milk-derived exosomes for ATS delivery. The Exo-ATS conjugates (EACs) which formed via a facile bio-conjugation of ATS to the exosomal surface, have been demonstrated to be able to not only boost the solubility and bioavailability of ATS but also enable a sustained-release of ATS from exosomes. Maximal improvement of 71.4-fold in the solubility of ATS was attained by EACs. The corresponding entrapment efficiency and drug loading capacities were found to be 90.3% and 73.9% for EACs, respectively. Further, in vivo pharmacokinetics study manifested that maximum 2.6-fold improved bioavailability of ATS was achieved by oral delivery of EACs. Moreover, EACs displayed a distinct sustained-release profile of maximum 36.2-fold prolonged half-life of ATS via intravenous delivery. We reported that for the first time the administration of EACs could be a potential drug delivery strategy aimed at ameliorating the pharmacokinetic profile of ATS based on our encouraging results and hoped that our work opened up a new avenue for the development of EDC delivery system.

Targeting delivery of partial VAR2CSA peptide guided N-2-Hydroxypropyl trimethyl ammonium chloride chitosan nanoparticles for multiple cancer types.

To developing a multiple cancer types targeting drug delivery carrier system, a 28 amino acids from the VAR2CSA was synthesized as the placental CSA-binding peptide (plCSA-BP). Its specific binding ability to cancer cells was tested on cancer tissue array, and the results showed that plCSA-BP could bind to multiple cancer types. Then, the plCSA-BP was used as a guiding peptide to coat nanoparticles synthesized from N-2-HACC (CSA/HACC-NPs) which were loaded with prodigiosin (CSA/HACC-PNPs) or indocyanine green (CSA/HACC-INPs). The cancer cells specific targeting and efficacy of the CSA/HACC-PNPs were tested by different cancer cells in vitro and various cancer xenograft model in vivo. A scramble peptide (SCR) was used as control and synthesized SCR/HACC-PNPs and SCR/HACC-INPs. The results showed that the CSA/HACC-INPs could specifically uptake by JEG-3, PC3 and A594 cells, and the CSA/HACC-PNPs exhibited better anti-cancer activity and lower toxic effect in subcutaneous choriocarcinoma and prostatic tumor models compared with the free prodigiosin, HACC-PNPs and SCR/HACC-PNPs. So, the CSA/HACC-NPs could be used as a specific delivery carrier for multiple cancer types, and provided an alternate treatment option of various cancers with a single recipe.

Targeted Delivery Prodigiosin to Choriocarcinoma by Peptide-Guided Dendrigraft Poly-l-lysines Nanoparticles.

The available and effective therapeutic means to treat choriocarcinoma is seriously lacking, mainly due to the toxic effects caused by chemotherapy and radiotherapy. Accordingly, we developed a method for targeting delivery of chemotherapeutical drugs only to cancer cells, not normal cells, in vivo, by using a synthetic placental chondroitin sulfate (CSA)-binding peptide (plCSA-BP) derived from malarial protein VAR2CSA. A 28 amino acids placental CSA-binding peptide (plCSA-BP) from the VAR2CSA was synthesized as a guiding peptide for tumor-targeting delivery, dendrigraft poly-L-lysines (DGL) was modified with plCSA-BP and served as a novel targeted delivery carrier. Choriocarcinoma was selected to test the effect of targeted delivery carrier, and prodigiosin isolated from Serratia marcescens subsp. lawsoniana was selected as a chemotherapeutical drug and encapsulated in the DGL modified by the plCSA-BP nanoparticles (DGL/CSA-PNPs). DGL/CSA-PNPs had a sustained slow-release feature at pH 7.4, which could specifically bind to the JEG3 cells and exhibited better anticancer activity than that of the controls. The DGL/CSA-PNPs induced the apoptosis of JEG3 cells through caspase-3 and the P53 signaling pathway. DGL/CSA-PNPs can be used as an excellent targeted delivery carrier for anticancer drugs, and the prodigiosin could be an alternative chemotherapeutical drug for choriocarcinoma.

Targeted delivery of doxorubicin by CSA-binding nanoparticles for choriocarcinoma treatment.

Gestational trophoblastic neoplasia (GTN) can result from the over-proliferation of trophoblasts. Treatment of choriocarcinoma, the most aggressive GTN, currently requires high doses of systemic chemotherapeutic agents, which result in indiscriminate drug distribution and severe toxicity. To overcome these disadvantages and enhance the chemotherapeutic efficacy, chondroitin sulfate A (CSA)-binding nanoparticles were developed for the targeted delivery of doxorubicin (DOX) to choriocarcinoma cells using a synthetic CSA-binding peptide (CSA-BP), derived from malarial protein, which specifically binds to the CSA exclusively expressed in the placental trophoblast. CSA-BP-conjugated nanoparticles rapidly bonded to choriocarcinoma (JEG3) cells and were efficiently internalized into the lysosomes. Moreover, CSA-BP modification significantly increased the anti-cancer activity of the DOX-loaded nanoparticles in vitro. Intravenous injections of CSA-BP-conjugated nanoparticles loaded with indocyanine green (CSA-INPs) were rapidly localized to the tumor. The CSA-targeted nanoparticles loaded with DOX (CSA-DNPs) strongly inhibited primary tumor growth and, more importantly, significantly suppressed metastasis in vivo. Collectively, our results highlight the potential of the CSA-BP-decorated nanoparticles as an alternative targeted delivery system of chemotherapeutic agents for treating choriocarcinoma and for developing new GTN therapies based on drug targeting.

Response of live Newcastle disease virus encapsulated in N-2-hydroxypropyl dimethylethyl ammonium chloride chitosan nanoparticles.

We have synthesized N-2-hydroxypropyl dimethylethyl ammonium chloride chitosan (N-2-HFCC) with higher water solubility than chitosan. To evaluate its potential as delivery carrier, NDV encapsulated in N-2-HFCC/CMC nanoparticles (NDV/La Sota-N-2-HFCC/CMC-NPs) with a diameter of 252.2±32.68nm, Zeta potential of 41.1±0.89mV, encapsulation efficiency of 96.6±0.72% and loading capacity of 53.2±1.11% were prepared. NDV/La Sota-N-2-HFCC/CMC-NPs are a novel type of attenuated live vaccine encapsulated in nanoparticles. These nanoparticles displayed lower cytotoxicity and higher stability. Their bioactivity was maintained when they were stored for three months at the room temperature. Release assay in vitro showed that NDV could be sustainably released after an initial burst release. In vivo immunization showed that immunization of specific pathogen free chickens with NDV/La Sota-N-2-HFCC/CMC-NPs intranasally induced high titers of serum antibody, significantly promoted lymphocyte proliferation and caused higher levels of interleukine-2 and interference-γ. These results indicated that N-2-HFCC/CMC nanoparticles could serve as an efficient and safe delivery vehicle for mucosal immunity, and have a great potential in medical applications.

O-2'-hydroxypropyltrimethyl ammonium chloride chitosan nanoparticles for the delivery of live Newcastle disease vaccine.

A novel complex chitosan derivative, O-2'-hydroxypropyltrimethyl ammonium chloride chitosan (O-2'-HACC), was synthesized and used to make nanoparticles as a delivery vehicle for live attenuated Newcastle disease vaccine. We found that O-2'-HACC had high antimicrobial activity, low toxicity, and a high safety level. Newcastle disease virus (NDV) was then encapsulated in the O-2'-HACC nanoparticles (NDV/La Sota-O-2'-HACC-NPs) by the ionic crosslinking method, and the properties of the resulting nanoparticles were determined by transmission electron microscopy, Zeta potential analysis, Fourier transform infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, and X-ray diffraction. NDV/La Sota-O-2'-HACC-NPs had regular spherical morphologies and high stability, with an encapsulation efficiency of 95.68 ± 2.2% and a loading capacity of 58.75 ± 4.03%. An in vitro release assay indicated that release of NDV from NDV/La Sota-O-2'-HACC-NPs occurred slowly. Specific pathogen-free chickens immunized with NDV/La Sota-O-2'-HACC-NPs intranasally had much stronger cellular, humoral and mucosal immune responses than did those immunized intramuscularly or with live attenuated Newcastle disease vaccine. NDV/La Sota-O-2'-HACC-NPs are a novel drug delivery carrier with immense potential in medical applications.