Targeted co-delivery of protein and drug to a tumor in vivo by sophisticated RGD-modified lipid-calcium carbonate nanoparticles

Abstract

Synchronized bio-distribution of combination therapies has several merits such as synergistic effects and reduced side-effects. Co-delivery of a protein and small molecule drug using a single nanocarrier is challenging because they possess totally different characteristics. Herein, we report the development of sophisticated nanoparticles composed of lipids, calcium carbonate and RGD peptide ligands for the co-delivery of a protein and small molecule drug combination via a simple preparation method. A 'one-step' ethanol injection method was employed to prepare the highly organized nanoparticles. The nanoparticles exhibited a spherical shape with ca. 130 nm diameter, and clearly had an integrated lipid layer covering the periphery. As a ligand, an RGDmodified lipid was post-inserted into the nanoparticles, which was important to overcome the 'PEG dilemma'. The pH-sensitivity of the targeted nanoparticles contributed to the efficient intracellular co-delivery of a protein and drug combination in Colon26 tumor cells, and noticeably improved their accumulation in the tumor region of xenograft mice. Synchronized bio-distribution of the protein and drug was achieved, which was the foundation for the synergistic effects of the combination. The targeting capability of the nanoparticles along with their pH-sensitive drug release and the synchronized bio-distribution of their cargos led to the significant antitumor activity of the SOD and paclitaxel combination in mice. This study provides novel information for the design and preparation of functionalized nanoparticles for the delivery of a protein/drug combination in vivo.

Gelatin Methacryloyl Hydrogels Control the Localized Delivery of Albumin-Bound Paclitaxel

“…To measure the release of Abraxane ® using fluorescence spectroscopy, we labeled the human serum albumin (HSA) part of the drug because it constitutes the majority of Abraxane ® (90%/10% HSA-Paclitaxel ratio). The fluorescent probe FITC is commonly used to label molecules of interests and especially albumin, which has been widely used as a model for protein delivery and is recognized as representative of the release profile of unlabeled compounds [63][64][65][66][67][68]. We assumed that the Paclitaxel-HSA bond remained stable throughout the assays since the detachment of Paclitaxel from HSA is triggered by the competition with other highly hydrophobic compounds such as fatty acids of the cell membrane [9,10,69], not present in the PBS in vitro system.…”

A pH-Adjustable Tissue Clearing Solution That Preserves Lipid Ultrastructures: Suitable Tissue Clearing Method for DDS Evaluation

“…Moreover, Seebest-PP would maximize multicolor deep imaging potency to simultaneously evaluate positional relationship of gene expression and/or lipidic carriers (such as liposomes and lipid nanoparticles) with biological structures (such as blood vessels, tissue surface and elastic fibers), oxidative stress and so on. Moreover, we have developed the quantification method of DDS carrier concentration in tissue homogenates using tissue clearing solutions [36]. We are currently optimizing the composition of Seebest-PP to determine the concentration of lipidic DDS carriers in tissues.…”

Biomineralization: An Opportunity and Challenge of Nanoparticle Drug Delivery Systems for Cancer Therapy

“…A highly organized nanoparticle composed of lipid, calcium carbonate, and arginylglycylaspartic acid (RGD) peptide targeting ligands was synthesized by Peng et al using a "one-step" ethanol injection method. [71] The synthesized nanoparticles exhibited the targeting ability, pH sensitivity, and synchronized biodistribution of the drugs. It was demonstrated that superoxide dismutase and paclitaxel combination had significant antitumor activity in mice.…”