Controlled Cellular Delivery of Amphiphilic Cargo by Redox‐Responsive Nanocontainers

Abstract

The specific transport of amphiphilic compounds such as fluorescently labeled phospholipids into cells is a prerequisite for the analysis of highly dynamic cellular processes involving these molecules, e.g., the intracellular distribution and metabolism of phospholipids. However, cellular delivery remains a challenge as it should not affect the physiological integrity and morphology of the cell membrane. To address this, polymer nanocontainers based on redox‐responsive cyclodextrin (CD) amphiphiles are prepared, and their potential to deliver fluorescently labeled phospholipids to intracellular membrane compartments is analyzed. It is shown that mixtures of reductively degradable cyclodextrin amphiphiles and different phospholipids form liposome‐like vesicles (CD–lipid vesicles, CSSLV) with a homogeneous distribution of each lipid. Host–guest‐mediated self‐assembly of a cystamine‐crosslinked polymer shell on these CSSLV produces polymer‐shelled liposomal vesicles (PSSCSSLV) with the unique feature of a redox‐sensitive CSSLV core and reductively degradable polymer shell. PSSCSSLV show high stability and a redox‐sensitive release of the amphiphilic cargo. Live cell experiments reveal that the novel PSSCSSLV are readily internalized by primary human endothelial cells and that the reductive microenvironment of the cells' endosomes triggers the release of the amphiphilic cargo into the cytosol. Thus, PSSCSSLV represent a highly efficient system to transport lipid‐like amphiphilic cargo into the intracellular environment.

Adamantane‐Terminated Polypeptides: Synthesis by N‐Carboxyanhydride Polymerization and Template‐Based Self‐Assembly of Responsive Nanocontainers via Host–Guest Complexation with β‐Cyclodextrin

“…In this communication, we report the synthesis of adamantane terminated polypeptides by NCA polymerization with the aim to replace the non biodegradable polyacrylates in our previous work. [24,25] Adamantane terminated poly-l-glutamic acid (Ad-PLG) was used to design anionic polypeptide shelled vesicle (PPSV), whereas adamantane poly-l-lysine formed cationic PPSV. Crosslinking using cystamine as a disulfide containing crosslinker provided PPSVss.…”

“…These findings are consistent with our data on polyacrylate shelled CDV. [25,26] The crosslinking of Ad-PLG on the CDV was quantified using fluorescein-5-maleimide (5-FM). In a typical experiment, the disulfides were reduced using tris(2-carboxyethyl) phosphine (TCEP), then the free thiols were reacted with 5-FM, and the absorption spectra (Figure 3e) were used to quantify the amount of crosslinking after the free dyes were removed by dialysis.…”

“…[ 24 ] Incorporation of amphiphilic lipid cargoes in to the cyclodextrin vesicles with redox responsive cyclodextrin amphiphile gave polymer‐shelled liposomal vesicles (PssCssLV). [ 25 ] The amphiphilic cargoes were released in the intracellular environment upon reduction by glutathione.…”

Supramolecular Prodrug Nanovectors for Active Tumor Targeting and Combination Immunotherapy of Colorectal Cancer

“…[ 9–12 ] Despite their specificity and binding affinity, the monoclonal antibody‐based immune checkpoint inhibitors may have several intrinsic disadvantages, including limited tumor penetration, immune‐related adverse effects, and inadequate pharmacokinetics. [ 13–19 ] To improve the response rate and overcome the disadvantages of monoclonal antibody‐based immune inhibitor remain a formidable challenge in ICB therapy.…”

The chemistry of cross-linked polymeric vesicles and their functionalization towards biocatalytic nanoreactors

“…1) [9][10][11][12][13]. Moreover, large variety of stimuli-responsive polymers have been designed, a class of "smart" polymers that can sense minimal changes in the environment (pH, light, temperature, enzymes, redox agents, ions, gas, mechanical force or electrochemistry) leading to physical or chemical structural changes in the final polymersome [12,[14][15][16][17][18][19][20][21][22][23][24][25]. These kinds of polymersomes receive internal or external stimuli to control the capture and release of drugs and chemicals and for the performance of enzymatic reactions.…”