Cell Permeating Nano-Complexes of Amphiphilic Polyelectrolytes Enhance Solubility, Stability, and Anti-Cancer Efficacy of Curcumin

Abstract

Many hydrophobic drugs encounter severe bioavailability issues owing to their low aqueous solubility and limited cellular uptake. We have designed a series of amphiphilic polyaspartamide polyelectrolytes (PEs) that solubilize such hydrophobic drugs in aqueous medium and enhance their cellular uptake. These PEs were synthesized through controlled (∼20 mol %) derivatization of polysuccinimide (PSI) precursor polymer with hydrophobic amines (of varying alkyl chain lengths, viz. hexyl, octyl, dodecyl, and oleyl), while the remaining succinimide residues of PSI were opened using a protonable and hydrophilic amine, 2-(2-amino-ethyl amino) ethanol (AE). Curcumin (Cur) was employed as a representative hydrophobic drug to explore the drug-delivery potential of the resulting PEs. Unprecedented enhancement in the aqueous solubility of Cur was achieved by employing these PEs through a rather simple protocol. In the case of PEs containing oleyl/dodecyl residues, up to >65000× increment in the solubility of Cur in aqueous medium could be achieved without requiring any organic solvent at all. The resulting suspensions were physically and chemically stable for at least 2 weeks. Stable nanosized polyelectrolyte complexes (PECs) with average hydrodynamic diameters (DH) of 150-170 nm (without Cur) and 220-270 nm (after Cur loading) were obtained by using submolar sodium polyaspartate (SPA) counter polyelectrolyte. The zeta potential of these PECs ranged from +36 to +43 mV. The PEC-formation significantly improved the cytocompatibility of the PEs while affording reconstitutable nanoformulations having up to 40 wt % drug-loading. The Cur-loaded PECs were readily internalized by mammalian cells (HEK-293T, MDA-MB-231, and U2OS), majorly through clathrin-mediated endocytosis (CME). Cellular uptake of Cur was directly correlated with the length of the alkyl chain present in the PECs. Further, the PECs significantly improved nuclear transport of Cur in cancer cells, resulting in their death by apoptosis. Noncancerous cells were completely unaffected under this treatment.

Rationally designed curcumin laden glycopolymeric nanoparticles: Implications on cellular uptake and anticancer efficacy

“…The blocking of clathrin assembly and dependent GLUT receptors significantly lowered the drug level from an optimized formulation in blocked cell (0.65 ± 0.09 μg/10 5 cells) compared to the unblocked cells (2.12 ± 0.34 μg/10 5 cells). This remarkable reduction of drug uptake in blocked cells bestowed the evidence of involvement of specific GLUTs receptor recognition and receptor‐mediated endocytosis of glucopyranoside carriers for internalization of curcumin …”

“…However, poor aqueous solubility, instability, low bioavailability, faster metabolism, and clearance impede its therapeutic efficacy. Literature reports have established that drug delivery systems like micro‐ and nanoparticles, drug‐polymer conjugates, solid lipid nanoparticles, micelles, liposomes, polyelectrolyte, and cyclodextrin complexes have improved cellular uptake and bioavailability of curcumin.…”

Amphiphilic Small Molecule Assemblies to Enhance the Solubility and Stability of Hydrophobic Drugs

“…pH triggered release of doxorubicin: Dox-M2 agg (1 mM M2) in PBS (pH 7.4) was prepared as described earlier. 800 µL of the dox-M2 agg solution was added in two separate dialysis tubes (6)(7)(8) and dialyzed at 37℃ against 40 mL PBS of pH 6.0 and 7.4 respectively. 400 µL of the dialysis buffer was aliquoted every 1 h. The dialysis solution was replenished with an equivalent amount of the buffer to keep the final volume constant.…”

Nano-Pharmaceuticals in Medicine

“…Once internalised, these nano complexes unravelled to release the entrapped peptide cargo intra-cellularly. This achievement was further elaborated by developing amphiphilic polymers towards delivering hydrophobic drugs such as Curcumin (Fatima et al, 2016). Facile solubilisation of commercial Curcumin powder in aqueous medium was achieved by utilising these polymers.…”