title: 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.
authors.affiliation: Department of Chemistry and §Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal , Bhauri, Bhopal By-pass Road, Bhopal 462 066, India.
authors.forename: Munazza T
authors.initials: MT
authors.lastname: Fatima
authors.affiliation: Department of Chemistry and §Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal , Bhauri, Bhopal By-pass Road, Bhopal 462 066, India.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Chanchal
authors.affiliation: Department of Chemistry and §Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal , Bhauri, Bhopal By-pass Road, Bhopal 462 066, India.
authors.forename: Prabhu S
authors.initials: PS
authors.lastname: Yavvari
authors.affiliation: Department of Chemistry and §Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal , Bhauri, Bhopal By-pass Road, Bhopal 462 066, India.
authors.forename: Somnath D
authors.initials: SD
authors.lastname: Bhagat
authors.affiliation: Department of Chemistry and §Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal , Bhauri, Bhopal By-pass Road, Bhopal 462 066, India.
authors.forename: Mansi
authors.initials: M
authors.lastname: Gujrati
authors.affiliation: Department of Chemistry and §Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal , Bhauri, Bhopal By-pass Road, Bhopal 462 066, India.
authors.forename: Ram K
authors.initials: RK
authors.lastname: Mishra
authors.affiliation: Department of Chemistry and §Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal , Bhauri, Bhopal By-pass Road, Bhopal 462 066, India.
authors.forename: Aasheesh
authors.initials: A
authors.lastname: Srivastava
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D002463:Cell Membrane Permeability; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000737:chemistry* / Q000494:pharmacology*; D004337:Drug Carriers; D016503:Drug Delivery Systems; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D053761:Nanocomposites / Q000008:administration & dosage / Q000737:chemistry*; D009369:Neoplasms / Q000188:drug therapy*; D000071228:Polyelectrolytes / Q000737:chemistry*; D012995:Solubility
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D000071228:Polyelectrolytes; D003474:Curcumin