Synergistic Combinations of Multiple Chemotherapeutic Agents in High Capacity Poly(2-oxazoline) Micelles

Abstract

Many effective drugs for cancer treatment are poorly water-soluble. In combination chemotherapy, needed excipients in additive formulations are often toxic and restrict their applications in clinical intervention. Here, we report on amphiphilic poly(2-oxazoline)s (POx) micelles as a promising high capacity delivery platform for multi-drug cancer chemotherapy. A variety of binary and ternary drugs combinations of paclitaxel (PTX), docetaxel (DTX), 17-allylamino-17-demethoxygeldanamycin (17-AAG), etoposide (ETO) and bortezomib (BTZ) were solubilized in defined polymeric micelles achieving unprecedented high total loading capacities of up to 50 wt.% drug per final formulation. Multi-drug loaded POx micelles showed enhanced stability in comparison to single-drug loaded micelles. Drug ratio dependent synergistic cytotoxicity of micellar ETO/17-AAG was observed in MCF-7 cancer cells and of micellar BTZ/17-AAG in MCF-7, PC3, MDA-MB-231 and HepG2 cells.

Design Strategies for Functionalized Poly(2-oxazoline)s and Derived Materials

“…Three different as-functionalized monomers, composed of a bis(imidazoline-2-ylidene)palladium(II) diiodide derivative covalently bound to the 2-oxazoline ring by alkyl spacers (n-butyl, n-hexyl, n-octyl), were incorporated into the block copolymers, which displayed self-assembly in aqueous solution and were furthermore used in Heck and Suzuki coupling reactions. Kabanov, Luxenhofer et al prepared pMeOx-block-p n BuOx-block-pMeOx-based micelles that could be loaded with large amounts of various hydrophobic anticancer agents [182]. These multidrug loaded poly(2-oxazoline) micelles were also found to be more stable compared to single-drug loaded micelles and to exhibit synergistic effects useful against several tumor models.…”

Polymeric Micelles for Multi-Drug Delivery in Cancer

“…Han et al developed polymeric micelles using amphiphilic poly(2-oxazoline) (POx) tri-block copolymers, poly(2-methyl-2-oxazoline)-block-poly(2-butyl-2-oxazoline)-block-poly(2-methyl-2-oxazoline) (P(MeOx-b-BuOx-b-MeOx)) in which PBuOx formed the core of polymeric micelles and PMeOx behaved like PEG, providing high hydrophilicity and exhibiting stealth properties in blood stream (54). POx polymeric micelles permitted fine-tuning of the hydrophilic (PMeOx)-hydrophobic (PBuOx) balance by varying length of side alkyl chains and allowed physical incorporation of PTX, DTX (microtubule stabilizer), 17-AAG, ETO, and bortezomib (BTZ, proteasome inhibitor), individually and in combination (PTX/17-AAG, DTX/17-AAG, PTX/ETO, ETO/17-AAG, PTX/BTZ, BTZ/17-AAG, PTX/17-AAG/ ETO, PTX/17-AAG/BTZ and DTX/PTX).…”

Investigating the influence of aromatic moieties on the formulation of hydrophobic natural products and drugs in poly(2-oxazoline) based amphiphiles

“…[15][16][17][18][19]. Despite the very low water solubility, PTX is a high affinity substrate for P-glycoprotein (P-gp) which leads to PTX resistance in cancer cells.…”

“…[15,17] Lübtow et al investigated a small library of structurally similar ABAtriblock copolymers based on poly(2-oxazoline)s and poly(2-oxazine)s and explored their solubilization capacity for PTX and curcumin (CUR [25]), another well-known natural compound featuring extremely low aqueous solubility, bioavailability and stability.…”