Poly(2‐oxazoline) block copolymer based formulations of taxanes: effect of copolymer and drug structure, concentration, and environmental factors

Abstract

Many current nanoformulations of taxanes are hampered by low drug-loading capacity and unfavorable physicochemical characteristics such as large particles size (>100 nm) and/or low size uniformity. We have previously reported on taxane nanoformulations, based on poly(2-oxazoline) polymeric micelles that display an extremely high taxane loading capacity (>40% w/w) and particle size below 50 nm. Previous work was based on a triblock copolymer having poly(2-butyl-2oxazoline) as the hydrophobic block and poly(2-methyl-2-oxazoline) as the hydrophilic blocks. This paper explores the effects of various formulation parameters such as (i) the drug and polymer structure; (ii) the drug and polymer concentration; and (iii) the composition of aqueous medium on the solubilization behavior and physicochemical properties of the resulting formulations. In addition, in vitro anticancer activity is reported. Despite numerous variations of the hydrophobicity, polarity or addition of aromatic residues in the hydrophobic core, the triblock copolymer with the poly(2-butyl-2-oxazoline) block remains the polymer with the highest drug-loading capacity. Notably, the formulation was easily scalable with uncompromised encapsulation efficacy, loading capacity, and physicochemical properties. The taxane formulations were stable upon storage (water, saline, and dextrose solution) for 1-2 weeks and could be lyophilized and re-dispersed without compromising the formulation properties. Furthermore, the micelles remained stable upon dilution. The drug-loaded poly(2-oxazoline) micelles showed high toxicity against several cancer cell lines. Taken together, these results underscore the potential of poly(2-oxazoline) micelles as formulation excipient for taxanes and possibly other hydrophobic drugs. Figure 10. Stability of 50 g/l T1 micelle formulations of (a) paclitaxel (39.7 g/l) and (b) docetaxel (40.6 g/l) in DI water, 5% dextrose solution (DEX) or phosphate buffered saline at room temperature. This figure is available in colour online at wileyonlinelibrary.com/journal/pat Y. SEO ET AL.wileyonlinelibrary.com/journal/pat

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

“…As previously reported [19] and independently reproduced here using a newly synthesized polymer, the introduction of benzylic moieties (A-p(BuOx-co-BzOx)-A)…”

“…[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.…”

“…[19] Testing a variety of structurally different taxanes led to similar high drug loadings and stability of the formulations.…”

Polymers and Nanomedicine: Considerations on Variability and Reproducibility When Combining Complex Systems

“…In four consecutive papers, three different batches of a polymer were investigated (Table 2) [39][40][41][42][43]. Similar to the work of Hoogenboom et al on homopoly(2-oxazoline)s [37], the standard deviation of the M n was approximately 5% of the average.…”

A high capacity polymeric micelle of paclitaxel: Implication of high dose drug therapy to safety and in vivo anti-cancer activity

“…The hydrophilic block is poly(2-methyl-2-oxazoline) (PMeOx), which imposes stealth properties similar if not superior to PEG [43,44]. The hydrophobic block, poly(2-butyl-2-oxazoline) (PBuOx) was screened as an ideal environment for solubilizing unprecedentedly high amount of PTX with outstanding formulation stability [14,15,45]. Moreover, triblock structure proved superior as compared to diblock structure [11].…”