The poor solubility of paclitaxel (PTX), the commercially most successful anticancer drug, has long been hampering the development of suitable formulations. Here, we present translational evaluation of a nanoformulation of PTX, which is characterized by a facile preparation, extraordinary high drug loading of 50 % wt. and PTX solubility of up to 45 g/L, excellent shelf stability and controllable, sub-100 nm size. We observe favorable in vitro and in vivo safety profiles and a higher maximum tolerated dose compared to clinically approved formulations. Pharmacokinetic analysis reveals that the higher dose administered leads to a higher exposure of the tumor to PTX. As a result, we observed improved therapeutic outcome in orthotopic tumor models including particularly faithful and aggressive “T11” mouse claudin-low breast cancer orthotopic, syngeneic transplants. The promising preclinical data on the presented PTX nanoformulation showcase the need to investigate new excipients and is a robust basis to translate into clinical trials.

Nanoparticle-based systems for concurrent delivery of multiple drugs can improve outcomes of cancer treatments, but face challenges because of differential solubility and fairly low threshold for incorporation of many drugs. Here we demonstrate that this approach can be used to greatly improve the treatment outcomes of etoposide (ETO) and platinum drug combination (“EP/PE”) therapy that is the backbone for treatment of prevalent and deadly small cell lung cancer (SCLC). A polymeric micelle system based on amphiphilic block copolymer poly(2-oxazoline)s (POx) poly(2-methyl-2-oxazoline-block-2-butyl-2-oxazoline-block-2-methyl-2-oxazoline) (P(MeOx-b-BuOx-b-MeOx) is used along with an alkylated cisplatin prodrug to enable co-formulation of EP/PE in a single high-capacity vehicle. A broad range of drug mixing ratios and exceptionally high two-drug loading of over 50% wt. drug in dispersed phase is demonstrated. The highly loaded POx micelles have worm-like morphology, unprecedented for drug loaded polymeric micelles reported so far, which usually form spheres upon drug loading. The drugs co-loading in the micelles result in a slowed-down release, improved pharmacokinetics, and increased tumor distribution of both drugs. A superior antitumor activity of co-loaded EP/PE drug micelles compared to single drug micelles or their combination as well as free drug combination was demonstrated using several animal models of SCLC and non-small cell lung cancer.

Concurrent delivery of multiple drugs using nanoformulations can improve outcomes of cancer treatments. Here we demonstrate that this approach can be used to improve the paclitaxel (PTX) and alkylated cisplatin prodrug combination therapy of ovarian and breast cancer. The drugs are co-loaded in the polymeric micelle system based on amphiphilic block copolymer poly(2methyl-2-oxazoline-block-2-butyl-2-oxazoline-block-2-methyl-2-oxazoline) (P(MeOx-b-BuOxb-MeOx). A broad range of drug mixing ratios and exceptionally high two-drug loading of over 50 #

The clinically and commercially successful taxanes, paclitaxel and docetaxel suffer from two major drawbacks, namely their very low aqueous solubility and the risk of developing resistance. Here, we present a method that overcomes both drawbacks in a very simple manner. We formulated 3rd generation taxoids, able to avoid common drug resistance mechanisms with doubly amphiphilic poly(2-oxazoline)s (POx), a safe and highly efficient polymer for the formulation of extremely hydrophobic drugs. We found excellent solubilization of different 3rd generation taxoids irrespective of the drug's chemical structures with essentially quantitative drug loading and final drug to polymer ratios around unity. The small, highly loaded micelles with a hydrodynamic diameter of less than 100 nm are excellently suited for parenteral administration. Moreover, a selected formulation with the taxoid SB-T-1214 is about one to two orders of magnitude more active in vitro than paclitaxel in the multidrug resistant breast cancer cell line LCC6-MDR. In contrast, in wild-type LCC6, no difference was observed. Using a q4d x 4 dosing regimen, we also found that POx/SB-T-1214 significantly inhibits the growth of LCC6-MDR orthotropic tumors, outperforming commercial paclitaxel drug Taxol and Cremophor EL formulated SB-T-1214.

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

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The combination chemotherapy regimen of cisplatin (CP) and docetaxel (DTX) is effective against a variety of cancers. However, combination therapies present unique challenges that can complicate clinical application, such as increases in toxicity and imprecise exposure of tumors to specific drug ratios that can produce treatment resistance. Drug co-encapsulation within a single nanoparticle (NP) formulation can overcome these challenges and further improve combinations’ therapeutic index. In this report, we employ a CP prodrug (CPP) strategy to formulate poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) NPs carrying both CPP and DTX. The dually loaded NPs display differences in drug release kinetics and in vitro cytotoxicity based on the structure of the chosen CPP. Furthermore, NPs containing both drugs showed a significant improvement in treatment efficacy versus the free drug combination in vivo.

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