Polymeric micelles for the pH-dependent controlled, continuous low dose release of paclitaxel

Abstract

Poly(ethylene glycol)-block-poly(aspartate-hydrazide) (PEG-p(Asp-Hyd)) was modified using either levulinic acid (LEV) or 4-acetyl benzoic acid (4AB) attached via hydrazone bonds. Paclitaxel (PTX) conjugated to the linkers formed PEG-p(Asp-Hyd-LEV-PTX) and PEG-p(Asp-Hyd-4AB-PTX). PEG-p(Asp-Hyd-LEV-PTX) and PEG-p(Asp-Hyd-4AB-PTX) assemble into unimodal polymeric micelles with diameters of 42 nm and 137 nm, respectively. PEG-p(Asp-Hyd-LEV-PTX) and PEG-p(Asp-Hyd-4AB-PTX) at a 1:1 and 1:5 molar ratio assemble into unimodal mixed polymeric micelles with diameters of 85 and 113 nm, respectively. PEG-p(Asp-Hyd-LEV-PTX) micelles release LEV-PTX faster at pH 5.0 than at pH 7.4 over 24 hr. At pH 7.4 mixed polymeric micelles at 1:5 ratio show no difference in LEV-PTX release from PEG-p(Asp-Hyd-LEV-PTX) micelles. Mixed polymeric micelles at 1:5 molar ratio gradually releases LEV-PTX at pH 5.0, with no release of 4AB-PTX. PEG-p(Asp-Hyd-LEV-PTX) micelles and mixed polymeric micelles exert comparable cytotoxicity against SK-OV-3 and MCF-7 cancer cell lines. In summary, mixed polymeric micelles based on PEG-p(Asp-Hyd-LEV-PTX) and PEG-p(Asp-Hyd-4AB-PTX) offer prospects for pH-dependent release of PTX, offering a novel pro-drug strategy for adjusting its pharmacokinetic and pharmacodynamic properties for cancer therapy. If successful this delivery system offers an alternative new mode of delivery for paclitaxel with a new scope for its efficacy along with a minimal synthetic framework needed to accomplish this.

Classification of stimuli–responsive polymers as anticancer drug delivery systems

“…Both are relatively stable at physiological pH and can release the bound drugs under low pH conditions. Some examples of polymer-drug conjugates containing hydrazone linkages are HPMA-Dox, PEG-Dox (Lu et al, 2011;Dong et al, 2013) PEG-epirubicin (Takahashi et al, 2013) and PEG-PTXL (Alani et al, 2010).…”

Combinatorial Polymeric Conjugated Micelles with Dual Cytotoxic and Antiangiogenic Effects for the Treatment of Ovarian Cancer

“…As seen in the drug release profile, the release of the drug from the polymer backbone is greater at pH 5.5 as compare to pH 7.4. This is expected as the hydrazone linker, LEV, is cleaved from the polymer backbone at acidic pH 42,[52][53][54]64 . The drugs release profile for the individual and mixed micelles did not reach 100% within 24 h, suggesting that some of the hydrazone bonds have not been cleaved during the experimental time frame.…”

“…Poly(ethylene glycol)-block-poly(β-benzyl Laspartate) (PEG-PBLA) is an ABC that has been used as a starting point for polymeric micelles to deliver various chemotherapeutics 39,40 . We have developed new pH-sensitive conjugated polymeric micellar nanocarriers that can be adapted for the delivery of chemotherapeutic agents 41,42 . The rate of drug release can be tuned, using different linkers, and allows the formation of mixed micelles containing multiple drugs in the core for simultaneously delivery within the targeted cell to achieve additive/synergistic effects ( Fig.…”

“…The number of LEV present in the PEG-LEV (5) is 40, corresponding to a 100% substitution and is confirmed by 1 H NMR (Fig.S3) and the M n (NMR & GPC), M w , and PDI of the PEG-LEV are presented in Table 1. PEG-LEV-PTX (6) is synthesized by conjugation of PTX via an ester bond on PEG-LEV using a previously described method 41,42 . The structure of PEG-LEV-PTX polymer is confirmed by 1 H NMR 41,42 .…”

“…PEG-LEV-PTX (6) is synthesized by conjugation of PTX via an ester bond on PEG-LEV using a previously described method 41,42 . The structure of PEG-LEV-PTX polymer is confirmed by 1 H NMR 41,42 . The number of PTX molecules present in PEG-LEV-PTX (6) is 15 as calculated from 1 H NMR 41,42 and GPC data (Table 1), corresponding to a 37.5% degree of drug substitution.…”