pH-responsive dendritic polyrotaxane drug-polymer conjugates forming nanoparticles as efficient drug delivery system for cancer therapy

Abstract

a Self-assembly of stimuli-responsive polymeric nanoparticles have attracted great attention in recent years due to their prospective biological applications. This paper developed a novel pH-sensitive amphiphilic dendritic polyrotaxane drug-polymer conjugate by covalently linking doxorubicin (DOX) and dendritic polyrotaxane via a pH-responsible hydrazone bond with 1.84 wt% (weight percent) of DOX. The drugpolymer conjugate was amphiphilic and could be self-assembled to micelles (PR-g-DOX micelles) in an aqueous solution. The globular morphology and compact micelles with a diameter of around 110 nm were observed by SEM and TEM. Moreover, the micelles showed a significantly faster DOX release at mildly acidic pH of 6.0 and 5.0 and almost no burst release at the physiological pH of 7.4. Notably, it was confirmed that this micelle could efficiently deliver DOX to the nuclei of the tumor cells, which led to a much greater cytotoxic effects in the A549 cancer cells than the parent DOX. In vivo results revealed better drug tolerability of PR-g-DOX micelles and a higher in vivo efficacy without any increase in the toxicity of the PR-g-DOX micelles. Furthermore, the maximum tolerated dose (MTD) results showed that PRg-DOX micelles showed an excellent safety profile with a two-fold higher MTD (10 mg kg −1 DOX) than that of free DOX (5 mg kg −1 DOX). We are convinced that the PR-g-DOX micelle has tremendous potentials for targeted cancer therapy.

Selective intracellular drug delivery from pH-responsive polyion complex micelle for enhanced malignancy suppression in vivo

“…Of them, the pH-responsive polymers can be broadly divided into two categories: polymers containing (1) ionizable group and (2) acid-degradable linkage [9]. Through utilizing the variations of pH values in tumor microenvironment, a large number of nanoformulations based on the above pH-responsive polymers, including polymeric micelles [10,11], nanogels [12,13], polymer-drug conjugates [14,15], etc., are developed for pH-triggered drug delivery. The smart polymeric platforms release the loaded antitumor drugs in response to the decreased pH in the intracellular compartments, which minimize the non-specific systemic toxicity and maximize the tumor-directed drug delivery efficiency [16].…”

Conjugation of a smart polymer to doxorubicin through a pH-responsive bond for targeted drug delivery and improving drug loading on graphene oxide

“…2 This bond has been linked between drugs and different polymers to study the effects of pH on the loading and distribution of anticancer drugs. [28][29][30][31] Kang et al 30 developed a pH-sensitive dendritic polyurethane conjugate (PR-g-Dox), in which DOX was attached to the terminal functional groups of the polymer by hydrazone bonding. Many nanoparticles can be used as potential nanocarriers for the delivery of Doxorubicin (DOX) to minimize the side effects and destructive effects of this drug.…”

One-pot synthesis of block-copolyrotaxanes through controlled rotaxa-polymerization

“…There are several CD-based polyrotaxanes known with homo- and block-copolymer axes, mostly based on poly(ethylene oxide), poly(propylene oxide) or their copolymers [ 15 – 21 ], since these polymers can form sufficiently stable complexes with CDs. The application potential of these polyrotaxanes was already investigated in the fields of biomedicine, as drug [ 22 ] or gene [ 23 ] delivery vehicles, or in materials sciences, as slide ring gels [ 6 ]. Polyrotaxanes are mostly synthesized by a threading approach [ 2 ], a multistep method starting from pre-synthesized (co)polymers.…”