Self‐Assembled Polyprodrug Amphiphile for Subcutaneous Xenograft Tumor Inhibition with Prolonged Acting Time In Vivo

Abstract

Polymeric drug delivery system termed as "polyprodrug amphiphile" poly(2-methylacryloyloxyethyl phosphorylcholine)-b-poly(10-hydroxy-camptothecin methacrylate (pMPC-b-pHCPT) is developed for the prolonged-acting cancer therapy. It is obtained by two-step reversible addition-fragmentation chain transfer polymerization of zwitterionic monomer MPC and an esterase-responsive polymerizable prodrug methacrylic anhydride-CPT, respectively. This diblock polymer is composed of both antifouling (pMPC) and bioactive (pHCPT) segments and the drug is designed as a building block to construct the polymer skeleton directly. Due to its distinct amphiphilicity, the polymer can self-assemble into micelles with different dynamic sizes by facilely tuning the ratio of MPC/HCPT under physiological conditions. The outer pMPC shell is superhydrophilic to form dense hydrate layer preventing the nanosystem from unwanted nonspecific protein adsorption, which is the main lead cause of the rapid clearance of nanoparticles in vivo, thus facilitating the accumulation of drugs in tumor sites via enhanced permeability and retention effect. The configuration of the polyprodrug amphiphile is confirmed by several measurements. The resistance to albumin adsorption, prolonged plasma retention time, accumulation in tumor sites, and anticancer activity of the micelles is also investigated in vitro and in vivo. This novel amphiphile can be expected as a promising agent for the passive targeted prolonged-acting cancer therapy.

Antifouling Strategies of Nanoparticles for Diagnostic and Therapeutic Application: A Systematic Review of the Literature

“…Chen et al [ 52 ] designed a polymer by combining zwitterionic molecule poly(2-methylacryloyloxyethyl phosphorylcholine) (pMPC), with a membrane-inspired structure, loaded with a chemotherapeutic prodrug poly(10-hydroxy-camptothecin methacrylate) (pHCPT) that possesses a broad spectrum of antitumor activity. The amphiphilic polymer pMPC-b-pHCPT self-assembled into micelles.…”

“…Antifouling zwitterionic coatings improved biocompatibility and bioavailability of metallic NPs [ 22 ], polymeric micelles [ 52 ], or dendrimers [ 27 ] and showed marked stability in vitro and/or in vivo over a high salt concentration and broad range of pHs. Furthermore, the antifouling zwitterionic strategy not only leads to low protein absorption (typically assessed in vitro by using FBS) [ 44 ] and non-specific cellular adhesion, but also it reduces RES uptake [ 52 , 54 ]. Furthermore, the half-lives and clearance for zwitterionic-coated NPs (sub-10 nm) have been found to be relatively short from minutes to hours [ 47 ].…”

Tailoring Materials with Specific Wettability in Biomedical Engineering

“…Chen et al proposed a linear diblock amphipathic polymer chain achieved from the polymerization of superhydrophilic poly(2-methylacryloyloxyethyl phosphorylcholine) and a typi-cal chemotherapy drug poly(10-hydroxy-camptothecin methacrylate), as shown in Figure 6e. [162] The synthesized polymer chain could then be assembled into micelles which not only improved the hydrophobic drug loading efficiency, but also presented superhydrophilic outer surface to prolong the retention of hydrophobic drugs in blood. In addition, the polyprodrug amphiphile could be rapidly hydrolyzed in response to the esterase that extensively distributed in tumor sites and other specific tissues, thus enhancing the targeting capacity.…”

“…Reproduced with permission. [ 162 ] Copyright 2017, Wiley‐VCH. f) Micelles with ultralow critical micelle concentration to stabilize hydrophobic cargoes even in extremely diluted conditions.…”

Nano‐assemblies based on biomacromolecules to overcome cancer drug resistance

“…Nano‐assemblies can specifically accumulate in tumor sites via the enrichment of drugs due to passive targeting and active targeting strategies. Passive targeting is achieved via the enhanced permeability and retention (EPR) effect, which relies on the increased pore size and hydraulic conductivity of vasculature, as well as on impaired lymphatic drainage 22,23 . The size of the nano‐assemblies can be tailored for extravasation through the vascular space in tumors, with the average size ideally between 10 and 200 nm 24 .…”