Tumor-Targeting Peptide Conjugated pH-Responsive Micelles as a Potential Drug Carrier for Cancer Therapy

Abstract

Herein, we prepared tumor-targeting peptide (AP peptide; CRKRLDRN) conjugated pH-responsive polymeric micelles (pH-PMs) in cancer therapy by active and pH-responsive tumor targeting delivery systems, simultaneously. The active tumor targeting and tumoral pH-responsive polymeric micelles were prepared by mixing AP peptide conjugated PEG-poly(d,l-lactic acid) block copolymer (AP-PEG-PLA) into the pH-responsive micelles of methyl ether poly(ethylene glycol) (MPEG)-poly(beta-amino ester) (PAE) block copolymer (MPEG-PAE). These mixed amphiphilic block copolymers were self-assembled to form stable AP peptide-conjugated and pH-responsive AP-PEG-PLA/MPEG-PAE micelles (AP-pH-PMs) with an average size of 150 nm. The AP-pH-PMs containing 10 wt % of AP-PEG-PLA showed a sharp pH-dependent micellization/demicellization transition at the tumoral acid pH. Also, they presented the pH-dependent drug release profile at the acidic pH of 6.4. The fluorescence dye, TRITC, encapsulated AP-pH-PMs (TRITC-AP-pH-PMs) presented the higher tumor-specific targeting ability in vitro cancer cell culture system and in vivo tumor-bearing mice, compared to control pH-responsive micelles of MPEG-PAE. For the cancer therapy, the anticancer drug, doxorubicin (DOX), was efficiently encapsulated into the AP-pH-PMs (DOX-AP-pH-PMs) with a higher loading efficiency. DOX-AP-pH-PMs efficiently deliver anticancer drugs in MDA-MB231 human breast tumor-bearing mice, resulted in excellent anticancer therapeutic efficacy, compared to free DOX and DOX encapsulated MEG-PAE micelles, indicating the excellent tumor targeting ability of AP-pH-PMs. Therefore, these tumor-targeting peptide-conjugated and pH-responsive polymeric micelles have great potential application in cancer therapy.

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

“…Polymeric micelles will get more clinical significance when some drawbacks of the conventional formulations, like their insufficient stability in systemic circulation and the premature drug leakage, that may cause side effects and a decrease of effectiveness, are overcome [332,337]. Some research is being done in this direction [338,339] either by stimuli-responsive approaches [340][341][342][343][344], core crosslinking, drug entrapment in the core by covalent binding with linkers [345,346], functionalization strategies with targeting moieties [347][348][349][350], or combinations [351,352].…”

Poly(2-(diethylamino)ethyl methacrylate)-based, pH-responsive, copolymeric mixed micelles for targeting anticancer drug control release

“…19 Wu used a linear block copolymer AP-b-PEG-b-polylactide (PLA) and mPEG-b-poly(β-amino ester) (PAE) to prepare a mixed micelle system, which was used to study the anticancer drug doxorubicin (DOX) loading and control release. 20 Compared to the mPEG-b-PAE micelles, the mixed micelle system showed a higher DOXloading efficiency and better anticancer therapeutic efficacy both in vitro and in vivo.…”

A pH-responsive prodrug delivery system of 10-HCPT for controlled release and tumor targeting

“…Polymer-drug prodrugs, which are obtained by covalent linkage of active drugs to water-soluble macromolecular carriers, have been investigated in a number of studies. [3][4][5] These prodrugs lead to the improvement of drug water solubility and chemical stability, 6 a much longer systemic circulation time or sustained release effect, 7 passive tumor targeting through an enhanced permeability and retention effect, 8 promotion of drug uptake into cells via endocytosis, 9 decreased toxicity, 10 better availability at the tumor site, and antimultidrug resistance. 11 Apart from introducing cell-targeting biomolecules for specific delivery, stimuli-responsive drug systems based on different internal environments in the human body can also enable controlled drug delivery and targeted therapeutics.…”