Tumor-targeted aggregation of pH-sensitive nanocarriers for enhanced retention and rapid intracellular drug release

Abstract

Development of nanocarriers, which can selectively accumulate and remain within the tumor tissue matrix, is beneficial for non-invasive cancer diagnosis and therapy. In this study, a well-defined pH-sensitive block copolymer, i.e., succinic anhydride (SA)-modified poly(2-diisopropylaminoethyl methacrylate)-block-poly(2aminoethyl methacrylate hydrochloride) (PDPA-b-PAMA/SA), was prepared by a two-step atom transfer radical polymerization (ATRP) and subsequent amidation. The low critical micelle concentration (CMC, 40.7 Â 10 À4 mg mL À1 ) of PDPA-b-PAMA/SA investigated in pH 7.4 aqueous solution confirmed the adequate thermodynamic stability of its self-assembly. In addition, the pH-sensitive aggregation behaviors of blank and drug-loaded PDPA-b-PAMA/SA were systematically studied at typical pH conditions (7.4 and 6.5) using dynamic light scattering (DLS) and transmission electron microscopy (TEM). Compared with the control sample, i.e., poly(D,L-lactide)-block-poly(2-aminoethyl methacrylate hydrochloride (PLA-b-PAMA/ SA), both blank and drug-loaded PDPA-b-PAMA/SA (PDPA-b-PAMA/SA@DOX$HCl) exhibited obvious aggregation through electric interaction between the positive charge of the protonated PDPA block and the negative charge of the PAMA/SA block at tumor sites under slightly acidic condition. Moreover, the drug-loaded nanocarriers exhibited accelerated drug release profiles in response to the acidic condition due to the electric repulsion between the protonated PDPA block and positive DOX$HCl. Cytotoxicity assay results demonstrated that the pH-sensitive block copolymer did not demonstrate obvious cytotoxicity, even at a concentration up to 100 mg mL À1 . The enhanced intracellular DOX$HCl distribution in nuclei was also confirmed by confocal laser scanning microscopy (CLSM). Thus, these results suggest that PDPA-b-PAMA/SA provides a feasible platform for efficient tumor-targeted therapy.

Co-delivery nanoparticles with characteristics of intracellular precision release drugs for overcoming multidrug resistance

“…[40][41][42] Figure 3C indicates the characteristic of VCR released from outer NP at pH values of the cancer cytoplasm (pH 5.8) and blood or normal organs (pH 7.4). Under a condition of pH 5.8, the cumulative release amount of VCR released from CS-ALG@TPGS-PLGA-VCR NPs was 63.8% during 24 h and 78.6% during 60 h. Nevertheless, the cumulative release amount of VCR only was 14.9% at 24 h and 19.5% at 60 h under a condition of pH 7.4.…”

pH-sensitive micelles self-assembled from polymer brush (PAE-<em>g</em>-cholesterol)-<em>b</em>-PEG-<em>b</em>-(PAE-<em>g</em>-cholesterol) for anticancer drug delivery and controlled release

“…[26][27][28] Therefore, increasing attention has been directed at pH-sensitive polymeric micelles. [29][30][31][32][33][34] It is well known that pH-responsive polymeric micelles exhibit core-shell architecture constructed with a hydrophobic core and a hydrophilic shell as well as a pH-sensitive segment. 35 The internal core could load anticancer drugs by hydrophobic interaction.…”

“…The pH-sensitivity of the system could be used to realize the drug controlled release. 32,34,36,37 In summary, an ideal pH-sensitive polymeric micelle used as an anticancer drug delivery carrier should possess high drug loading content (LC), long-time circulation, low cytotoxicity, and sharp pH-sensitivity. For example, amphiphilic diblock pH-sensitive polymer poly(β-amino ester)-b-poly(ethylene glycol) (MPEG-b-PAE) was synthesized successfully, and its self-assembled micelle was developed as a carrier for co-delivery of CPT and DOX.…”

Dual tumor-targeted poly(lactic-<em>co</em>-glycolic acid)&ndash;polyethylene glycol&ndash;folic acid nanoparticles: a novel biodegradable nanocarrier for secure and efficient antitumor drug delivery

“…As such, nanocarriers inherently possess the passive target function to enhance antitumor therapy. [16][17][18][19][20] However, it is notable that passive target efficiency is relatively low and limited in terms of providing sufficient therapy efficacy for significant acceleration of tumor-cell apoptosis. By contrast, specific overexpressed antigens or receptors on tumor-cell surfaces have been widely exploited to help in nanocarrier targeted delivery to tumor locations by modifying paired ligands or antibodies on carrier surfaces.…”

“…As such, these nanoparticles are still feasible for biomedical drug-delivery applications, even under extremely high-dilution conditions. 16,[42][43][44][45][46][47][48] In this study, copolymer self-assembled nanoparticles were prepared using dialysis. (Figures 2A and S2), hydrodynamic diameter/surface potential of PLGA and PLGA-PEG-FA were 82.5±4.1 nm/-27.2±1.2 mV and 130.8±3.4 nm/-25.3±0.7 mV, respectively.…”