MMP-2 sensitive poly(malic acid) micelles stabilized by π-π stacking enable high drug loading capacity.

Poly(ß-l-malic acid) (PMLA) together with its derivatives is an aliphatic polyester with superior bio-properties for anti-tumor drugs. In order to surmount the obstacles of low drug loading and rapid premature release during the circulation of polyester-based micelles, micelles based on poly(ß-benzyl malate)-b-polyethylene glycol (PBM-PEG) were developed in this study. The micelles had high drug loading capacity (>20 wt%) and held robust stability, owing to the π-π stacking interactions between polymer chains, and between the polymer and drug. Computer simulation also confirmed that there was the strongest binding free energy between PBMs, and PBM and doxorubicin (DOX), compared with other polyesters. A cell-penetrating moiety (TAT) was employed, and furthermore, a protective outer shell (PEG5k) was also introduced via a matrix metalloproteinase-2 (MMP-2) cleavable peptide. Before reaching the tumor site, the TAT peptide was shielded by long chain PEG, and the micelles showed low bioactivity. While at the tumor tissues where MMP-2 was highly expressed, the cleavage of the linker leads to the exposure of TAT, thus enhancing the cellular internalization. The desired therapeutic consequent was also observed, with no accompanying systemic toxicity detected. Our findings indicated that this MMP-2 sensitive PBM polymeric micelle would be a promising antitumor drug carrier with enhanced therapeutic effects.

[Corrigendum] Preparation and biological evaluation of a novel pH-sensitive poly (ß-malic acid) conjugate for antitumor drug delivery.

Following the publication of the above article, the authors have realized that the chemical structure presented for the intermediate product in Fig 3 was drawn incorrectly; specfically, the 'N's had been omitted from the structure. The structure as it should have appeared is shown in the revised version of Fig. 3 opposite. All the authors agree to the contents of this Corrigendum, and apologize to the Editor of International Journal of Molecular Medicine and to the readership for any inconvenience caused. [the original article was published in International Journal of Molecular Medicine 42: 3495­3502, 2018; DOI: 10.3892/ijmm.2018.3893].

Preparation and biological evaluation of a novel pH-sensitive poly (ß-malic acid) conjugate for antitumor drug delivery.

Poly (ß­malic acid), referred to as PMLA, has been synthesized and introduced as a polymeric drug carrier due to its desirable biological properties. In the present study, a novel pH­sensitive polymer­drug conjugate based on PMLA, PMLA­Hz­doxorubicin (DOX), was prepared, and another conjugate, PMLA­ami­DOX, was synthesized as a comparison. The structures, conjugation efficiency, and drug release properties of the prodrugs were determined. The cytotoxicity and cell uptake were assessed using the HT1080 human fibrosarcoma cell line as an in vitro cell model. The release of DOX in the two conjugates were pH­dependent in PBS buffer at a pH of 5.6, 6.0, 6.8 and 7.4. The quantity of drug released increased with the decrease in pH, and PMLA­ami­DOX released twice as much as PMLA­Hz­DOX (12 h). The cytotoxicity of PMLA­Hz­DOX at pH 7.4 was lower than that of free DOX and increased with the decrease in pH, indicating that the cytotoxicity of PMLA­Hz­DOX was pH­sensitive. Flow cytometry and confocal experiments confirmed the efficiency of the PMLA­Hz­DOX conjugate. Therefore, bonding DOX to PMLA via an acid­sensitive hydrazone bond may be used to reduce its toxic side effects on normal tissues while responding to tumor pH and releasing the drug.