Vitamin-H Channeled Self-Therapeutic P-gp Inhibitor Curcumin-Derived Nanomicelles for Targeting the Tumor Milieu by pH- and Enzyme-Triggered Hierarchical Disassembly

Abstract

An effective nanocarrier-mediated drug delivery to cancer cells primarily faces limitations like the presence of successive drug delivery barriers, insufficient circulation time, drug leakage, and decreased tumor penetration capacity. With the aim of addressing this paradox, a self-therapeutic, curcumin-derived copolymer was synthesized by conjugation with PEGylated biotin via enzyme- and acid-labile ester and acetal linkages. This copolymer is a prodrug of curcumin and self-assembles into ∼150–200 nm-sized nanomicelles; it is capable of encapsulating doxorubicin (DOX) and hence can be designated as self-therapeutic. pH- and enzyme-responsive linkages in the polymer skeleton assist in its hierarchical disassembly only in the tumor microenvironment. Further, the conjugation of biotin and poly­(ethylene glycol) (PEG) imparts features of tumor specificity and improved circulation times to the nanocarrier. The dynamic light scattering (DLS) analysis supports this claim and demonstrates rapid swelling and disruption of micelles under acidic pH. UV–vis spectroscopy provided evidence of an accelerated acetal degradation at pH 4.0 and 5.0. The in vitro release studies revealed a controlled release of DOX under acidic conditions and curcumin release in response to the enzyme. The value of the combination index calculated on HepG2 cells was found to be <1, and hence, the drug pair curcumin and DOX acts synergistically for tumor regression. To prove the efficiency of acid-labile linkages and the prodrug strategy for effective cancer therapy, curcumin-derived polymers devoid of sensitive linkages were also prepared. The prodrug stimuli-responsive nanomicelles showed enhanced cell cytotoxicity and tumor penetration capability on HepG2 cells as well as drug-resistant MCF-7 cell lines and no effect on normal NIH/3T3 fibroblasts as compared to the nonresponsive micelles. The results were also supported by in vivo evidence on a hepatocellular carcinoma (HCC)-induced nude mice model. An evident decrease in MMP-2, MMP-9, and α-fetoprotein (AFP), the biomarkers specific to tumor progression, was observed along with metastasis upon treatment with the drug-loaded dual-responsive nanomicelles. These observations corroborated with the SGOT and SGPT data as well as the histoarchitecture of the liver tissue in mice.

Modulation of Macrophages Using Nanoformulations with Curcumin to Treat Inflammatory Diseases: A Concise Review

“…Notably, besides blending Cur with amphiphilic block copolymers and self-assembling it into Cur-loaded polymer micelles, covalently linking Cur to the hydrophilic polymer backbone to form amphiphilic block copolymers has also been proposed to prepare Cur-loaded polymeric micelles [ 61 , 62 , 63 ]. Recently, amphiphilic dendron [ 22 , 64 ] and amphiphilic polypeptide [ 65 ] have been designed to form micelles for Cur delivery.…”

A pH-Sensitive Lignin-Based Material for Sustained Release of 8-Hydroxyquinoline

“…Although the research on lignin-based pH-responsive polymers is still in its infancy, other types of pH-sensitive conjugates with different responsive mechanisms are rela-tively mature. For instance, a polymer fabricated with acid-unstable bonds, such as ester bonds [1][2][3], hydrazones [4,5], imines [6][7][8], phosphoramidates [9], acetals [10,11], cyclic acetals [12], and β-thiopropionate bonds [13][14][15], can realize pH response dissociation via the breaking of the weakly covalent bonds. Obviously, the ester bonds can be easily constructed in lignin by a simple esterification reaction.…”