d‑α-Tocopheryl Succinate/Phosphatidyl Ethanolamine Conjugated Amphiphilic Polymer-Based Nanomicellar System for the Efficient Delivery of Curcumin and To Overcome Multiple Drug Resistance in Cancer

Nanomedicines have emerged as a promising treatment strategy for cancer. Multiple drug resistance due to overexpression of various drug efflux transporters and upregulation of apoptotic inhibitory pathways in cancer cells are major barriers that limit the success of chemotherapy. Here, we developed a d-α-tocopherol (α-TOS)/lipid-based copolymeric nanomicellar system (VPM) by conjugating phosphatidyl ethanolamine (PE) and α-TOS with poly­(ethylene glycol) (PEG) via an amino acid linkage. The synthesized polymers were characterized by Fourier transform IR, gas-phase chromatography, and ¹H and ¹³C NMR spectroscopy. VPM exhibited mean hydrodynamic diameter of 141.0 ± 0.94 nm with low critical micelles concentrations (CMC) of 15 μM compared to plain PEG–PE micelles (PPM) with size of 23.9 ± 0.34 nm and CMC 20 μM. The bigger hydrophobic compartment in VPM resulted in improved loading of a potent chemotherapeutic drug, curcumin (Cur), and increased encapsulation efficiency (EE) (% drug loading 98.3 ± 1.92, and 85.3 ± 3.29; EE 14.8 ± 0.16 and 12.8 ± 0.09 for VPM and PPM, respectively). Curcumin loaded Vitamin E based micelles exhibited higher cytotoxicity compared to Curcumin loaded PEG-PE micelles in tested cancer cell lines. C-VPM demonstrated ∼3.2 and ∼2.7-fold higher ability to reverse multiple drug resistance compared to PPM and verapamil (concentration used 30 μM), respectively. In the in vivo study by using B16F10 implanted C57Bl6/J mice, C-VPM reduced the tumor volume and weight more efficiently than C-PPM by inducing apoptosis as analyzed by TUNEL assay on tumor cryosections. The newly developed polymeric micelles, VPM with improved drug loadability and ability to reverse the drug resistance could successfully be utilized as a nanocarrier system for hydrophobic chemotherapeutic agents for the treatment of drug-resistant solid tumors

Cholesterol-conjugated poly(D, L-lactide)-based micelles as a nanocarrier system for effective delivery of curcumin in cancer therapy

<p>Polymeric micelles have been widely explored preclinically as suitable delivery systems for poorly soluble chemotherapeutic drugs in cancer therapy. The present study reported the development of cholesterol (Ch)-conjugated poly(D,L-Lactide) (PLA)-based polymeric micelles (mPEG–PLA-Ch) for effective encapsulation and delivery of curcumin (CUR) at the tumor site. Cholesterol conjugation dramatically affected the particle size and improved drug loading (DL) and encapsulation efficiency (EE). mPEG–PLA-Ch-CUR showed bigger hydrodynamic diameter (104.6 ± 2.1 nm, and 169.3 ± 1.52 nm for mPEG–PLA and mPEG–PLA-Ch, respectively) due to increased size of the hydrophobic core. The newly developed polymer exhibited low critical micelles concentration (CMC) (25 μg/mL) which is close to lipid-based polymer, PEG-phosphatidyl ethanolamine (12.5 μg/mL) compared to mPEG–PLA (50 μg/mL). mPEG–PLA-Ch micelles exhibited relatively higher EE (93.74 ± 1.6%) and DL (11.86 ± 0.8%) compared to mPEG–PLA micelles (EE 91.89 ± 1.2% and DL 11.06 ± 0.8%). mPEG–PLA-Ch micelles were internalized by the cancer cells effectively and exhibited higher cytotoxicity compared to free CUR in both, murine melanoma (B16F10) and human breast cancer (MDA-MB-231) cells. mPEG–PLA-Ch exhibited satisfactory hemocompatibility indicating their potential for systemic application. Further, mPEG–PLA-Ch-CUR demonstrated higher rate of reduction of tumor volume in B16F10-xenografted tumor-bearing mice compared to free CUR. At the end of 22 days, the tumor reduced to 1.87-fold (627.72 ± 0.9 mm³ versus 1174.68 ± 1.64 mm³) compared to the treatment with free CUR. In conclusion, the experimental data <i>in vitro</i> and <i>in vivo</i> indicated that the newly developed CUR-mPEG–PLA-Ch micelles may have promising applications in solid tumors.</p