A Modular Coassembly Approach to All-In-One Multifunctional Nanoplatform for Synergistic Codelivery of Doxorubicin and Curcumin

Abstract

Synergistic combination therapy by integrating chemotherapeutics and chemosensitizers into nanoparticles has demonstrated great potential to reduce side effects, overcome multidrug resistance (MDR), and thus improve therapeutic efficacy. However, with regard to the nanocarriers for multidrug codelivery, it remains a strong challenge to maintain design simplicity, while incorporating the desirable multifunctionalities, such as coloaded high payloads, targeted delivery, hemodynamic stability, and also to ensure low drug leakage before reaching the tumor site, but simultaneously the corelease of drugs in the same cancer cell. Herein, we developed a facile modular coassembly approach to construct an all-in-one multifunctional multidrug delivery system for the synergistic codelivery of doxorubicin (DOX, chemotherapeutic agent) and curcumin (CUR, MDR modulator). The acid-cleavable PEGylated polymeric prodrug (DOX-h-PCEC), tumor cell-specific targeting peptide (CRGDK-PEG-PCL), and natural chemosensitizer (CUR) were ratiometrically assembled into in one single nanocarrier (CUR/DOX-h-PCEC@CRGDK NPs). The resulting CUR/DOX-h-PCEC@CRGDK NPs exhibited several desirable characteristics, such as efficient and ratiometric drug loading, high hemodynamic stability and low drug leakage, tumor intracellular acid-triggered cleavage, and subsequent intracellular simultaneous drug corelease, which are expected to maximize a synergistic effect of chemotherapy and chemosensitization. Collectively, the multifunctional nanocarrier is feasible for the creation of a robust nanoplatform for targeted multidrug codelivery and efficient MDR modulation.

Recent advances in "smart" delivery systems for extended drug release in cancer therapy

“…This smart-delivery system is particularly advantageous due to its noninvasive delivery and drug release, because the FA-DABA-SMA polymer circulates in the bloodstream and pH changes trigger drug release at the tumor site. 5 International Journal of Nanomedicine downloaded from https://www.dovepress.com/ by 44.224.250.200 on 18-Aug-2020 For personal use only. Preclinical evidence of curcumin-loaded FA-DABA-SMA polymer demonstrates significant toxicity and cell death in PANC1 pancreatic cancer cells, with the empty FA-DABA-SMA polymer being nontoxic.…”

“…3 Currently, poor patient outcomes are attributed in part to the low stability, drug solubility and bioavailability, poor pharmacokinetic (PK) and pharmacodynamic (PD) parameters, aspecific distribution, cytotoxicity, and chemoresistance that are characteristic of traditional chemotherapeutic agents. 4,5 As a result, nanomedicine-based drug delivery has been of increasing research interest because NPs have been shown to substantially improve the therapeutic efficacy of chemotherapeutic agents by overcoming the various anatomical, physiological, chemical, and clinical barriers associated with intravenous drug administration. 4 However, the lack of efficacy in the clinic has made innovative NP-design and -delivery approaches increasingly important in the translation of these promising therapies from bench to bedside.…”

“…9,10 The widespread use of NPs in cancer therapy has also been precluded due to traditional NPs exhibiting suboptimal stability in the body, slow intracellular drug release, low accumulation in tumor sites, and low cellular uptake and aspecific targeting. 5 Furthermore, the complexity of the multistep process required for NP preparation, safety of the components involved, and stability of the final product contribute to the barriers that limit the use of NPs in clinical practice. 1 This review aims to briefly summarize the physiological and clinical relevance and characteristics of SER NPs.…”

pH‐Responsive Nanoparticles for Controllable Curcumin Delivery: The Design of Polycation Core with Different Structures

“…This might be because the surface charge of PELA x NPs‐pH7.4 was all below 15 mV and CUR loaded in hydrophobic core enhanced the compactness of the core hindering the protonation of PAEMA in the core. Moreover, as a measurement of fluorescence intensity of CUR, the value for images, as a gross approximation, was determined using the image analysis . As shown in Figure C, the gray values of CUR‐loaded PELA x NPs‐pH7.4 was obviously stronger than that of free CUR and there was no significant difference of the gray value among these five CUR‐loaded PELA x NPs‐pH7.4.…”

The Application of Nanotechnology in the Codelivery of Active Constituents of Plants and Chemotherapeutics for Overcoming Physiological Barriers during Antitumor Treatment

“…e synergistic antitumor effects of these nanoparticles have the following four aspects: (1) increased stability in blood circulation; (2) passive targeting due to EPR; (3) active targeting by recognition of CRGDK to neuropilin-1 receptor; and (4) high stability and low drug leakage under physiological pH, while the acidic environment dissociates the prodrugs to release DOX and CUR into the cells [83]. Based on the expression of Rf in the bloodbrain barrier and glioma cells, human TfR ligand T7 (sequence: HAIYPRH)-modified magnetic PLGA nanoparticle (MNP/T7PLGA NPs) target tumors and release PTX and CUR.…”