Ultralong Circulating Lollipop‐Like Nanoparticles Assembled with Gossypol, Doxorubicin, and Polydopamine via π–π Stacking for Synergistic Tumor Therapy

Abstract

Long blood circulation in vivo remains a challenge to dual-drug-loaded nanocarriers for synergistic chemotherapy. Herein, a novel strategy to prepare lollipop-like dual-drug-loaded nanoparticles (DOX-PDAgossypol NPs) is developed based on the self-assembly of gossypol, doxorubicin (DOX), and polydopamine (PDA) via π-π stacking. Dopamine polymerizes to PDA and fills the gaps between the gossypol and DOX molecules to form the super compact long-circulating nanoparticles. The DOX-PDA-gossypol NPs show a suitable particle size of 59.6 ± 9.6 nm, high drug loading of 91%, superb stability, high maximum-tolerated dose (MTD) of over 60 mg kg -1 , and negligible toxicity. These NPs also exhibit pH-dependent drug release and low combination index (0.23). Notably, they show dramatically ultralong blood circulation (>192 h) with elimination half times 458-fold and 258-fold longer than that of free DOX and free gossypol, respectively. These values are markedly higher than most of the reported results. Therefore, the DOX-PDA-gossypol NPs have a high tumor accumulation of 12% remaining on the 8th day postinjection. This characteristic contributes to the excellent tumor comprehensive synergistic therapeutic efficacy (TIR > 90%) with low administration dosage and is benefitted for widening the drug therapeutic window. Thus, the proposed strategy has remarkable potential for tumor synergistic therapy.The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/adfm.201805582. Recent studies have developed various methods to prolong the blood circulation of NCS. These methods mainly include the surface modification of hydrophilic polymers or nonionic Tumor Therapy

Polyphenol-Based Particles for Theranostics

“…PDA particles with different nanostructures have also been engineered. Wu and co-workers reported lollipop-like PDA nanoparticles (50-70 nm) loaded with two anti-cancer drugs, which showed pH-responsiveness and ultra-long circulation in vivo 81. In the reported system, PDA acted as a cross-linker between the hydrophilic DOX (hydrochloride) and the hydrophobic gossypol via π-π stacking and hydrogen bonds.…”

“…Dense lollipop-like PDA nanoparticles loaded with dual drugs showed high stability in physiological environments (Figure 5A). At acidic pH, the amine groups on PDA and the DOX were protonated, which partially broke the π-π stacking between PDA and the drugs, resulting in the pH-triggered drug release 81. Therefore, the low pH in the acidic intracellular compartments (e.g., endosome and lysosome) could trigger the release of both drugs from lollipop-like PDA nanoparticles, which enabled the inhibition of tumor by these two drugs synergistically.…”

“…PDA-based particles derived from naturally occurring monomers maintain high biosafety and biocompatibility. The application of PDA-based particles did not cause significant immune responses or obvious damage to normal tissues or major organs in vivo 32, 39, 44, 75, 81. Therefore, a series of PDA particles have been reported for diverse diagnostic or therapeutic applications.…”

Smart Porous Core–Shell Cuprous Oxide Nanocatalyst with High Biocompatibility for Acid‐Triggered Chemo/Chemodynamic Synergistic Therapy

“…Because of the satisfactory porosity and stability, chemotherapy drug DOX was then loaded into Cu 2 O-PEG NCs via physical absorption and strong π−π stacking interaction of DOX, [23] denoted as DOX@Cu 2 O-PEG NCs. As can be seen from Figure 2B, the color of suspension changed from the yellow of Cu 2 O-PEG NCs to the tawny of DOX@Cu 2 O-PEG NCs.…”

Morphological transformation enhances Tumor Retention by Regulating the Self-assembly of Doxorubicin-peptide Conjugates

“…The key to the successful construction of a transformable drug delivery system (DDS) for intravenous injection can be summarized as follows: First, the stability of the drug in the process of morphological transformation must be ensured, and the drug can be slowly released in the lesion. Second, the DDS should be equipped with suitable surface potential 8 - 10 , hydrophilicity 11 - 13 , an appropriate size and morphology 14 - 16 to ensure good biocompatibility 17 - 19 , and enough stability and circulation time in blood 20 - 22 . Third, after reaching the tumor through the enhanced permeability and retention (EPR) effect 23 , 24 , the drug must be able to reside in the lesion.…”