MT1-MMP Responsive Doxorubicin Conjugated Poly(lactic-<i>co</i>-glycolic Acid)/Poly(styrene-<i>alt</i>-maleic Anhydride) Core/Shell Microparticles for Intrahepatic Arterial Chemotherapy of Hepatic Cancer

In this study, we demonstrated that the MT1-MMP-responsive peptide (sequence: GPLPLRSWGLK) and doxorubicin-conjugated poly­(lactic-<i>co</i>-glycolic acid/poly­(styrene-<i>alt</i>-maleic anhydride) core/shell microparticles (PLGA/pSMA MPs) can be applied for intrahepatic arterial injection for hepatocellular carcinoma (HCC). PLGA/pSMA MPs were prepared with a capillary-focused microfluidic device. The particle size, observed by scanning electron microscopy (SEM), was around 22 ± 3 μm. MT1-MMP-responsive peptide and doxorubicin (DOX) were chemically conjugated with pSMA segments on the shell of MPs to form a PLGA/pSMA-peptide-DOX complex, resulting in high encapsulation efficiency (91.1%) and loading content (2.9%). DOX was released from PLGA/pSMA-peptide-DOX MPs in a pH-dependent manner (∼25% at pH 5.4 and ∼8% at pH 7.4) and accumulated significantly in an MT1-MMP-overexpressing Hep3B cell line. An in vivo intrahepatic injection study showed localization of MPs on the hepatic vessels and hepatic lobes up to 24 h after the injection without any shunting to the lung. Moreover, MPs efficiently inhibited tumor growth of Hep3B hepatic tumor xenografted mouse models. We expect that PLGA/pSMA-peptide-DOX MPs can be utilized as an effective intrahepatic drug delivery system for the treatment of HCC

Enhanced thermodynamic, pharmacokinetic and theranostic properties of polymeric micelles via hydrophobic core-clustering of superparamagnetic iron oxide nanoparticles

Abstract Background Superparamagnetic iron oxide nanoparticles (SPIO) have been applied for decades to design theranostic polymeric micelles for targeted cancer therapy and diagnostic MR imaging. However, the effects of SPIO on the physicochemical, and biological properties of polymeric micelles have not yet been fully elucidated. Therefore, we investigated potential effect of SPIO on the physical and biological properties of theranostic polymeric micelles using representative cancer drug (doxorubicin; Doxo) and polymer carrier (i.e., poly (ethylene glycol)-co-poly(D,L-lactide), PEG-PLA). Methods SPIO were synthesized from Fe(acetyl acetonate)3 in an aryl ether. SPIO and Doxo were loaded into the polymeric micelles by a solvent-evaporation method. We observed the effect of SPIO-clustering on drug loading, micelle size, thermodynamic stability, and theranostic property of PEG-PLA polymeric micelles. In addition, cellular uptake behaviors, pharmacokinetic and biodistribution study were performed. Results SPIO formed hydrophobic geometric cavity in the micelle core and significantly affected the integrity of micelles in terms of micelle size, Doxo loading, critical micelle concentration (CMC) and in vitro dissociation. In vivo pharmacokinetic studies also showed the enhanced Area Under Curve (AUC) and elongated the half-life of Doxo. Conclusions Clustered SPIO in micelles largely affects not only MR imaging properties but also biological and physical properties of polymeric micelles

T1-Positive Mn2+-Doped Multi-Stimuli Responsive poly(L-DOPA) Nanoparticles for Photothermal and Photodynamic Combination Cancer Therapy

In this study, we designed near-infrared (NIR)-responsive Mn2+-doped melanin-like poly(L-DOPA) nanoparticles (MNPs), which act as multifunctional nano-platforms for cancer therapy. MNPs, exhibited favorable &pi;-&pi; stacking, drug loading, dual stimuli (NIR and glutathione) responsive drug release, photothermal and photodynamic therapeutic activities, and T1-positive contrast for magnetic resonance imaging (MRI). First, MNPs were fabricated via KMnO4 oxidation, where the embedded Mn2+ acted as a T1-weighted contrast agent. MNPs were then modified using a photosensitizer, Pheophorbide A, via a reducible disulfide linker for glutathione-responsive intracellular release, and then loaded with doxorubicin through &pi;-&pi; stacking and hydrogen bonding. The therapeutic potential of MNPs was further explored via targeted design. MNPs were conjugated with folic acid (FA) and loaded with SN38, thereby demonstrating their ability to bind to different anti-cancer drugs and their potential as a versatile platform, integrating targeted cancer therapy and MRI-guided photothermal and chemotherapeutic therapy. The multimodal therapeutic functions of MNPs were investigated in terms of T1-MR contrast phantom study, photothermal and photodynamic activity, stimuli-responsive drug release, enhanced cellular uptake, and in vivo tumor ablation studies

The Induction of Combined Hyperthermal Ablation Effect of Irreversible Electroporation with Polydopamine Nanoparticle-Coated Electrodes

Irreversible electroporation (IRE) is a prominent non-thermal ablation method widely employed in clinical settings for the focal ablation therapy of solid tumors. Utilizing high-voltage, short-duration electric pulses, IRE induces perforation defects in the cell membrane, leading to apoptotic cell death. Despite the promise of irreversible electroporation (IRE) in clinical applications, it faces challenges concerning the coverage of target tissues for ablation, particularly when compared to other thermal ablation therapies such as radiofrequency ablation, microwave ablation, and cryoablation. This study aims to investigate the induced hyperthermal effect of IRE by applying a polydopamine nanoparticle (Dopa NP) coating on the electrode. We hypothesize that the induced hyperthermal effect enhances the therapeutic efficacy of IRE for cancer ablation. First, we observed the hyperthermal effect of IRE using Dopa NP-coated electrodes in hydrogel phantom models and then moved to in vivo models. In particular, in in vivo animal studies, the IRE treatment of rabbit hepatic lobes with Dopa NP-coated electrodes exhibited a two-fold higher increase in temperature (ΔT) compared to non-coated electrodes. Through a comprehensive analysis, we found that IRE treatment with Dopa NP-coated electrodes displayed the typical histological signatures of hyperthermal ablation, including the disruption of the hepatic cord and lobular structure, as well as the infiltration of erythrocytes. These findings unequivocally highlight the combined efficacy of IRE with Dopa NPs for electroporation and the hyperthermal ablation of target cancer tissues

DSC curves of paclitaxel, DMβCD, physical mixture, and inclusion complex.

<p>DSC curves of paclitaxel, DMβCD, physical mixture, and inclusion complex.</p

Sol-gel transition temperature of blank gel (A) and drug-loaded 20% PF 127 gel (B) formulations (n = 3).

<p>Sol-gel transition temperature of blank gel (A) and drug-loaded 20% PF 127 gel (B) formulations (n = 3).</p

Solubilizing effect of PF127 content on paclitaxel (n = 3).

<p>Solubilizing effect of PF127 content on paclitaxel (n = 3).</p

X-ray diffraction patterns of paclitaxel, DMβCD, physical mixture, and inclusion complex.

<p>X-ray diffraction patterns of paclitaxel, DMβCD, physical mixture, and inclusion complex.</p

Cell viability of blank (A) and drug-loaded (B) hydrogels (n = 5).

<p>Cell viability of blank (A) and drug-loaded (B) hydrogels (n = 5).</p

SEM images of paclitaxel (A), DMβCD (B), physical mixture (C), and inclusion complex (D).

<p>SEM images of paclitaxel (A), DMβCD (B), physical mixture (C), and inclusion complex (D).</p