Dataset Information

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

ABSTRACT: 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 ?-? 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 ?-? 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.

SUBMITTER: Kang S

PROVIDER: S-EPMC7656312 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Kang Sumin S Baskaran Rengarajan R Ozlu Busra B Davaa Enkhzaya E Kim Jung Joo JJ Shim Bong Sup BS Yang Su-Geun SG

Biomedicines 20201014 10

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 π-π 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 ...[more]

PMID: 33066425

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Project description:Photodynamic therapy (PDT) and photothermal therapy (PTT) have garnered considerable interest as non-invasive cancer treatment modalities. However, these approaches remain limited by low solubility, poor stability and inefficient targeting of many common photosensitizers (PSs) and photothermal agents (PTAs). To overcome these limitations, we have designed biocompatible and biodegradable tumor-targeted upconversion nanospheres with imaging capabilities. The multifunctional nanospheres consist of a sodium yttrium fluoride core doped with lanthanides (ytterbium, erbium and gadolinium) and bismuth selenide (NaYF 4 :Yb/Er/Gd,Bi 2 Se 3 ) within a mesoporous silica shell that encapsulates a PS, Chlorin e6 (Ce6), in its pores. NaYF 4 :Yb/Er converts deeply penetrating near-infrared (NIR) light to visible light, which excites the Ce6 to generate cytotoxic reactive oxygen species (ROS), while the PTA Bi 2 Se 3 efficiently converts absorbed NIR light to heat. Additionally, Gd enables magnetic resonance imaging (MRI) of the nanospheres. The mesoporous silica shell is coated with lipid/polyethylene glycol (DPPC/cholesterol/DSPE-PEG) to ensure retention of the encapsulated Ce6 and minimize interactions with serum proteins and macrophages that impede tumor targeting. Finally, the coat is functionalized with the acidity-triggered rational membrane (ATRAM) peptide, which promotes specific and efficient internalization into cancer cells within the mildly acidic tumor microenvironment. Following uptake by cancer cells in vitro , NIR laser irradiation of the nanospheres caused substantial cytotoxicity due to ROS production and hyperthermia. The nanospheres facilitated tumor MRI and thermal imaging, and exhibited potent NIR laser light-induced antitumor effects in vivo via combined PDT and PTT, with no observable toxicity to healthy tissue, thereby substantially prolonging survival. Our results demonstrate that the ATRAM-functionalized, lipid/PEG-coated upconversion mesoporous silica nanospheres (ALUMSNs) offer multimodal diagnostic imaging and targeted combinatorial cancer therapy.

Project description:Stimuli-responsive biomaterials are used to facilitate drug and gene delivery by shielding the drug/gene during circulation times and selectively releasing the cargo at the desired target. Within stimuli-responsive materials, pH-responsive materials are exploited for delivery to specific organs, intracellular compartments, cancer cells, site of inflammation or infection as those sites are characterized by pH that is different from the blood pH. In this paper we use molecular dynamics (MD) simulations to design such pH-responsive biomaterials where the balance between the various intermolecular interactions (e.g., electrostatics, van der Waals) within the biomaterials allow biofunctional molecules to be reversibly shielded and exposed to the environment with change in pH. In our model the shielding aspect is imparted by a polyethylene glycol (PEG) brush and the pH-responsive component is a PEG-tethered oligopeptide that undergoes changes in conformations via protonation of residues upon changes in pH. Starting with a PEG-tethered peptide in a monodisperse short PEG brush, we first vary the composition and sequence of histidine (H), lysine (K), and glutamate (E) along the oligopeptide sequence to find the design parameters that maximize the shielding and exposure of the oligopeptide at pH ? 7.0 and pH < 7.0, respectively. Then, we probe the effect of the PEG brush on the conformations of the oligopeptides by simulating PEG-tethered peptide in a bimodal PEG brush containing short PEG and long PEG chains. We characterize the intermolecular interactions involving the PEG, peptide, and solvent that influence the shielded and exposed conformations of the oligopeptides at the two different pHs. In a short monodisperse PEG brush, with a longer PEG-tethered peptide containing large blocks of histidines that undergo change in protonation state as a response to pH change, placed between a protonated lysine and deprotonated glutamate, the PEG brush exhibits maximum shielding and exposure with pH change. This change from shielded to exposed state is driven by electrostatic repulsion upon H protonation. The presence of long PEG chains in a bimodal PEG brush leads to dominating PEG-peptide attractive interactions that reduces the contrast in shielded and exposed conformations of the PEG-tethered peptide upon protonation of histidines.

Dataset Information

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

Publications

T<sub>1</sub>-Positive Mn<sup>2+</sup>-Doped Multi-Stimuli Responsive poly(L-DOPA) Nanoparticles for Photothermal and Photodynamic Combination Cancer Therapy.

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