Guo-Feng Luo

Multifunctional Envelope-Type Mesoporous Silica Nanoparticles for Tumor-Triggered Targeting Drug Delivery

A novel type of cellular-uptake-shielding multifunctional envelope-type mesoporous silica nanoparticle (MEMSN) was designed for tumor-triggered targeting drug delivery to cancerous cells. β-Cyclodextrin (β-CD) was anchored on the surface of mesoporous silica nanoparticles via disulfide linking for glutathione-induced intracellular drug release. Then a peptide sequence containing Arg-Gly-Asp (RGD) motif and matrix metalloproteinase (MMP) substrate peptide Pro-Leu-Gly-Val-Arg (PLGVR) was introduced onto the surface of the nanoparticles via host-guest interaction. To protect the targeting ligand and prevent the nanoparticles from being uptaken by normal cells, the nanoparticles were further decorated with poly(aspartic acid) (PASP) to obtain MEMSN. In vitro study demonstrated that MEMSN was shielded against normal cells. After reaching the tumor cells, the targeting property could be switched on by removing the PASP protection layer via hydrolyzation of PLGVR at the MMP-rich tumor cells, which enabled the easy uptake of drug-loaded nanoparticles by tumor cells and subsequent glutathione-induced drug release intracellularly.

Redox-sensitive shell cross-linked PEG–polypeptide hybrid micelles for controlled drug release

Novel PEG–polypeptide hybrid drug carriers, poly(ethylene glycol)-b-poly(L-cysteine)-b-poly(L-phenylalanine) (PEG-PCys-PPhe) triblock copolymers, were prepared via the ring-opening polymerization of amino acid N-carboxyanhydrides. The copolymers can self-assemble to form core–shell–corona micelles in aqueous solutions. The shell of the micelles has the ability to self-cross-link (SCL) by the oxidation of thiol groups in the PCys segments. The morphology and stability of SCL micelles were characterized by TEM, DLS and SEM. The results showed the SCL micelles could hold the physical structure of micelles in severe environments. The in vitro drug release in response to GSH was also studied. It was found that the cross-linked shell could be helpful to reduce the drug loss in the extracellular environment. Under a reductive environment, the micelles would undergo the destruction of the cross-linked shell due to the cleavage of disulfide bonds, followed by accelerated drug release from the micelles. The glutathione-responsive SCL micelles could be easily uptaken by HeLa cells, suggesting these micelles might have great potential in intracellular drug delivery.

Multifunctional Enveloped Mesoporous Silica Nanoparticles for Subcellular Co-delivery of Drug and Therapeutic Peptide

A multifunctional enveloped nanodevice based on mesoporous silica nanoparticle (MSN) was delicately designed for subcellular co-delivery of drug and therapeutic peptide to tumor cells. Mesoporous silica MCM-41 nanoparticles were used as the core for loading antineoplastic drug topotecan (TPT). The surface of nanoparticles was decorated with mitochondria-targeted therapeutic agent (Tpep) containing triphenylphosphonium (TPP) and antibiotic peptide (KLAKLAK)2 via disulfide linkage, followed by coating with a charge reversal polyanion poly(ethylene glycol)-blocked-2,3-dimethylmaleic anhydride-modified poly(L-lysine) (PEG-PLL(DMA)) via electrostatic interaction. It was found that the outer shielding layer could be removed at acidic tumor microenvironment due to the degradation of DMA blocks and the cellular uptake was significantly enhanced by the formation of cationic nanoparticles. After endocytosis, due to the cleavage of disulfide bonds in the presence of intracellular glutathione (GSH), pharmacological agents (Tpep and TPT) could be released from the nanoparticles and subsequently induce specific damage of tumor cell mitochondria and nucleus respectively with remarkable synergistic antitumor effect.

Encapsulation of an Adamantane-Doxorubicin Prodrug in pH-Responsive Polysaccharide Capsules for Controlled Release

Supramolecular microcapsules (SMCs) with the drug-loaded wall layers for pH-controlled drug delivery were designed and prepared. By using layer-by-layer (LbL) technique, the SMCs were constructed based on the self-assembly between polyaldenhyde dextran-graft-adamantane (PAD-g-AD) and carboxymethyl dextran-graft-β-CD (CMD-g-β-CD) on CaCO(3) particles via host-guest interaction. Simultaneously, adamantine-modified doxorubicin (AD-Dox) was also loaded on the LbL wall via host-guest interaction. The in vitro drug release study was carried out at different pHs. Because the AD groups were linked with PAD (PAD-g-AD) or Dox (AD-Dox) by pH-cleavable hydrazone bonds, AD moieties can be removed under the weak acidic condition, leading to destruction of SMCs and release of Dox. The pH-controlled drug release can enhance the uptake by tumor cells and thus achieve improved cancer therapy efficiency.

Dual-Targeting Pro-apoptotic Peptide for Programmed Cancer Cell Death via Specific Mitochondria Damage

Mitochondria are vital organelles to eukaryotic cells. Damage to mitochondria will cause irreversible cell death or apoptosis. In this report, we aim at programmed cancer cell death via specific mitochondrial damage. Herein, a functionalized pro-apoptotic peptide demonstrates a dual-targeting capability using folic acid (FA) (targeting agent I) and triphenylphosphonium (TPP) cation (targeting agent II). FA is a cancer-targeting agent, which can increase the cellular uptake of the pro-apoptotic peptide via receptor-mediated endocytosis. And the TPP cation is the mitochondrial targeting agent, which specifically delivers the pro-apoptotic peptide to its particular subcellular mitochondria after internalized by cancer cells. Then the pro-apoptotic peptide accumulates in mitochondria and causes its serious damage. This dual-targeting strategy has the potential to effectively transport the pro-apoptotic peptide to targeted cancer cell mitochondria, inducing mitochondrial dysfunction and triggering the mitochondria-dependent apoptosis to efficiently eliminate cancer cells.

Charge-reversal plug gate nanovalves on peptide-functionalized mesoporous silica nanoparticles for targeted drug delivery

To develop a smart nanovalve on mesoporous silica nanoparticles (MSNs) for biomedical applications, a new type of peptide-functionalized MSN with a plug-gate nanovalve (PGN) was designed for targeted drug release in cancer cells. The outer shell of MSN was functionalized with K8 peptide (octa-lysine sequence) by click chemistry, followed by reacting with citraconic anhydride viaα,β-unsaturated bond to prepare negatively charged MSN-K8(Cit). Subsequently, a cationic K8(RGD)2 peptide containing two Arg-Gly-Asp (RGD) sequences for targeting was introduced via electrostatic interaction to the negatively charged surface of MSN-K8(Cit) to form PGN. It was found that, at pH 5.0 (simulating the endo/lysosomal environment), the surface charge of MSN-K8(Cit) could convert from -41 mV to +19 mV due to the hydrolysis of the acid-labile amides in the acidic condition, implying the subsequent electrostatic repulsion to induce opening of the nanovalves and release of anticancer drug, DOX. According to the drug release studies, 79% of DOX was released within 48 h at pH 5.0, while much less DOX was released at pH 6.5 and 7.4. Furthermore, in vitro cellular experiments confirmed that the drug delivery system had enhanced cellular association and cell inhibition effect on αvβ3-positive U87 MG cancerous cells.

One-Pot Construction of Functional Mesoporous Silica Nanoparticles for the Tumor-Acidity-Activated Synergistic Chemotherapy of Glioblastoma

Mesoporous silica nanoparticles (MSNs) have proved to be an effective carrier for controlled drug release and can be functionalized easily for use as stimuli-responsive vehicles. Here, a novel intelligent drug-delivery system (DDS), camptothecin (CPT)-loaded and doxorubicin (DOX)-conjugated MSN (CPT@MSN-hyd-DOX), is reported via a facile one-pot preparation for use in synergistic chemotherapy of glioblastoma. DOX was conjugated to MSNs via acid-labile hydrazone bonds, and CPT was loaded in the pores of the MSNs. At pH 6.5 (analogous to the pH in tumor tissues), a fast DOX release was observed that was attributed to the hydrolysis of the hydrazone bonds. In addition, a further burst release of DOX was found at pH 5.0 (analogous to the pH in lyso/endosomes of tumor cells), leading to a strong synergistic effect. In all, CPT and DOX could be delivered simultaneously into tumor cells, and this intelligent DDS has great potential for tumor-trigged drug release for use in the synergistic chemotherapy of tumors.

Theranostic GO‐Based Nanohybrid for Tumor Induced Imaging and Potential Combinational Tumor Therapy

Graphene oxide (GO)-based theranostic nanohybrid is designed for tumor induced imaging and potential combinational tumor therapy. The anti-tumor drug, Doxorubicin (DOX) is chemically conjugated to the poly(ethylenimine)-co-poly(ethylene glycol) (PEI-PEG) grafted GO via a MMP2-cleavable PLGLAG peptide linkage. The therapeutic efficacy of DOX is chemically locked and its intrinsic fluorescence is quenched by GO under normal physiological condition. Once stimulated by the MMP2 enzyme over-expressed in tumor tissues, the resulting peptide cleavage permits the unloading of DOX for tumor therapy and concurrent fluorescence recovery of DOX for in situ tumor cell imaging. Attractively, this PEI-bearing nanohybrid can mediate efficient DNA transfection and shows great potential for combinational drug/gene therapy. This tumor induced imaging and potential combinational therapy will open a window for tumor treatment by offering a unique theranostic approach through merging the diagnostic capability and pathology-responsive therapeutic function.

Multifunctional Theranostic Nanoplatform for Cancer Combined Therapy Based on Gold Nanorods

Nanomaterials that integrate diagnostic and therapeutic functions within a single nanoplatform promise great advances in revolutionizing cancer therapy. A smart multifunctional theranostic drug-delivery system (DDS) based on gold nanorods (abbreviated as GNR/TSDOX) is designed for cancer-targeted imaging and imaging-guided therapy. In this intelligent theranostic DDS, the active targeting ligand biotin is introduced to track cancer sites in vivo. With the aid of photothermal/photoacoustic imaging, GNR/TSDOX can ablate cancer specifically and effectively. When stimulated with a single near-infrared (NIR) light source, this NIR light energy is effectively absorbed and converted into heat by GNR/TSDOX for localized photothermal therapy and the increase in temperature also further triggers the cascaded release of the anticancer drug for combined thermo-chemotherapy. More importantly, the in vivo cure effect can be well guided by regulating the irradiation time and intensity of the NIR light.

Overcoming the Heat Endurance of Tumor Cells by Interfering with the Anaerobic Glycolysis Metabolism for Improved Photothermal Therapy

In this study, we developed a general method to decorate plasmonic gold nanorods (GNRs) with a CD44-targeting functional polymer, containing a hyaluronic acid (HA)-targeting moiety and a small molecule Glut1 inhibitor of diclofenac (DC), to obtain GNR/HA-DC. This nanosystem exhibited the superiority of selectively sensitizing tumor cells for photothermal therapy (PTT) by inhibiting anaerobic glycolysis. Upon specifically targeting CD44, sequentially time-dependent DC release could be achieved by the trigger of hyaluronidase (HAase), which abundantly existed in tumor tissues. The released DC depleted the Glut1 level in tumor cells and induced a cascade effect on cellular metabolism by inhibiting glucose uptake, blocking glycolysis, decreasing ATP levels, hampering heat shock protein (HSP) expression, and ultimately leaving malignant cells out from the protection of HSPs to stress (e.g., heat), and then tumor cells were more easy to kill. Owing to the sensitization effect of GNR/HA-DC, CD44 overexpressed tumor cells could be significantly damaged by PTT with an enhanced therapeutic efficiency in vitro and in vivo.