Guoyun Wan

A polymeric prodrug of cisplatin based on pullulan for the targeted therapy against hepatocellular carcinoma

A polymeric prodrug of cisplatin (CP) with simple chemical structure was synthesized based on pullulan and its therapeutic effects on human hepatocellular carcinoma (HCC) were studied in vitro and in vivo. Briefly, CP was linked to pullulan monosuccinate (SUPA) via coordination bond to form prodrug of CP-SUPA with the CP weight content of 18.7%. CP-SUPA exhibited in vitro sustained releases and strong interactions with genomic DNA. CP-SUPA could effectively inhibit the proliferation of HCC HepG2 cells by promoting the cell apoptosis and arresting the cell cycle, and showed a significantly higher cytotoxicity on HepG2 cells than that on human lung epithelial A549 cells. Compared to free CP, CP-SUPA obviously prolonged the survival times of Balb/c mice after intravenous injection at CP doses of 15 and 30 μmol/kg, and no signs of toxic effects in main tissues were detected by histologic examination. In MHCC-97H tumor-bearing nude mice, CP-SUPA was mainly distributed in the liver and the tumor after 24h post administration and evidently inhibited the tumor growth at CP doses of 3.5 and 7.0 μmol/kg. In conclusion, CP-SUPA was an ideal candidate of polymeric prodrug for the targeted therapy against HCC.

Recent advances of sonodynamic therapy in cancer treatment

Sonodynamic therapy (SDT) is an emerging approach that involves a combination of low-intensity ultrasound and specialized chemical agents known as sonosensitizers. Ultrasound can penetrate deeply into tissues and can be focused into a small region of a tumor to activate a sonosensitizer which offers the possibility of non-invasively eradicating solid tumors in a site-directed manner. In this article, we critically reviewed the currently accepted mechanisms of sonodynamic action and summarized the classification of sonosensitizers. At the same time, the breath of evidence from SDT-based studies suggests that SDT is promising for cancer treatment.

Dual pH-responsive multifunctional nanoparticles for targeted treatment of breast cancer by combining immunotherapy and chemotherapy

In the present study, a dual pH-responsive multifunctional nanoparticle system was designed for combining immunotherapy and chemotherapy to treat breast cancer through targeting immune cells and cancer cells. A proven anti-tumor immune regulator, R848, was encapsulated with poly(L-histidine) (PHIS) to form PHIS/R848 nanocores. Doxorubicin (DOX) was conjugated to hyaluronic acid (HA) through an acid-cleavable hydrazone bond linkage to synthesize polymeric prodrug HA-DOX, which was subsequently coated outside PHIS/R848 nanocores to form HA-DOX/PHIS/R848 nanoparticles. Ionization of PHIS around pH 6.5 (a pH value close to that of tumor microenvironment) switched the nature of this material from hydrophobic to hydrophilic, and thus triggered the release of R848 to exert immunoregulatory action. The rupture of hydrazone bond in HA-DOX at about pH 5.5 (pH of endo/lysosomes) accelerated the release of DOX to exert cytotoxic effects. In immune cells, PHIS/R848 nanocores exhibited strong immunoregulatory activities similar to those induced by free R848. In breast cancer cells overexpressing CD44, HA-DOX was specially internalized by CD44-mediated endocytosis and significantly inhibited the cell growth. In 4T1 tumor-bearing mice, HA-DOX/PHIS/R848 nanoparticles showed excellent tumor-targeting ability and remarkably inhibited the tumor growth by regulating tumor immunity and killing tumor cells. In summary, this multifunctional nanoparticle system could deliver R848 and DOX respectively to tumor microenvironment and breast cancer cells to achieve synergistic effects of immunotherapy and chemotherapy against breast cancer. STATEMENT OF SIGNIFICANCE Combination of immunotherapy and chemotherapy is becoming a promising new treatment for cancer. The major challenge is to target cancer and immune cells simultaneously and specifically. In this study, a dual pH-responsive multifunctional nanoparticle system based on poly(L-histidine) and hyaluronic acid was designed for co-loading R848 (immune-regulator) and doxorubicin (chemotherapeutic drug) through different encapsulation modes. By responding to the acidic pHs of tumor microenvironment and intracellular organelles, this multifunctional nanoparticle system could release R848 extracellularly and deliver DOX targetedly to breast cancer cells, thus achieving synergistic effects of immunotherapy and chemotherapy against breast cancer.

Hyaluronic acid-coated poly(β-amino) ester nanoparticles as carrier of doxorubicin for overcoming drug resistance in breast cancer cells

Drug resistance is a major challenge for the clinical application of chemotherapeutic drugs. In this study, a nanoparticle system containing hyaluronic acid (HA) shell and poly(β-amino) ester (PBAE) core was designed as a carrier for doxorubicin (DOX), a commonly used chemotherapeutic drug in clinical, to overcome the drug resistance in breast cancer cells. DOX-loaded PBAE (PBAE/DOX) nanoparticles were firstly prepared using the O/W emulsion solvent evaporation method, and followed by the surface coating of HA via charge interaction. HA-coated PBAE/DOX (HA/PBAE/DOX) nanoparticles had a classic “core–shell” structure with a size of 185.0 nm and displayed obvious pH-responsive in vitro drug release property. Compared to free DOX and PBAE/DOX nanoparticles, HA/PBAE/DOX nanoparticles exhibited the enhanced cytotoxicity, cell apoptosis and S-phase cell cycle arrest in drug-resistant human breast cancer MCF-7/ADR cells, in which P-glycoprotein (P-gp), a typical and well-known mediator of cancer drug resistance, and CD44, a cell-surface adhesion receptor, were over-expressed. As HA was a natural ligand for CD44, HA/PBAE/DOX nanoparticles could enter MCF-7/ADR cells via CD44-mediated endocytosis, thus efficiently avoided the efflux effect of P-gp and improved the cellular accumulation of DOX. In summary, HA/PBAE nanoparticle system could be used as a potential carrier of chemotherapeutic drugs for the reversal of drug resistance in cancers.

A multifunctional nanoparticle system combines sonodynamic therapy and chemotherapy to treat hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common and deadly malignancies worldwide. To date, the survival of patients with HCC has not improved because of the insensitivity of HCC to conventional treatments. Sonodynamic therapy (SDT) is a promising new approach that shows remarkable potential in the treatment of HCC. Here, we designed a simple, biocompatible, and multifunctional nanosystem that combines SDT and chemotherapy to treat HCC. This nanosystem, called HPDF nanoparticles, had a core–shell structure in which hematoporphyrin (HP) was complexed with doxorubicin (DOX) to form the hydrophobic core and the surface was coated with Pluronic F68 to form the hydrophilic shell. In HCC cells, HPDF nanoparticles in combination with ultrasonic irradiation (1.0 MHz, 1.5 W/cm2, 30 s) exhibited potent cytotoxicity, resulting from the synergistic effects of a large amount of reactive oxygen species generated from HP and DOX-induced DNA damage. Notably, HPDF nanoparticles in combination with ultrasonic irradiation significantly reversed drug resistance in Nanog-positive cancer stem cells (CSCs) in HCC. In nude mice bearing HCC tumors, HPDF nanoparticles efficiently accumulated in the tumors and reached the maximum levels within 6‒8 h, post intravenous injection. HPDF nanoparticles, in combination with ultrasonic irradiation (1.0 MHz, 3 W/cm2, 5 min), suppressed tumor growth, angiogenesis, and collagen deposition, considerably. In summary, our results show that HPDF nanoparticles can effectively combine SDT and chemotherapy to inhibit HCC growth and progression through multiple mechanisms in both cellular and animal models.

Dual-responsive nanoparticles based on oxidized pullulan and a disulfide-containing poly(β-amino) ester for efficient delivery of genes and chemotherapeutic agents targeting hepatoma

A dual-responsive nanoparticle system was designed based on oxidized pullulan (oxPL) and a disulfide-containing poly(β-amino) ester (ssPBAE) for the efficient delivery of genes and chemotherapeutic agents through polymer degradation responding to the tumor intracellular pH and redox state. oxPL containing abundant aldehyde groups was obtained through the periodate oxidation of pullulan. ssPBAE was modified with diethylenetriamine and then grafted onto oxPL by the Schiffs base reaction. Doxorubicin was conjugated to ssPBAE-oxPL via the acid-cleavable hydrazone bond, thus obtaining ssPBAE-oxPL-DOX in which the DOX content was about 3.6%. ssPBAE-oxPL-DOX exhibited in vitro hepatoma-targeting properties to some extent and good ability for condensing genes including plasmid DNA (pDNA) and fluorescein-labeled oligoDNA (FAM-DNA). ssPBAE-oxPL-DOX/pDNA nanoparticles had non-spherical shapes and relatively uniform sizes. The in vitro releases of DOX and pDNA from ssPBAE-oxPL-DOX/pDNA nanoparticles displayed significant pH- and redox-responsive properties. In hepatoma HepG2 cells, ssPBAE-oxPL-DOX/pDNA nanoparticles effectively inhibited cell proliferation, and induced cell apoptosis and cell cycle arrest at the S-phase. Moreover, ssPBAE-oxPL-DOX/FAM-DNA nanoparticles efficiently delivered DOX and FAM-DNA respectively into the nucleus and the cytoplasm in HepG2 cells, and also exhibited distinct hepatoma targeting properties in HepG2 tumor-bearing mice after intravenous injection. In summary, this novel dual-responsive nanoparticle system showed great potential for the combined gene therapy and chemotherapy on hepatoma.

Pullulan-coated phospholipid and Pluronic F68 complex nanoparticles for carrying IR780 and paclitaxel to treat hepatocellular carcinoma by combining photothermal therapy/photodynamic therapy and chemotherapy

IR780, a near-infrared dye, can also be used as a photosensitizer both for photothermal therapy (PTT) and photodynamic therapy (PDT). In this study, we designed a simple but effective nanoparticle system for carrying IR780 and paclitaxel, thus hoping to combine PTT/PDT and chemotherapy to treat hepatocellular carcinoma (HCC). This nanosystem, named PDF nanoparticles, consisted of phospholipid/Pluronic F68 complex nanocores and pullulan shells. IR780 and paclitaxel were loaded separately into PDF nanoparticles to form PDFI and PDFP nanoparticles, which had regular sphere shapes and relatively small sizes. Upon near-infrared laser irradiation at 808 nm, PDFI nanoparticles showed strong PTT/PDT efficacy both in vitro and in vivo. In MHCC-97H cells, the combined treatment of PDFI nanoparticles/laser irradiation and PDFP nanoparticles exhibited significant synergistic effects on inhibiting cell proliferation and inducing cell apoptosis and cell cycle arrest at G2/M phase. In MHCC-97H tumor-bearing mice, PDFI nanoparticles exhibited excellent HCC-targeting and accumulating capability after intravenous injection. Furthermore, the combined treatment of PDFI nanoparticles/laser irradiation and PDFP nanoparticles also effectively inhibited the tumor growth and the tumor angiogenesis in MHCC-97H tumor-bearing mice. In summary, we put forward a therapeutic strategy for HCC treatment by combining PTT/PDT and chemotherapy.

PEGylated doxorubicin nanoparticles mediated by HN-1 peptide for targeted treatment of oral squamous cell carcinoma

HN-1, a 12-amino acid peptide, has been reported to possess strong capabilities for targeting and penetrating head and neck squamous cell carcinoma. Here, we designed a simple but effective nanoparticle system for the delivery of doxorubicin (DOX) targeting oral squamous cell carcinoma (OSCC) through the mediation of HN-1. PEGylated DOX (PD) was firstly synthesized by the conjugation of DOX with bis-amino-terminated poly(ethylene glycol) via succinyl linkage, and then PD nanoparticles were prepared by a modified nanoprecipitation method. After that, PD nanoparticles were surface-modified with HN-1 to form HNPD nanoparticles, which had a uniform spherical shape and a small size about 150nm. In human OSCC cells (CAL-27 and SCC-25), HNPD nanoparticles exhibited significantly higher cellular uptakes and cytotoxicities than PD nanoparticles. Furthermore, HNPD nanoparticles showed a certain degree of functional selectivity for CAL-27 and SCC-25 cells as compared to human hepatoma HepG2 cells. In SCC-25 tumor-bearing nude mice, HNPD nanoparticles showed remarkably enhanced tumor-targeting and penetrating efficiencies as compared to PD nanoparticles, and effectively inhibited the tumor growth. In conclusion, our study demonstrated for the first time that HN-1 could be used for mediating the OSCC-targeted delivery of nanoparticles.

Hematoporphyrin and doxorubicin co-loaded nanomicelles for the reversal of drug resistance in human breast cancer cells by combining sonodynamic therapy and chemotherapy

Drug resistance is a main reason for the failure of chemotherapy in cancer treatments. Sonodynamic therapy (SDT) shows great potential for reversing drug resistance of chemotherapy. Here, a sonosensitizer hematoporphyrin (HP) and a chemotherapeutic drug doxorubicin (DOX) were co-loaded into Pluronic F68 nanomicelles for combining SDT and chemotherapy to reverse cancer drug resistance. This multi-functional nanosystem, called HPDF nanomicelle, had a classic “core–shell” structure and a size smaller than 100 nm. In drug-resistant human breast cancer MCF-7/ADR cells that over-express P-glycoprotein (P-gp), HPDF nanomicelles combined with a low-intensity ultrasound could effectively inhibit cell proliferation, promote cell apoptosis and arrest cell cycle at S-phase. Compared free DOX, HPDF nanomicelles significantly reversed drug resistance in MCF-7/ADR cells and the reversal index reached up to 19.0. Apparently, the synergistic effects of combination treatment of SDT and chemotherapy induced by HPDF nanomicelles played important roles in the reversal process against drug resistance. In summary, our study provides a novel strategy for overcoming drug resistance in breast cancer by combining SDT and chemotherapy.

Reactive Oxygen Species-Responsive Nanoparticles Based on PEGlated Prodrug for Targeted Treatment of Oral Tongue Squamous Cell Carcinoma by Combining Photodynamic Therapy and Chemotherapy

In this study, a reactive oxygen species (ROS)-responsive nanoparticle system was designed for combining photodynamic therapy (PDT) and chemotherapy for oral tongue squamous cell carcinoma (OTSCC)-targeted treatment. A PEGlated prodrug (RPTD) of doxorubicin (DOX) via thioketal linkage and cRGD peptide modification was synthesized and then used to prepare nanoparticles for encapsulating photosensitizer hematoporphyrin (HP). Thus, the obtained HP-loaded RPTD (RPTD/HP) nanoparticles had a regular spherical shape and small size, approximately 180 nm. The RPTD/HP nanoparticles showed a remarkable PDT efficiency and successfully induced ROS generation upon laser irradiation both in vitro and in vivo. DOX exhibited significant ROS-responsive release property from RPTD/HP nanoparticles because of the rupture of the thioketal linker. In OTSCC cells, RPTD/HP nanoparticles were efficiently internalized and showed potent effects on cell growth inhibition and apoptosis induction after laser irradiation. In OTSCC tumor-bearing mice, RPTD/HP nanoparticles displayed excellent tumor-targeting ability and notably suppressed tumor growth through multiple mechanisms after local laser irradiation. Taken together, we supplied a novel therapeutic nanosystem for OTSCC treatment through combining PDT and chemotherapy.