Wei Tao

Effect of hydrophobicity of core on the anticancer efficiency of micelles as drug delivery carriers.

Recently, micelles, which are self-assembled by amphiphilic copolymers, have attracted tremendous attention as promising drug delivery systems for cancer treatment. Thus, the hydrophobic core of the micelles, which could efficiently encapsulate small molecular drug, will play a significant role for the anticancer efficiency. Unfortunately, the effect of hydrophobicity of micellar core on its anticancer efficiency was rarely reported. Herein, the amphiphilic diblock polymers of poly(ethylene glycol) and polyphosphoester with different side groups (butyl, hexyl, octyl) were synthesized to tune the hydrophobicity of the micellar core. We found that the in vitro cytotoxicity of the DOX-loaded micelles decreased with the increasing hydrophobicity of micellar core due to the drug release rate. However, following systemic delivery, the DOX-loaded micelles with the most hydrophobic core exhibited the most significant inhibition of tumor growth in a MDA-MB-231 tumor model, indicating the importance of hydrophobicity of core on the antitumor efficacy of drug delivery systems.

Chlorin e6-Encapsulated Polyphosphoester Based Nanocarriers with Viscous Flow Core for Effective Treatment of Pancreatic Cancer

Lack of effective treatment results in the low survival for patients with pancreatic cancer, and photodynamic therapy (PDT) with photosensitizers has emerged as an effective therapeutic option for treatment of various tumors by light-generated cytotoxic reactive oxygen species (ROS) to induce cell apoptosis or necrosis. However, the poor solubility, rapid blood clearance, and weak internalization of the photosensitizer seriously inhibit its anticancer efficacy. To overcome these obstacles, a polyphosphoester-based nanocarrier (NP-PPE) is employed as the carrier of the hydrophobic photosensitizer, chlorin e6 (Ce6), for photodynamic therapy. The Ce6-encapsulated nanocarrier (NP-PPE/Ce6) significantly promoted the cellular internalization of Ce6, enhanced the generation of ROS in the tumor cells after irradiation. Therefore, the cellular phototoxicity of NP-PPE/Ce6 against BxPC-3 pancreatic cancer cells was markedly enhanced than that of free Ce6 in vitro. Furthermore, NP-PPE/Ce6 improved accumulation of Ce6 in tumor tissue and treatment with NP-PPE/Ce6 significantly enhanced antitumor efficacy in human BxPC-3 pancreatic cancer xenografts. These results suggest that using a polyphosphoester-based nanocarrier as the delivery system for a photosensitizer has great potential for PDT of pancreatic cancer.

Polyphosphoester-based nanoparticles with viscous flow core enhanced therapeutic efficacy by improved intracellular drug release.

The intracellular drug release rate from the hydrophobic core of self-assembled nanoparticles can significantly affect the therapeutic efficacy. Currently, the hydrophobic core of many polymeric nanoparticles which are usually composed of poly(ε-caprolactone) (PCL), polylactide (PLA), or poly(D, L-lactide-co-glycolide) (PLGA) may hinder the diffusion of drug from the core because of their glassy state at room temperature. To investigate the effect of the hydrophobic core state on therapeutic efficacy, we synthesized an amphiphilic diblock copolymers of hydrophilic poly(ethylene glycol) (PEG) and hydrophobic polyphosphoester, which were in a viscous flow state at room temperature. The obtained copolymers self-assembled into core-shell nanoparticles, which efficiently encapsulate doxorubicin (DOX) in the hydrophobic polyphosphoester core (NP(PPE)/DOX). As speculated, compared with the nanoparticles bearing glassy core (hydrophobic PLA core, NP(PLA)/DOX), the encapsulated DOX was more rapidly released from NP(PPE)/DOX with viscous flow core, resulting in significantly increased cytotoxicity. Accordingly, the improved intracellular drug release from viscous flow core enhances the inhibition of tumor growth, suggesting the nanoparticles bearing viscous flow core show great potential in cancer therapy.

Design of Tumor Acidity-Responsive Sheddable Nanoparticles for Fluorescence/Magnetic Resonance Imaging-Guided Photodynamic Therapy

Imaging-guided cancer therapy, which integrates diagnostic and therapeutic functionalities into a single system, holds great promise to enhance the accuracy of diagnosis and improve the efficacy of therapy. Specifically, for photodynamic therapy (PDT), it is highly desirable to precisely focus laser light onto the tumor areas to generate reactive oxygen species (ROS) that are cytotoxic tumor cells and avoid light-associated side effects. Herein, a distinct three-layer nanostructured particle with tumor acidity-responsiveness (S-NP) that encapsulates the photosensitizer chlorin e6 (Ce6) and chelates Gd3+ is successfully developed for fluorescence/magnetic resonance (MR) dual-model imaging-guided precision PDT. We show clear evidence that the outer PEG layer significantly prolongs circulation time, and the inner poly(ε-caprolactone) (PCL) core can physically encapsulate Ce6. More interestingly, the middle layer of the S-NP, acting as a molecular fence to keep Ce6 in the circulation system, was dismantled by the slightly acidic tumor microenvironment. Afterwards, the PEG shell is deshielded from the S-NP at the tumor tissue, resulting in improved cell uptake, enlarged MR signal intensity, rapid release of Ce6 within tumor cells, and elevated PDT efficacy. Our results suggest that tumor-acidity-responsive nanoparticles with fine design could serve as a theranostic platform with great potential in imaging-guided PDT treatment of cancer.

Redox-Responsive Polyphosphoester-Based Micellar Nanomedicines for Overriding Chemoresistance in Breast Cancer Cells.

Multidrug resistance (MDR) has been recognized as a key factor contributing to the failure of chemotherapy for cancer in the clinic, often due to insufficient delivery of anticancer drugs to target cells. For addressing this issue, a redox-responsive polyphosphoester-based micellar nanomedicine, which can be triggered to release transported drugs in tumor cells, has been developed. The micelles are composed of diblock copolymers with a hydrophilic PEG block and a hydrophobic polyphosphoester (PPE) block bearing a disulfide bond in a side group. After incubating the redox-responsive micelles with drug-resistant tumor cells, the intracellular accumulation and retention of DOX were significantly enhanced. Moreover, after internalization by MDR cancer cells, the disulfide bond in the side group was cleaved by the high intracellular glutathione levels, resulting in a hydrophobic to hydrophilic transition of the PPE block and subsequent disassembly of the micelles. Thus, the encapsulated DOX was rapidly released, and abrogation of drug resistance in the cancer cells was observed in vitro. Moreover, the DOX-loaded redox-responsive micelles exhibited significantly enhanced inhibition of tumor growth in nude mice bearing MCF-7/ADR xenograft tumors via tail vein injection, indicating that such micelles have great potential in overcoming MDR for cancer therapy.

Sequential Growth of NaYF4:Yb/Er@NaGdF4 Nanodumbbells for Dual-Modality Fluorescence and Magnetic Resonance Imaging

Upconversional core-shell nanostructures have gained considerable attention due to their distinct enhanced fluorescence efficiency, multifunctionality, and specific applications. Recently, we have developed a sequential growth process to fabricate unique upconversion core-shell nanoparticles. Time evolution of morphology for the NaYF4:Yb/Er@NaGdF4 nanodumbbells has been extensively investigated. An Ostwald ripening growth mechanism has been proposed to illustrate the formation of NaYF4:Yb/Er@NaGdF4 nanodumbbells. The hydrophilic NaYF4:Yb/Er@NaGdF4 core-shell nanodumbbells exhibited strong upconversion fluorescence and showed higher magnetic resonance longitudinal relaxivity (r1 = 7.81 mM-1 s-1) than commercial contrast agents (Gd-DTPA). NaYF4:Yb/Er@NaGdF4 nanodumbbells can serve as good candidates for high efficiency fluorescence and magnetic resonance imaging.

Encapsulation of cisplatin in a pegylated calcium phosphate nanoparticle (CPNP) for enhanced cytotoxicity to cancerous cells

HYPOTHESIS Exchange of the chloride ion (Cl-) ligands of cisplatin with carboxylates is widely used in fabricating cisplatin loaded nanoparticles for improved cancer therapy. However, the dynamic exchange may cause premature cisplatin release and even disintegration of the nanoparticles in Cl--containing medium such as in plasma. Molecules bearing carboxylates are capable of mediating the mineralization process of calcium phosphate; therefore, it is possible to overcome the disadvantage by sequestering cisplatin in a calcium phosphate nanoparticle (CPNP). EXPERIMENTS With the hypothesis, precipitation reaction of calcium nitrate and disodium hydrogen phosphate was performed in a solution of poly(ethylene glycol)-poly(acrylic acid) block copolymers with their carboxylates partly conjugated with cisplatin. Then, structure, physicochemical properties, and bioactivity of the product were carefully investigated with multiple characterization methods. FINDINGS It was revealed a pegylated, cisplatin encapsulated CPNP was prepared; and with appropriate mole ratio of cisplatin to carboxylates, the nanoparticle encapsulated cisplatin efficiently (>90%), was stable and almost entirely prevented the cisplatin release in Cl--containing medium at pH 7.4 but released them in an acidic condition, and showed moderately and greatly enhanced cytotoxicities to the lung cancer cell line A549 and its cisplatin resistance form A549R respectively in comparison with the free cisplatin.

Fabrication of Upconverting Hybrid Nanoparticles for Near-Infrared Light Triggered Drug Release

Low tissue penetration and harmful effects of (ultraviolet) UV or visible light on normal tissue limit exploiting nanocarriers for the application of light-controlled drug release. Two strategies may solve the problem: one is to improve the sensitivity of the nanocarriers to light to decrease the radiation time; the other one is using more friendly light as the trigger. In this work, we fabricated a core-shell hybrid nanoparticle with an upconverting nanoparticle (UCNP) as the core and thermo- and light-responsive block copolymers as the shell to combine the two strategies together. The results indicated that the sensitivity of the block copolymer to light could be enhanced by decreasing the photolabile moieties in the polymer, and the UCNP could transfer near-infrared (NIR) light, which is more friendly to tissue and cell, to UV light to trigger the phase conversion of the block polymers in situ. Using Nile Red (NR) as the model drug, the hybrid nanoparticles were further proved to be able to act as carriers with the character of NIR triggered drug release.

ROS-sensitive thioketal-linked polyphosphoester-doxorubicin conjugate for precise phototriggered locoregional chemotherapy

Minimizing drug leakage at off-target sites and triggering sufficient drug release in tumor tissue are major objectives for effective nanoparticle (NP)-based cancer therapy. The current covalent and cleavable drug-NP conjugation strategy is promising but lacks high controllability to realize tumor-specific release. As a proof-of-concept, the reactive oxygen species (ROS)-activatable thioketal (TK) bond was explored as the linkage between doxorubicin (DOX) and polyphosphoester (PPE-TK-DOX). The Ce6@PPE-TK-DOX NPs constructed by co-self-coassembly of PPE-TK-DOX and the photosensitizer Ce6 efficiently prevented premature drug leakage in the off-target tissue and cells because of the high stability of the TK bond under physiological conditions. Once circulating into the tumor site, the 660-nm red light was precisely employed to irradiate the tumor area under the guidance of fluorescence/magnetic resonance (MR) dual-model imaging, which can induce localized ROS generation, resulting in rapid cleavage of the TK bond. Consequently, the DOX prodrug was locoregionally released and activated, achieving tumor-specific drug delivery with high controllability by light. Such phototriggered prodrug release and activation at the desired site significantly enhanced the therapeutic efficacy and minimized the side effect, providing new avenues to develop drug delivery systems for remote on-demand drug delivery in vivo.

A Method to Encapsulate Small Organic Molecules in Calcium Phosphate Nanoparticles Based on the Supramolecular Chemistry of Cyclodextrin

Calcium phosphate nanoparticles (CPNPs) encapsulating small organic molecules, such as imaging agents and drugs, are considered to be ideal devices for cancer diagnosis or therapy. However, it is generally difficult to encapsulate small organic molecules in CPNPs because of the lack of solubility in water or binding affinity to calcium phosphate. To solve these issues, we utilized the carboxymethyl β-cyclodextrin (CM-β-CD) to increase the solubility and binding affinity to small organic molecules for the encapsulation into CPNPs in this work. The results indicated that the model molecules, hydrophilic rhodamine B (RB) and hydrophobic docetaxel (Dtxl), are successfully encapsulated into CPNPs with the assistance of CM-β-CD. We also demonstrated the CPNPs could be remarkably internalized into A549 cells, resulting in the efficient inhibition of tumor cells’ growth.