Furong Cheng

Characteristic of core materials in polymeric micelles effect on their micellar properties studied by experimental and dpd simulation methods

Polymeric micelles are one important class of nanoparticles for anticancer drug delivery, but the impact of hydrophobic segments on drug encapsulation and release is unclear, which deters the rationalization of drug encapsulation into polymeric micelles. This paper focused on studying the correlation between the characteristics of hydrophobic segments and encapsulation of structurally different drugs (DOX and β-carotene). Poly(ϵ-caprolactone) (PCL) or poly(l-lactide) (PLLA) were used as hydrophobic segments to synthesize micelle-forming amphiphilic block copolymers with the hydrophilic methoxy-poly(ethylene glycol) (mPEG). Both blank and drug loaded micelles were spherical in shape with sizes lower than 50 nm. PCL-based micelles exhibited higher drug loading capacity than their PLLA-based counterparts. Higher encapsulation efficiency of β-carotene was achieved compared with DOX. In addition, both doxorubicin and β-carotene were released much faster from PCL-based polymeric micelles. Dissipative particle dynamics (DPD) simulation revealed that the two drugs tended to aggregate in the core of the PCL-based micelles but disperse in the core of PLLA based micelles. In vitro cytotoxicity investigation of DOX loaded micelles demonstrated that a faster drug release warranted a more efficient cancer-killing effect. This research could serve as a guideline for the rational design of polymeric micelles for drug delivery.

Correlation of polymeric micelle sizes and their cellular internalization in vitro and tumor targeting in vivo

In order to explore the size effect of polymeric micelles on cellular internalization and tumor targeting, chrysin modified mPEG–PCL copolymer micelles with different particle sizes were fabricated to load Nile red as fluorescence probes. Four kinds of micelles with the mean sizes of 20, 40, 80 and 120 nm and narrow size distributions were prepared. The zeta potentials of the micelles were within −2 to 0 mV. The micelles were stable at low concentration (10−3 mg mL−1) for a long time of storage. The micelles were incubated with C2C12 myoblasts and 4T1 breast cancer cells to investigate their cellular uptake. It was found that the cellular internalization of the polymeric micelles was dependent on the cell line and particle size. The cellular uptake of the micelles in 4T1 cells was much better than that in C2C12 cells, and the polymeric micelles with a size of 120 nm exhibited the strongest red fluorescence. The Nile red loaded polymeric micelles were injected in mice via their tail vein to study tumor targeting in vivo. The micelles were mainly accumulated in the liver and kidney, however, different from the results in vitro, the red fluorescence intensity in the tumor administrated with polymeric micelles with a size of 40 nm was the strongest compared with the other three particles, which implied that micelles with a size of 40 nm exhibited efficient tumor targeting. This work provides guidelines for the rational design of polymeric micelles as carriers for efficient targeted drug delivery.

Framework effect of amphiphilic polyesters on their molecular movement and protein adsorption-resistance properties.

Surface chemical characteristics of biomedical polymers, which are determined by the migration and rearrangement of polymeric chains, play an important role in the protein adsorption. In this work, the relationship between the architectures of amphiphilic polyesters and their protein adsorption resistance was investigated. Three poly (ɛ-caprolactone)s containing sulfobetaines (PCL-b-PDEAS) segments with linear, four arms and six arms star-shaped architectures were synthesized with the combination of ring-opening polymerization (ROP) and atom transfer radical polymerization (ATRP). The structures of the amphiphiles were confirmed by (1)H NMR and FTIR. Water contact angles (WCA) and X-ray photoelectron spectroscopy (XPS) were used to study the surface properties of the amphiphilic copolymer films. The water contact angles were decreased due to the surface migration of hydrophilic segments. Transmission electron microscopy (TEM) displayed the occurrence of microphase separation phenomena for PCL-b-PDEAS above glass transition temperature (Tg). The results showed that the hydrophilic segments in the copolymers would migrate to the surface of the films, which resulted in the surface more hydrophilic to resist protein adsorption. The adsorption of both fibrinogen (Fg) and bovine serum albumin (BSA) were studied. The results showed that protein adsorption was depended on not only the hydrophilic chain migration but also the shape of proteins.

Multifunctional nanoparticles self-assembled from polyethylenimine-based graft polymers as efficient anticancer drug delivery

Multiple functionalization of nanoparticles has attracted great interest in drug delivery. In this paper, polymeric amphiphiles of polyethylenimine (PEI) conjugated with methoxy poly(ethylene glycol) aldehyde (mPEG-CHO), poly(ε caprolactone) aldehyde (PCL-CHO) and pyrene-1-carboxaldehyde (Py-CHO) were synthesized via Schiffs reaction. The conjugates self-assembled into nanoparticles with pH-sensitivity to load anticancer drug doxorubicin (DOX), further coated with hyaluronic acid (HA) for tumor targeting. The mean size of nanoparticles was about 100nm and the stability of the nanoparticles was well in aqueous solution. The nanoparticles coated with HA showed faster disassembly in acidic solution, resulting in faster drug release in the medium with pH 5.0 compared to uncoated nanoparticles. Moreover, the nanoparticles exhibited an endosomal escape function to accelerate the release of DOX in cancer cells, which led to low IC50s to kill breast cancer cells (4T1) and liver cancer cells (HepG2) in vitro.

In vitro and in vivo anti-tumor efficiency comparison of phosphorylcholine micelles with PEG micelles

Polymer micelles for anticancer drug delivery have shown many advantages. In this study, poly(ε-caprolactone)-b-poly(2-methacryloyloxyethyl phosphorylcholine) (PCL-PMPC) with bio-inspired structure self-assembled into small and uniform micelles as traditional poly(ε-caprolactone)-b-poly(ethylene glycol) (PCL-PEG). The in vitro and in vivo anti-tumor efficiency of PCL-PMPC and PCL-PEG micelles were detailedly evaluated. The both micelles were able to load DOX with high efficiency. PCL-PMPC micelles exhibited faster drug release at pH 5.5 than that of PCL-PEG micelles. Confocal laser scanning microscopy and flow cytometry results showed that PCL-PMPC micelles were more effectively internalized by tumor cells. DOX-loaded PCL-PMPC micelles presented higher cytotoxicity to tumor cells. PCL-PMPC micelles displayed not only longer circulation time in pharmacokinetics investigation, but also higher accumulation at the tumor site in in vivo imaging study in comparison with PCL-PEG micelles. More importantly, in a tumor model DOX-loaded PCL-PMPC micelles showed better therapeutic efficacy than DOX-loaded PCL-PEG micelles along with mild side effects. Therefore, PCL-PMPC micelles are deemed to be promising drug carriers for cancer therapy.

Intracellular pH-induced fluorescence used to track nanoparticles in cells

A nanoparticle with pH-induced fluorescence was reported for intracellular tracking. The fluorescence was evoked by the isomerization of the ring-closed form spiropyran (SP) to the ring-open form merocyanine (MC) in the weak acidic environment of cells. The SP-MC switch accelerated the dissociation of nanoparticles to trigger the release of trapped paclitaxel.

Hierarchical nanocomposites of graphene oxide and PEGylated protoporphyrin as carriers to load doxorubicin hydrochloride for trimodal synergistic therapy

Multimodal and synergistic therapy of cancer has appeared as one of the most promising strategies in treating cancer. Here, we report a supramolecular hierarchical nanocomposite for combination photodynamic, photothermal, and chemotherapy. Graphene oxide (GO, photothermal agent for photothermal therapy, PTT), protoporphyrin IX (PpIX, photosensitizer for photodynamic therapy, PDT), and hydrophilic anticancer drug doxorubicin hydrochloride (DOX·HCl, therapeutic for chemotherapy) are involved in hierarchical self-assembled nanocomposites via supramolecular interactions. PEGylated PpIX (PEG-PpIX) is prepared to improve the stability of GO in physiological conditions. The nanocomposite GO(PEG-PpIX) is non-cytotoxic in the dark and phototoxic with light irradiation to exhibit efficient PTT and PDT effects. The drug loading content of the nanocomposite DOX/GO(PEG-PpIX) is as high as 15.9% and the drug release shows a pH-dependent profile. The combined PDT, PTT, and chemotherapy shows an excellent in vivo antitumor effect and side effect reduction. This work presents a facile yet robust strategy to fabricate a nanocomposite for multimodal synergistic therapy.