Jin-Zhi Du

Tailor-Made Dual pH-Sensitive Polymer–Doxorubicin Nanoparticles for Efficient Anticancer Drug Delivery

Efficient delivery of therapeutics into tumor cells to increase the intracellular drug concentration is a major challenge for cancer therapy due to drug resistance and inefficient cellular uptake. Herein, we have designed a tailor-made dual pH-sensitive polymer-drug conjugate nanoparticulate system to overcome the challenges. The nanoparticle is capable of reversing its surface charge from negative to positive at tumor extracellular pH (∼6.8) to facilitate cell internalization. Subsequently, the significantly increased acidity in subcellular compartments such as the endosome (∼5.0) further promotes doxorubicin release from the endocytosed drug carriers. This dual pH-sensitive nanoparticle has showed enhanced cytotoxicity in drug-resistant cancer stem cells, indicating its great potential for cancer therapy.

Surface charge switchable nanoparticles based on zwitterionic polymer for enhanced drug delivery to tumor.

Two faced nanoparticles: A zwitterionic polymer-based nanoparticle with response to tumor acidity is developed for enhanced drug delivery to tumors. The nanoparticles are neutrally charged at physiological conditions and show prolonged circulation time; after leaking into tumor sites, in the acidic extracellular tumor environment (pH(e) ), nanoparticles are activated and become positively charged and are therefore efficiently taken up by tumor cells, leading to enhanced therapeutic effects in cancer treatment.

Shell-detachable micelles based on disulfide-linked block copolymer as potential carrier for intracellular drug delivery.

Aiming at development of a micellar nanoparticle system for intracellular drug release triggered by glutathione in tumor cells, a disulfide-linked biodegradable diblock copolymer of poly(epsilon-caprolactone) and poly(ethyl ethylene phosphate) was synthesized. It formed biocompatible micelles loaded with doxorubicin in aqueous solution but detached the shell material under glutathione stimulus, resulting in rapid drug release with destruction of micellar structure. These glutathione-sensitive micelles also rapidly released the drug molecules intracellularly and led to enhanced growth inhibition to A549 tumor cells, suggesting that this nanoparticle system may have potential for improving drug delivery efficacy.

Gold Nanoparticles Capped with Polyethyleneimine for Enhanced siRNA Delivery

An efficient and safe delivery system for small interfering RNA (siRNA) is required for clinical application of RNA interfering therapeutics. Polyethyleneimine (PEI)-capped gold nanoparticles (AuNPs) are successfully manufactured using PEI as the reductant and stabilizer, which bind siRNA at an appropriate weight ratio by electrostatic interaction and result in well-dispersed nanoparticles with uniform structure and narrow size distribution. With siRNA binding, PEI-capped AuNPs induce more significant and enhanced reduction in targeted green fluorescent protein expression in MDA-MB-435s cells, though more internalized PEI/siRNA complexes in cells are evidenced by confocal laser scanning microscopy observation and fluorescence-activated cell sorting analyses. PEI-capped AuNPs/siRNA targeting endogenous cell-cycle kinase, an oncogene polo-like kinase 1 (PLK1), display significant gene expression knockdown and induce enhanced cell apoptosis, whereas it is not obvious when the cells are treated with PLK1 siRNA using PEI as the carrier. Without exhibiting cellular toxicity, PEI-capped AuNPs appear to be suitable as a potential carrier for intracellular siRNA delivery.

Sheddable Ternary Nanoparticles for Tumor Acidity-Targeted siRNA Delivery

Drug delivery systems for cancer therapy usually need to be sterically stabilized by a poly(ethylene glycol) (PEG) layer during blood circulation to minimize nonspecific interactions with serum components. However, PEGylation significantly reduces cellular uptake of the delivery systems after they accumulate at the tumor site, which markedly impairs the in vivo antitumor efficiency. Here, we develop a ternary small interfering RNA (siRNA) delivery system with tumor acidity-activated sheddable PEG layer to overcome the challenge. The sheddable nanoparticle is fabricated by introducing a tumor acidity-responsive PEGylated anionic polymer to the surface of positively charged polycation/siRNA complexes via electrostatic interaction. We show clear evidence that introducing the PEGylated anionic polymer to the surface of a nanoparticle markedly reduces its nonspecific interactions with protein. We further demonstrate that the nanoparticle is capable of deshielding the PEG layer at the slightly acidic tumor extracellular microenvironment to facilitate the delivery of siRNA to the tumor cells after accumulation at the tumor site. Accordingly, this promotes the RNA-interfering efficiencies and enhances the inhibition of tumor growth. Such delivery system with the ability to deshield the PEG layer at the target tissues has remarkable potential in cancer therapy.

Recent Progress in Polyphosphoesters: From Controlled Synthesis to Biomedical Applications

Polyphosphoesters (PPEs) with repeating phosphoester bonds in the backbone are structurally versatile, biocompatible, and biodegradable through hydrolysis as well as enzymatic digestion under physiological conditions. They are appealing for biological applications because of their potential functionality, biocompatibility, and similarity to biomacromolecules such as nucleic acids. The expanding scope of PPEs in materials science, especially as biomaterials, is described in this review. We mainly focus on controlled synthetic methods of PPEs, which provide access to novel and complex polymer structures, especially for block copolymers. The hydrolytic and enzymatic degradation of PPEs, thermoresponsive PPEs, and biomedical applications have also been discussed.

Evaluation of Polymeric Micelles from Brush Polymer with Poly(ε-caprolactone)-b-Poly(ethylene glycol) Side Chains as Drug Carrier

Brush polymers PHEMA-g-(PCL-b-PEG) with poly(2-hydroxyethyl methacrylate) (PHEMA) as the backbone and poly(epsilon-caprolactone)-b-poly(ethylene glycol) (PCL-b-PEG) block copolymers as side chains were synthesized and evaluated as drug delivery vehicles. Two brush polymers were synthesized, and their structures were confirmed by gel permeation chromatography analyses and (1)H NMR measurements. The brush polymers self-assembled into micelles in aqueous solution, and the critical micellization concentrations of brush polymers were 2-fold lower than that of the linear diblock copolymer PCL-b-PEG with structure similar to that of the grafted side chains of brush polymers, indicating the higher aqueous stability of brush polymer micelles. The micelles were spherical with average diameters below 100 nm. Brush polymer micelles exhibited higher loading doxorubicin capacity compared with micelles from linear PCL-b-PEG block copolymer by the dialysis method, and the burst doxorubicin release from the brush polymer micelles was significantly suppressed. Doxorubicin-loaded brush polymer micelles can be effectively internalized by A549 human lung carcinoma cells and slowly released the encapsulated drug molecules as demonstrated by the drug accumulation in cytoplasm, which was opposite to free doxorubicin, which accumulated rapidly in the cell nuclei.

A biodegradable amphiphilic and cationic triblock copolymer for the delivery of siRNA targeting the acid ceramidase gene for cancer therapy

One of the key challenges in the development of RNA interference-based cancer therapy is the lack of an efficient delivery system for synthetic small interfering RNAs (siRNAs) that would enable efficient uptake by tumor cells and allow for significant knockdown of a target transcript in vivo. Here, we describe a micelleplex system based on an amphiphilic and cationic triblock copolymer, which can systemically deliver siRNA targeting the acid ceramidase (AC) gene for cancer therapy. This triblock copolymer, consisting of monomethoxy poly(ethylene glycol), poly(ε-caprolactone) and poly(2-aminoethyl ethylene phosphate), self-assembles into micellar nanoparticles (MNPs) in aqueous solution with an average diameter of 60 nm and a zeta potential of approximately 48 mV. The resulting micelleplex, formed by the interaction of MNPs and siRNA, was effectively internalized by BT474 breast cancer cells and siRNA was subsequently released, resulting in significant gene knockdown. This effect was demonstrated by significant down-regulation of luciferase expression in BT474-luciferase cells which stably express luciferase, and suppression of AC expression in BT474 cells at both the transcriptional and protein level, following delivery of specific siRNAs by the micelleplex. Furthermore, a micelleplex carrying siRNA targeting the AC (micelleplex(siAC)) gene was found to induce remarkable apoptosis and reduce the proliferation of cancer cells. Systemic delivery of micelleplex(siAC) significantly inhibited tumor growth in a BT474 xenograft murine model, with depressed expression of AC and no positive activation of the innate immune response, suggesting therapeutic promise for micelleplex siRNA delivery in cancer therapy.

Cancer stem cell therapy using doxorubicin conjugated to gold nanoparticles via hydrazone bonds

Nanoparticle-mediated delivery of chemotherapies has demonstrated enhanced anti-cancer efficacy, mainly through the mechanisms of both passive and active targeting. Herein, we report other than these well-elucidated mechanisms, rationally designed nanoparticles can efficiently deliver drugs to cancer stem cells (CSCs), which in turn contributes significantly to the improved anti-cancer efficacy. We demonstrate that doxorubicin-tethered gold nanoparticles via a poly(ethylene glycol) spacer and an acid-labile hydrazone bond mediate potent doxorubicin delivery to breast CSCs, which reduces their mammosphere formation capacity and their cancer initiation activity, eliciting marked enhancement in tumor growth inhibition in murine models. The drug delivery mediated by the nanoparticles also markedly attenuates tumor growth during off-therapy stage by reducing breast CSCs in tumors, while the therapy with doxorubicin alone conversely evokes an enrichment of breast CSCs. Our findings suggest that with well-designed drug delivery system, the conventional chemotherapeutic agents are promising for cancer stem cell therapy.

Tumor extracellular acidity-activated nanoparticles as drug delivery systems for enhanced cancer therapy.

pH-responsive nanoparticles (NPs) are currently under intense development as drug delivery systems for cancer therapy. Among various pH-responsiveness, NPs that are designed to target slightly acidic extracellular pH environment (pHe) of solid tumors provide a new paradigm of tumor targeted drug delivery. Compared to conventional specific surface targeting approaches, the pHe-targeting strategy is considered to be more general due to the common occurrence of acidic microenvironment in solid tumors. This review mainly focuses on the design and applications of pHe-activated NPs, with special emphasis on pHe-activated surface charge reversal NPs, for drug and siRNA delivery to tumors. The novel development of NPs described here offers great potential for achieving better therapeutic effects in cancer treatment.