Yong-E Gao

Multifunctional silica nanoparticles as a promising theranostic platform for biomedical applications

Theranostic nanoplatforms represent an important tool in the diagnosis and therapy of many major diseases, especially in the field of cancer theranostics, for which a myriad of nanoplatforms, such as polymeric micelles, liposomes and inorganic nanoparticles (NPs), have been designed and developed in recent decades. Among these nanoplatforms, silica NPs provide many advantages over other similar systems for therapeutics, bioimaging, bio-adhesives and many other biomedical applications. Therapeutic nanoplatforms based on mesoporous silica NPs (typically of pore size 2–50 nm) have been reviewed extensively. Herein, we provide an overview of recent advances in the development of theranostic nanoplatforms based on nonporous silica NPs within a size range of 1–200 nm for many critical biomedical applications, particularly stimuli-triggered drug delivery, precise cancer diagnosis as well as tissue bio-adhesive materials.

pH-Responsive unimolecular micelles based on amphiphilic star-like copolymers with high drug loading for effective drug delivery and cellular imaging

Herein, we report pH-responsive star-like polymers (denoted as CPO) with amphiphilic diblock copolymers poly(2-(diisopropylamino) ethylmethacrylate)-b-poly[(ethylene glycol) methyl ether methacrylate] (PDPA-b-POEGMA) grafted from β-cyclodextrin (β-CD) for efficient antitumor drug delivery. A series of amphiphilic CPO polymers were synthesized via two-step atom transfer radical polymerization (ATRP) utilizing β-CD-21Br as an initiator. Transmission electron microscopy and dynamic light scattering results demonstrated that these amphiphilic star-like polymers formed unimolecular micelles (UMs) in aqueous media and showed favorable robust micellar stability. The PDPA blocks are hydrophobic at pH = 7.4, which enabled these UMs to carry hydrophobic drugs such as doxorubicin (DOX) in their inner layer with a high drug loading content. Under an acidic environment, the hydrophobility-hydrophilicity transition of PDPA blocks induced the rapid pH-triggered release of drugs for cancer therapy. To endow these UMs with diagnostic functions, near-infrared fluorescent dye cyanine 5 (Cy5) was incorporated by post-decoration on the amine-functionalized precursor where their inner layer was replaced with copolymerized blocks of P(DPA-co-AMA). The UMs of the obtained Cy5 containing polymers (denoted as CPO-Cy5) exhibited switchable fluorescence in response to different pH conditions, where the fluorescence intensity could be enhanced by 7-fold with the change of pH from 9 to 4. The cytotoxicity experiments demonstrated that the DOX-loaded CPO or CPO-Cy5 micelles presented high cytotoxicity against HeLa and MCF-7 cancer cells but low cytotoxicity against normal L929 cells, likely implying their potential tumor-specific targeting ability. The integration of NIR imaging and effective therapeutic functions made DOX-loaded CPO-Cy5 a promising nanomedicine, providing new insights into the design of theranostic nanoplatforms.

pH-responsive polymeric micelles based on poly(ethyleneglycol)-b-poly(2-(diisopropylamino) ethyl methacrylate) block copolymer for enhanced intracellular release of anticancer drugs

We present a pH-responsive poly(ethyleneglycol)-b-poly(2-(diisopropylamino) ethyl methacrylate) block copolymer (MPEG-PPDA) that can self-assemble into micelles at very low critical micelle concentration. The formed micelles exhibit superior stability in physiological environment and pH-triggered transforming capability between self-assembly and disassembly. Moreover, the resulting micelles can load hydrophobic anticancer drug molecules such as doxorubicin in the core of micelles. The pH-triggered drug release kinetics matches the classical hydrazone bond model. The blank micelles demonstrate minimal cytotoxicity while the drug-loaded micelles exhibit significantly improved anticancer efficacy. These results indicate that this MPEG-PPDA block copolymer could be utilized as a universal pH-responsive delivery system for controlled release of hydrophobic anticancer drug in chemotherapy.

Acid-Activatable Theranostic Unimolecular Micelles Composed of Amphiphilic Star-like Polymeric Prodrug with High Drug Loading for Enhanced Cancer Therapy.

Stimuli-responsive nanomedicine with theranostic functionalities with reduced side-effects has attracted growing attention, although there are some major obstacles to overcome before clinical applications. Herein, we present an acid-activatable theranostic unimolecular micelles based on amphiphilic star-like polymeric prodrug to systematically address typical existing issues. This smart polymeric prodrug has a preferable size of about 35 nm and strong micellar stability in aqueous solution, which is beneficial to long-term blood circulation and efficient extravasation from tumoral vessels. Remarkably, the polymeric prodrug has a high drug loading rate up to 53.1 wt%, which induces considerably higher cytotoxicity against tumor cells (HeLa cells and MCF-7 cells) than normal cells (HUVEC cells) suggesting a spontaneous tumor-specific targeting capability. Moreover, the polymeric prodrug can serve as a fluorescent nanoprobe activated by the acidic microenvironment in tumor cells, which can be used as a promising platform for tumor diagnosis. The superior antitumor effect in this in vitro study demonstrates the potential of this prodrug as a promising platform for drug delivery and cancer therapy.

Highly cell-penetrating and ultra-pH-responsive nanoplatform for controlled drug release and enhanced tumor therapy

A stimuli-triggered drug release strategy could considerably reduce side effects while improving the bioavailability of chemotherapeutics. Here, we report that a series of ultra-pH-responsive copolymers are highly efficient drug delivery systems for near-infrared (NIR) imaging and controlled drug release. These polymers self-assemble into nano-sized micelles due to their amphipathic structure and deliver hydrophobic drugs (maximum drug loading rate ∼10wt%) into tumor cells via a controlled and pH-triggered modality. By altering the proportion of hydrophilic and hydrophobic chains, the drug loading rate and the in vitro drug release efficiency can be regulated. Moreover, the drug-loaded micelles with optimized compositions exhibited excellent antitumor efficacy in HeLa and MCF-7 cells, while the blank micelles had minimal cytotoxicity. Cellular uptake experiments further indicated that the ultra-pH-responsive micelles could be rapidly internalized in the tumor cells. This study demonstrated the strong potential of the ultra-pH-responsive platform as a universal carrier for the delivery of anticancer drugs to maximize their therapeutic effect.

Reduction stimuli-responsive unimolecular polymeric prodrug based on amphiphilic dextran-framework for antitumor drug delivery

We report a new reduction-responsive amphiphilic polymeric prodrug based on a linear dextran (DEX) backbone, which was conjugated with an hydrophobic camptothecin (CPT) prodrug block and an hydrophilic poly[poly(ethylene glycol) methyl ether methacrylate] (POEGMA) block [DEX-PCPT-b-POEGMA (DCO)] by atom transfer radical polymerization (ATRP). This amphiphilic prodrug has a unique molecular structure with prominent features, including strong practicability for methacrylate prodrug monomer, high drug loading rate (up to 23wt%), adjustable proportion of hydrophobic and hydrophobic portions, superior stability in aqueous solution, and easy access to cells. Introduction of a disulfide bond linker between the drug and the carrier can realize the function of reduction-responsive controlled drug-release. The experimental study indicated that the prodrug exhibited notable antitumor activity against HeLa cells and MCF-7 cells in vitro. Compared to similar DCO prodrug based on double carbon bond, the disulfide bond-conjugated DCO prodrug induced higher level of tumor cell apoptosis. Considering the drug-loading efficiency, micellar stability, cost of preparation and controlled drug release, the presented prodrug is more advantageous than traditional unimolecular prodrug and represents a promising approach for design of stimuli-responsive polymeric prodrug for effective cancer therapeutics.

Reduction-active polymeric prodrug micelles based on α-cyclodextrin polyrotaxanes for triggered drug release and enhanced cancer therapy

As one of the medical polymers approved by US Food and Drug Administration (FDA), poly(ethylene glycol) has low toxicity, high stability, good biocompatibility, unique physical and chemical properties. Cyclodextrin is an ideal candidate as a drug carrier due to its special structures and characteristics. These two materials were successfully assembled through chemosynthesis in combination with the hydrophilic poly(ethylene glycol) methyl ether methacrylate (OEGMA) chain and hydrophobic polymeric camptothecin (CPT) chain by atom transfer radical polymerization (ATRP). The introduction of disulfide bond of monomer was aimed to realize reduction agent-triggered release of active CPT. The obtained amphipathic prodrug [(Denoted as PC-PCPT-b-POEGMA (PCCO)] could form nano-sized polymeric micelles, which could release more than 85% of the loaded CPT via triggered cleavage of the disulfide linker. The cellular co-localization study revealed the potential pathway of drug internalization. Moreover, the PCCO micelles showed good biocompatibility in vivo after intravenous injection on a mouse model. This new CPT-loaded prodrug system could be prepared with low cost, and showed efficient and controlled drug release and favorable biocompatibility, demonstrating a promising potential as a stimuli-responsive polymeric prodrug for future clinical applications.

Irinotecan delivery by unimolecular micelles composed of reduction-responsive star-like polymeric prodrug with high drug loading for enhanced cancer therapy

Nanomedicine based polymeric prodrug have showed high impact in the inhibition of tumor growth due to its high therapeutic efficiency and improved biocompatibility. Herein, we synthesized a novel star-like amphiphilic copolymer [β-CD-P(Ir-co-OEGMA), denoted as CPIO] through atom transfer radical polymerization (ATRP) to deliver the hydrophilic anticancer drug irinotecan (Ir). The polymer could form monodisperse unimolecular micelles and had excellent stability in aqueous solution. Moreover, the reduction-responsive feature of the micelles facilitated controlled release of drug, thus achieving targeted therapy and reduced toxicity to healthy cells. The in vitro cytotoxicity assays indicated that CPIO had a notable anticancer effect against HeLa and MCF-7 tumor cells. The confocal laser scanning microscopy and flow cytometry experiments revealed that CPIO micelles could be internalized into tumor cells efficiently. Furthermore, the obtained prodrug micelles produced better efficacy compared to free Ir. Moreover, the CPIO micelles showed excellent biocompatibility in vivo after intravenous injection on a mouse model. This study demonstrated that CPIO carrier could provide a rational design of a stimuli-responsive polymeric prodrug for delivery of irinotecan.