Chunhua Guo

Dendronized heparin-doxorubicin conjugate based nanoparticle as pH-responsive drug delivery system for cancer therapy.

Heparin drug conjugates are currently investigated as excellent candidates for drug delivery vehicles. In this study, we report the preparation and characterization of dendronized heparin-doxorubicin (heparin-DOX) conjugate as pH-sensitive drug delivery vehicle by combination of the features of dendrimer and heparin. Dynamic light scattering (DLS) and transmission electron microscope (TEM) studies demonstrated the dendronized heparin-DOX conjugate self-assembled into compact nanoparticles with negatively charged surface. The nanoparticles with 9.0 wt% (weight percent) of doxorubicin (DOX) showed pH-sensitive property due to the faster drug release rate at pH 5.0 and slow release rate at pH 7.4 aqueous. The nanoparticles were shown to effectively kill cancer cells in vitro. Notablely, the nanoparticles resulted in strong antitumor activity, high antiangiogenesis effects and induced apoptosis on the 4T1 breast tumor model due to the evidences from mice weight shifts, tumor weights, tumor growth curves, immunohistochemical assessment and histological analysis. Its also noteworthy that dendronized heparin and its nanoparticle with drug demonstrated no significant toxicity to healthy organs of both tumor-bearing and healthy mice, which was confirmed by histological analysis compared with free drug DOX. The dendronized heparin-DOX conjugate based nanopatilce with high antitumor activity and low side effects may be therefore a potential nanoscale drug delivery vehicle for breast cancer therapy.

Amphiphilic peptide dendritic copolymer-doxorubicin nanoscale conjugate self-assembled to enzyme-responsive anti-cancer agent.

Peptide dendrimer drug conjugate based nanoparticles are recently developed as a potential candidate for drug delivery vehicle. In this study, we prepared and characterized the enzyme-sensitive amphiphilc mPEGylated dendron-GFLG-DOX conjugate via two-step highly efficient click reaction. Dynamic light scattering (DLS) and transmission electron microscope (TEM) studies demonstrated the mPEGylated dendron-GFLG-DOX conjugate self-assembled into compact nanoparticles with negatively charged surface. The nanoparticles with 9.62 wt% (weight percent) of DOX showed enzyme-sensitive property by drug release tests. The nanoparticles were shown to effectively kill cancer cells in vitro. The fluorescent image indicated that the nanoparticles could accumulate and retain within tumor for a long time. Moreover, the nanoparticles substantially enhanced antitumor efficacy compared to the free DOX, exhibiting much higher effects on inhibiting proliferation and inducing apoptosis of the 4T1 murine breast cancer model confirmed as the evidences from tumor growth curves, tumor growth inhibition (TGI), immunohistochemical analysis and histological assessment. The nanoparticles reduced DOX-induced toxicities and presented no significant side effects to normal organs of both tumor bearing and healthy mice as measured by body weight shifts and histological analysis. Therefore, the mPEGylated dendron-GFLG-DOX conjugate based nanoparticle serves as a potential drug delivery vehicle for breast cancer therapy.

Dendrimer–doxorubicin conjugate as enzyme-sensitive and polymeric nanoscale drug delivery vehicle for ovarian cancer therapy

Peptide dendrimer-based nanoparticles have presented significant potential as candidates for drug delivery system. In this study, we synthesized and characterized enzyme-responsive mPEGylated peptide dendrimer–GFLG–doxorubicin conjugate (dendrimer–GFLG–DOX) as a chemotherapeutic drug delivery nano-carrier via a two-step highly efficient copper-catalyzed alkyne–azide click cycloaddition (CuAAC) reaction. The tetra-peptide sequence Gly–Phe–Leu–Gly (GFLG) was explored as an enzyme-responsive linker to connect the doxorubicin (DOX) to the periphery of mPEGylated peptide dendrimer. The dendrimer–GFLG–DOX was capable of self-assembling into nanoparticle, which was proven by dynamic light scattering (DLS) and transmission electron microscopy (TEM) studies. Compared to the free drug DOX, the dendrimer–GFLG–DOX conjugate based nanoparticle demonstrated higher accumulation and retention within SKOV-3 ovarian tumor tissue, resulting in a higher antitumor activity as evidenced from tumor growth curves, tumor growth inhibition analysis, immunohistochemical assessment and in vivo imaging. Moreover, no obvious systemic toxicity was observed via histological assessment. Thus, the mPEGylated peptide dendrimer–DOX conjugate-based nanoparticle may be a promising candidate as a nanoscale and enzyme-sensitive drug delivery vehicle for ovarian cancer therapy.

Peptide Dendrimer–Doxorubicin Conjugate‐Based Nanoparticles as an Enzyme‐Responsive Drug Delivery System for Cancer Therapy

Peptide dendrimers have shown promise as an attractive platform for drug delivery. In this study, mPEGylated peptide dendrimer-doxorubicin (dendrimer-DOX) conjugate-based nanoparticle is prepared and characterized as an enzyme-responsive drug delivery vehicle. The drug DOX is conjugated to the periphery of dendrimer via an enzyme-responsive tetra-peptide linker Gly-Phe-Leu-Gly (GFLG). The dendrimer-DOX conjugate can self-assemble into nanoparticle, which is confirmed by dynamic light scattering, scanning electron microscopy, and transmission electron microscopy studies. At equal dose, mPEGylated dendrimer-DOX conjugate-based nanoparticle results in significantly high antitumor activity, and induces apoptosis on the 4T1 breast tumor model due to the evidences from tumor growth curves, an immunohistochemical analysis, and a histological assessment. The in vivo toxicity evaluation demonstrates that nanoparticle substantially avoids DOX-related toxicities and presents good biosafety without obvious side effects to normal organs of both tumor-bearing and healthy mice as measured by body weight shift, blood routine test, and a histological analysis. Thus, the mPEGylated peptide dendrimer-DOX conjugate-based nanoparticle may be a potential nanoscale drug delivery vehicle for the breast cancer therapy.

PEGylated dendritic diaminocyclohexyl-platinum (II) conjugates as pH-responsive drug delivery vehicles with enhanced tumor accumulation and antitumor efficacy.

Environmentally responsive peptide dendrimers loaded with drugs are suitable candidates for cancer therapy. In this study, we report the preparation and characterization of mPEGylated peptide dendrimer-linked diaminocyclohexyl platinum (II) (dendrimer-DACHPt) conjugates as pH-responsive drug delivery vehicles for tumor suppression in mice. The DACHPt has a molecular structure, is and activity closely related to oxaliplatin and was linked to dendrimer via N,O-chelate coordination. The products were pH-responsive and released drug significantly faster in acidic environments (pH 5.0) than pH 7.4. Consequently, the conjugates suppressed tumor growth better than clinical oxaliplatin(®) without inducing toxicity in an SKOV-3 human ovarian cancer xenograft. Through the systemic delivery of conjugates, 25-fold higher tumor platinum uptake at 36 h post-injection was seen observed due to the enhanced permeability and retention (EPR) effect thereby remarkably enhancing the therapeutic indexes of this small-molecule drug. Thus, the mPEGylated peptide dendrimer-linked DACH-platinum conjugates are novel potential drug delivery systems with implications in future ovarian cancer therapy.

A stimuli-responsive Janus peptide dendron–drug conjugate as a safe and nanoscale drug delivery vehicle for breast cancer therapy

Smart nanoscale drug delivery systems have been investigated as potential candidates for drug delivery vehicles. Here, we used a breast cancer model to determine if the enzyme-responsive Janus dendron (mPEGylated dendron-PVGLIG-DOX) conjugate-based nanoscale system would be an effective and safe drug delivery vehicle for chemotherapy. To this end, we prepared and characterized the matrix metalloprotease-2 (MMP-2)/MMP-9-sensitive linker of the proline-valine-glycine-leucine-isoleucine-glycine (Pro-Val-Gly-Leu-Ile-Gly, PVGLIG) oligopeptide via a convenient and fast liquid-phase synthesis. Second, using a rational design strategy, the Janus dendron (Boc-G2L-G3L-OMe) was successfully modified with mPEG and PVGLIG-DOX via a two-step highly efficient copper-catalyzed alkyne-azide click cycloaddition (CuAAC) reaction. Morphology studies such as dynamic light scattering, scanning electron microscopy, and atomic force microscopy were performed to confirm that the Janus mPEGylated dendron-PVGLIG-DOX conjugate self-assembled into compact nanoparticles with a slightly negatively charged surface. The nanoscale system, which included nanoparticles with 4.0 wt% (weight percent) of doxorubicin (DOX), was analyzed using ultraviolet-visible absorption spectra, fluorescence emission spectra, and matrix assisted laser desorption/ionization time-of-flight. Nanoscale systems incubated with exogenous MMP-2 killed breast cancer cells were more effective than those lacking MMP-2. Compared to free DOX, the nanoscale system substantially reduced the side effects accompanied by a similar antitumor efficacy. Moreover, it had minimal systemic toxicities, especially DOX-induced toxicities to the normal organs of both tumor bearing and healthy mice, as determined by changes in the body weight and histological analysis. These data demonstrate that the Janus dendron drug conjugate-based nanoscale system may be an effective chemotherapy delivery vehicle for breast cancer.

A dendronized heparin–gadolinium polymer self-assembled into a nanoscale system as a potential magnetic resonance imaging contrast agent

We reported the preparation and characterization of a dendronized heparin–gadolinium polymer (Dendronized-heparin–Gd) based nanoscale system as a potential MRI contrast agent, which combined the advantages of heparin and the peptide dendron. The dendronized polymer self-assembled into a compact nanoscale system, which was confirmed by dynamic light scattering (DLS) and scanning electron microscopy (SEM) results, and a negative charge was observed. The content of gadolinium (Gd(III)) was 6% as a weight percentage, determined by inductively coupled plasma mass spectrometry (ICP-MS) analysis. The in vitro and in vivo toxicity studies demonstrated that the Dendronized-heparin–Gd polymeric nanoscale system exhibited good biocompatibility – no obvious side effects to normal cells and organs of healthy mice were observed by a cytotoxicity assay, body weight shift and histological analysis. The polymeric nanoscale system showed a 7-fold increase in the T1 relaxivity compared to the clinical agent Magnevist (Gd-DTPA). In vivo MR imaging studies on the mice bearing 4T1 breast tumors showed that the nanoscale system had a much higher contrast enhancement in the tumor than Gd-DTPA. The distribution of Gd(III) in the tissues at different times after administration indicated a higher Gd(III) accumulation in the tumor for the nanoscale system compared to Gd-DTPA. Overall, the dendronized heparin polymer based nanoscale system with a high contrast enhancement in tumors and low side effects may be used as a MRI contrast agent for disease diagnosis.

The potential of peptide dendron functionalized and gadolinium loaded mesoporous silica nanoparticles as magnetic resonance imaging contrast agents

In this study, an MSN-dendron-Gd conjugate based nanoprobe was synthesized using an easy and efficient method with high purity and the nanoprobe was studied for its efficiency in contrast imaging applications. The nanoprobe was synthesized using the Cu(i)-catalyzed azide-alkyne based method, which overcame the challenges of stereospecific blockade of mesoporous silica nanohybrid synthesis. Moreover, the nanoprobe showed an approximately 11-fold increase in the relaxivity (from 5.55 mM-1 s-1 to 60.56 mM-1 s-1) and enhancement of MR images. The higher relaxivity rates were obtained via the properties of the nanoprobe contributing to an increase in the rotational correlation time, thereby increasing relaxivity. In addition, the nanoprobe displayed excellent biosafety as confirmed by in vitro and in vivo toxicity tests. Overall, the nanoprobe displayed great potential for biomedical use as a MRI contrast agent.