Dayi Pan

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.

Biodegradable and amphiphilic block copolymer–doxorubicin conjugate as polymeric nanoscale drug delivery vehicle for breast cancer therapy

Polymeric nanoparticles have shown great promise as attractive vehicles for drug delivery. In this study, we designed, prepared and characterized biodegradable amphiphilic triblock HPMA copolymer-doxorubicin (copolymer-DOX) conjugate based nanoparticle as enzyme-sensitive drug delivery vehicle. The enzyme-sensitive peptide GFLGKGLFG was introduced to the main chain of the copolymer with hydrophilic and hydrophobic blocks. The triblock HPMA polymer-DOX conjugate with high molecules (Mw 90 kDa) can be degraded to product with low molecule weight (Mw 44 kDa) below the renal threshold. The copolymer-DOX conjugate can self-assemble into compact nanoparticle, which was characterized by scanning electron microscope (SEM) and atomic force microscope (AFM) studies. This polymeric nanoparticle substantially enhanced antitumor efficacy compared to the free DOX, exhibiting much higher effects on inhibiting proliferation and inducing apoptosis on the 4T1 murine breast cancer model confirmed by the evidences from mice weight shifts, tumor growth curves, tumor growth inhibition (TGI), immunohistochemical analysis and histological assessment. The in vivo toxicity evaluation demonstrated that the polymeric nanoparticle 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 shift, blood routine test and histological analysis. Therefore, the triblock HPMA copolymer-DOX conjugate based nanoparticle is promising 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.

Enzyme-responsive peptide dendrimer-gemcitabine conjugate as a controlled-release drug delivery vehicle with enhanced antitumor efficacy

Stimuli-responsive peptide dendrimer-drug conjugates have presented significant potential for cancer therapy. To develop an effective nanoscale chemotherapeutic prodrug, we developed a novel enzyme-responsive PEGylated lysine peptide dendrimer-gemcitabine conjugate (Dendrimer-GEM) based nanoparticle via the highly efficient click reaction. Owing to the glycyl phenylalanyl leucyl glycine tetra-peptide (GFLG) as an enzyme-cleavable linker to conjugate gemcitabine (GEM), the prepared nanoparticles were able to release drug significantly faster in the tumor cellular environments, which specifically contains secreted Cathepsin B, quantifiably more than 80% GEM was released with Cathepsin B compared to the condition without Cathepsin B at 24h. This nanoparticle demonstrated enhanced antitumor efficacy in a 4T1 murine breast cancer model without obvious systemic toxicity, resulting in significantly suppressed relative tumor volumes (86.17±38.27%) and a 2-fold higher value of tumor growth inhibition (∼90%) than GEM·HCl treatment. These results suggest that the PEGylated peptide dendrimer-gemcitabine conjugate can be an effective antitumor agent for breast cancer therapy. Statement of Significance We found that the functionalized dendrimer based nanoscale drug delivery vehicles exhibited enhanced therapeutic indexes and reduced toxicity as compared to the free drug gemcitabine. Compared with current nanoparticles, such as dendritic anticancer drug delivery systems, the new design was capable of self-assembling into nanoscale particles with sizes of about 80-110nm, which is suitable as antitumor drug delivery vehicle due to the potential longer intravascular half-life and higher accumulation in tumor tissue via EPR effect. Owing to the optimized architecture, the system was given the enzyme-responsive drug release feature, and showed excellent antitumor activity on the 4T1 breast tumor model due to the evidences from tumor growth curves, immunohistochemical analysis and confocal laser scanning microscopy. Meanwhile, no significant side effect was observed by histological analysis. This study demonstrated that PEGylated peptide dendritic architecture may be used as efficient and safe nanoscale drug delivery vehicle for cancer therapy.

Cross-Linked and Biodegradable Polymeric System as a Safe Magnetic Resonance Imaging Contrast Agent

Owing to the low efficacy of clinically used small-molecule gadolinium (Gd)-based magnetic resonance imaging (MRI) agents, we designed and explored biodegradable macromolecular conjugates as MRI contrast agents. The linear polymeric structure and core-cross-linked formulation possessed different characteristics and features, so we prepared and comparatively studied the two kinds of Gd-based N-(2-hydroxypropyl) methacrylamide (HPMA) polymeric systems (the core-cross-linked pHPMA-DOTA-Gd and the linear one) using the clinical agent diethylene-triamine pentaacetic acid-Gd(III) (DTPA-Gd) as a control. This study was aimed to find the optimal polymeric formulation as a biocompatible and efficient MRI contrast agent. The high molecular weight (MW, 181 kDa) and core-cross-linked copolymer was obtained via the cross-linked block linear copolymer and could be degraded to low-MW segments (29 kDa) in the presence of glutathione (GSH) and cleaned from the body. Both core-cross-linked and linear pHPMA-DOTA-Gd copolymers displayed 2-3-fold increased relaxivity (r1 value) than that of DTPA-Gd. Animal studies demonstrated that two kinds of macromolecular systems led to much longer blood circulation time, higher tumor accumulation, and much higher signal intensity compared with the linear and clinical ones. Finally, in vivo and in vitro toxicity studies indicated that the two macromolecular agents had great biocompatibility. Therefore, we performed preliminary but important studies on the Gd-based HPMA polymeric systems as biocompatible and efficient MRI contrast agents and found that the biodegradable core-cross-linked pHPMA-DOTA-Gd copolymer might have greater benefits for the foreground.

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.