cRGD mediated redox and pH dual responsive poly(amidoamine) dendrimer-poly(ethylene glycol) conjugates for efficiently intracellular antitumor drug delivery.

To improve antitumor efficiency of chemotherapy and reduce side effect, according to the physiological characteristics of tumor tissues and tumor intracellular microenvironment, a multifunctional drug delivery system with properties of long circulation, active targeting, redox and pH triggered drug release was established based on the Generation 4 polyamidoamine dendrimer (PAMAM). First, the redox cleavable disulfide bonds (SS) were introduced for linking polyethylene glycol (PEG) with PAMAM to form PAMAM-S-S-PEG (PSSP). Then cRGD peptide was applied to the PEG end of PSSP to construct RGD-PSSP conjugates. Finally, encapsulating the antitumor chemotherapy drug doxorubicin (DOX) into the hydrophobic cavity of RGD-PSSP conjugates constructed the RGD-PSSP/DOX drug delivery system. The in vitro experiments displayed that RGD-PSSP/DOX NPs showed obviously redox and pH dual sensitive drug release profile. MTT and cell uptake observation elucidated cRGD modification could increase the cytotoxicity, and promote the uptake of B16 cells and HUVEC cells both overexpressing integrin ανß3on cell membrane. Cell uptake mechanism investigation further revealed that RGD-PSSP/DOX interacted with plasma membrane via specific recognition of cRGD peptide with integrin ανß3, and was subsequently internalized mainly through clathrin- and caveolin-mediated endocytosis. Remarkably, RGD-PSSP/DOX presented superior anticancer activity and lower heart and kidney toxicity in vivo, which could be regarded as a potential candidate for efficient antitumor chemotherapy drug delivery.

Chondrocyte affinity peptide modified PAMAM conjugate as a nanoplatform for targeting and retention in cartilage.

AIM: To develop a nanocarrier for targeted delivery of agents to the cartilage. MATERIALS & METHODS: Chondrocyte affinity peptide modified PEGylated polyamidoamine conjugates (CAP-PEG-PAMAM) were prepared and rhodamine B isothiocyanate (RB) fluorophore was linked on them for comparative biological tracing and profiling. RESULTS: CAP4-PP-RB exhibited much more efficient cellular uptake in vitro than that of PEG-PAMAM-RB. Both the conjugates were likely internalized by chondrocytes via clathrin and caveolin co-mediated endocytosis, and delivered to lysosomes. In vivo imaging demonstrated the fluorescein-labeled nanocarrier was capable to persist in the joint cavity of rats for a prolonged time. Furthermore, the CAP4-PEG-PAMAM showed a good biocompatibility and enhanced penetration effects in vivo. CONCLUSION: CAP-PEG-PAMAM could be an effective nanocarrier for intra-articular delivery of agents to cartilage.

Polyethylene glycol modified PAMAM dendrimer delivery of kartogenin to induce chondrogenic differentiation of mesenchymal stem cells.

Partly PEGylated polyamidoamine (PAMAM) dendrimer was used as the nanocarrier for the cytoplasmic delivery of kartogenin (KGN) to induce chondrogenic differentiation of mesenchymal stem cells (MSCs). Here, KGN was conjugated to the surface of PAMAM and the end group of polyethylene glycol (PEG) to obtain PEG-PAMAM-KGN (PPK) and KGN-PEG-PAMAM (KPP) conjugate, respectively. The effects of PPK and KPP on the in vitro chondrogenic differentiation of MSCs were evaluated. KPP induced higher expression of chondrogenic markers than PPK and free KGN. In particular, after treatment of KPP, CBF ß nuclear localization intensity was significantly increased, indicating enhanced efficacy of chondrogenesis. The fluorescein labeled PEG-PAMAM was capable to persist in the joint cavity for a prolonged time of both healthy and osteoarthritis (OA) rats. Thus, PEG-PAMAM could be a useful nanocarrier for intra-articular (IA) delivery of drug to treat OA.