Novel, nano-sized, liposome-encapsulated polyamidoamine dendrimer derivatives facilitate tumour targeting by overcoming the polyethylene glycol dilemma and integrin saturation obstacle.

Drug delivery systems (DDSs) commonly employ arginine-glycine-aspartic acid (RGD) peptides with polyethylene glycol (PEG)-dependent enhanced permeability and retention (EPR) effect to optimise tumour-targeting. However, the PEG dilemma and integrin saturation obstacle are major challenges. To address these issues, we constructed a novel, nano-sized DDS by encapsulating doxorubicin (DOX)-loaded folic acid derivatives of polyamidoamine dendrimer (PAMAM G5.0) in cyclic RGD-tyrosine-lysine pentapeptide (c[RGDyK])-modified liposomes (RGD-SL[FND/DOX]), prepared using thin-film hydration, film-dispersion and hydration-sonication. The liposomes were PEGylated, sterically stabilised and pH-sensitive. In vitro, RGD-SL[FND/DOX] showed pH-sensitive holistic FND/DOX release, and pH-dependent uptake and cytotoxicity in human cancer KB cells. At pH 7.4, RGD-SL[FND/DOX] demonstrated greater cellular uptake and cytotoxicity than relevant control formulations (except FND/DOX) did, although this advantage disappeared at pH 6.5. In vivo, RGD-SL[FND/DOX] inhibited S180 sarcoma xenografted tumour growth in Kunming mice more effectively than FND/DOX did. These findings demonstrate the feasibility of constructing double-stage tumour-targeting nano-sized DDSs such as RGD-SL[FND/DOX]. c[RGDyK] and the EPR effect, facilitated by the particle size (about 110 nm) and PEGylation, helped to target the DDS to the tumour tissue, while the subsequent pH-dependent release of FND/DOX and folic acid-mediated endocytosis specifically targeted the tumour cells, thereby overcoming the PEG dilemma and integrin saturation obstacle.

[Pharmacodynamics of liposomes modified with different chain length of sialic acid derivatives].

A large number of experimental and clinical data indicates that tumor-associated macrophages(TAMs) were involved in the whole process of tumor growth, invasion and metastasis. Like macrophages in other tissues, TAMs originate from blood monocytes, which are recruited to the tumor tissues by cytokines and then differentiated into TAMs. It is interesting that the monocytes overexpress siglec receptor in their surface, which has a high binding specificity to sialic acid(SA). From this point of view, we hypothesize that if SA was used as a ligand in the surfaces of drug delivery systems, SA would enhance the targeting efficiency to monocytes, and thus to achieve a higher specificity to TAMs. In our previous study, an SA derivative of SA-octadecylamine(SA-18) was synthesized and was found to enhance cytotoxicity on TAMs in vitro. The chain length is a critical factor for SA efficiency in liposomes and it has a significant influence on the TAM targeting effects of the carriers. So in this study, four kinds of different chain length of SA fatty amine derivatives were synthesized, including SA-18, SA-hexadecylamine(SA-16), SA-tetradecylamine(SA-14) and SA-dodecylamine(SA-12), and were modified on the surfaces of blank liposomes(BLK-Sn L, n = 18, 16, 14, 12) and pixantrone maleate-loaded liposomes(Pix-Sn L, n = 18, 16, 14, 12). TAM targeting effects of these SA derivatives were evaluated by acute toxicity and antitumor efficacy in vivo. The results of acute toxicity experiments showed that the toxicities of the SA derivatives deceased gradually with the reduction in the length of lipophilic chain. The in vivo antitumor efficacies of SA-modified blank liposomes showed that these blank formulations had no effect on the tumor inhibition except BLK-S14L(61.4% ± 18.8%), and BLK-S16 L even promoted the tumor growth(-31.7% ± 13.1%, the 18 th day). The in vivo antitumor efficacies of SA-modified Pix liposomes showed that the tumor inhibition effects were Pix-S18L(97.4% ± 2.1%) > Pix-S14L(73.1% ±21.1%) > Pix-S12L(53.9% ± 17.8%) > Pix-S16L(32.9%). Because of the relatively strong binding ability of SA-18, it was hard to fall off from the liposomes in the transport process, leading to a good TAM targeting ability and less toxicity to the normal tissues. Meanwhile, 50% of the mice in Pix-S18 L group showed "tumor shedding" and "wound healing" phenomena without recurrence in two months following the treatment. Therefore, SA-18 is the most potential TAM targeting material among these SA fatty amine derivatives.

Clinical research on zishengukang pill (see text) used to treat delayed union of fracture.

OBJECTIVE: To observe the curative effect of Zishengukang Pill (see text) on delayed union of fracture. METHODS: Sixty-four patients with delayed union of fracture were randomly divided into a control group of 32 cases treated with Western medicine and a treatment group of 32 cases treated with Western medicine and Zishengukang Pill. After 3 courses of treatment with 30 days as a course, the curative effects in the two groups were evaluated and their clinical symptoms, union rate and union time of fracture were compared. RESULTS: The treatment resulted in cure in 25 cases, improvement in 6 cases and ineffectiveness in 1 case with the effective rate at 96.8% in the treatment group, higher than 81.3% in the control group (P < 0.05). The union rate of fracture in the treatment group was higher than that in the control group (34.3% vs. 12.5%, P < 0.05). The union time of fracture in the treatment group was shorter than that in the control group ((4.0 +/- 1.7) months vs. (5.0 +/- 1.4) months, P < 0.05). CONCLUSION: Zishengukang Pill with obvious curative effect in the treatment of delayed union of fracture is worth popularizing.

Clinical research on treatment of vertebroarterial type of cervical spondylosis with 5-step manipulation and traction.

OBJECTIVE: To observe the therapeutic effect of 5-step manipulation and traction of cervical vertebrae on vertebroarterial type of cervical spondylosis and probe its mechanism. METHODS: The 120 patients were randomly divided into a treatment group (manipulation group) and a control group (traction group) with 60 cases in each. The curative effects in the two groups were evaluated after treatment. RESULTS: The curative rate and the total effective rate is 26.7% and 93.4% respectively in the treatment group, and 13.3% and 86.7% respectively in the control group, with statistical significance in the total effective rate of the two groups (P < 0.05). CONCLUSION: Manipulation and traction of cervical vertebrae can effectively improve the clinical symptoms of vetebroarterical type of cervical spondylosis with a good therapeutic effect.