Macromolecular prodrugs obtained by covalently conjugating small molecular drugs with polymeric carriers were proven to accomplish controlled and sustained release of the therapeutic agents in vitro and in vivo. Polyethylene glycol (PEG) has been extensively used due to its low toxicity, low immunogenicity and high biocompatibility. However, for linear PEG macromolecules, the number of available hydroxyl groups for drug coupling does not change with the length of polymeric chain, which limits the application of PEG for drug conjugation purposes. To increase the drug loading and prolong the retention time of 5-fluorouracil (5-Fu), a macromolecular prodrug of 5-Fu, 5-fluorouracil-1 acid-PAE derivative (5-FA-PAE) was synthesized and tested for the antitumor activity in vivo.PEG with a molecular weight of 38 kDa was selected to synthesize the multi-hydroxyl polyethylene glycol derivative (PAE) through an addition reaction. 5-fluorouracil-1 acetic acid (5-FA), a 5-Fu derivative was coupled with PEG derivatives via ester bond to form a macromolecular prodrug, 5-FA-PAE. The in vitro drug release, pharmacokinetics, in vivo distribution and antitumor effect of the prodrug were investigated, respectively.The PEG-based prodrug obtained in this study possessed an exceedingly high 5-FA loading efficiency of 10.58%, much higher than the maximum drug loading efficiency of unmodified PEG with the same molecular weight, which was 0.98% theoretically. Furthermore, 5-FA-PAE exhibited suitable sustained release in tumors.This study provides a new approach for the development of the delivery to tumors of anticancer agents with PEG derivatives.
Abstract Insufficient apoptosis of inflammatory macrophages and osteoclasts (OCs) in rheumatoid arthritis (RA) joints contributes toward the persistent progression of joint inflammation and destruction. Here, we deliver celastrol (CEL) to selectively induce apoptosis of OCs and macrophages in arthritic joints, with enzyme-responsive nanoparticles (termed PRNPs) composed of RGD modified nanoparticles (termed RNPs) covered with cleavable PEG chains. CEL-loaded PRNPs (CEL-PRNPs) dually target OCs and inflammatory macrophages derived from patients with RA via an RGD-αvβ3 integrin interaction after PEG cleavage by matrix metalloprotease 9, leading to increased apoptosis of these cells. In an adjuvant-induced arthritis rat model, PRNPs have an arthritic joint-specific distribution and CEL-PRNPs efficiently reduce the number of OCs and inflammatory macrophages within these joints. Additionally, rats with advanced arthritis go into inflammatory remission with bone erosion repair and negligible side effects after CEL-PRNPs treatment. These findings indicate potential for targeting chemotherapy-induced apoptosis in the treatment of advanced inflammatory arthritis.
AIM:To study the anticarcinogenic effect and acute toxicity of liver targeting mitoxantrone nanospheres.METHODS:The anticarcinogenic effect of mitoxan-trone polybutylcyanoacrylate nanoparticles (DHAQ-PBCA-NP) was investigated by using heterotopic and orthotopic transplantation models of human hepatocellular carcinoma (HCC) in nude mice and was compared with mitoxantrone (DHAQ) and doxorubicin (ADR).The acute toxicity of DHAQ-PBCA-NP lyophilized injection in mice was also studied.RESULTS:The tumor inhibition rates of ADR, DHAQ, DHAQ-PBCA-NP to orthotopically transplanted HCC were 60.07%, 67.49% and 99.44%, respectively, but regard to heterotopically transplanted HCC, these were 80.03%, 86.18% and 92.90%, which were concordant with the results acquired by mitosis counting and proliferating cell nuclear antigen (PCNA). After iv administration to mice with DHAQ-PBCA-NP, the LD(50) was 16.9mg/kg ± 3.9mg/kg, no obvious local irritation was observed and there was no significant damage to the structure of liver cells, and that of the heart, spleen and kidneys.CONCLUSION:The effect of DHAQ-PBCA-NP was significantly higher than that of DHAQ and ADR in the anti orthotopically transplanted HCC and the acute toxicity was relatively low.
AIM:To prepare valaciclovir polybutylcyan_oacrylate nanoparticles (VACV-PBCA-NP) with liver targeting and hepatocyte permeable charateristics.METHODS: Emulsion polymerization method was employed to prepare VACV-PBCA-NP.The formula and preparation conditions were optimized by using the uniform design. The organ distribution of the intravenously injected VACV-PBCA-NP and VACV in animal was determined using HPLC. The hepatocytes permeability of VACV-PBCA-NP was demonstrated by cell uptake experiment in vitro.RESULTS:The drug loading and the drug embedding ratio of VACV-PBCA-NP were 11.20% and 84.85% respectively, with an average diameter of 104.77nm ±11.78nm. The releasing characteristics in vitro fitted the two-phase kinetics. 74.49% of the drug was found to localize in the liver 15min after the administration of VACV-PBCA-NP in the mice. Compared with VACV, VACV-PBCA-NP showed distinct characteristic of sustainedrelease in vivo and the drug entering hepatocytes were also greatly increased.CONCLUSION:VACV-PBCA-NP has the char_acteristic of liver targeting and can increase the permeability of VACV to hepatocytes.
Biological membranes often play important functional roles in biomimetic drug delivery systems. We discover that the circulation time and targeting capability of biological membrane coated nanovehicles can be significantly improved by reducing cholesterol level in the coating membrane. A proof-of-concept system using cholesterol-reduced and PD-1-overexpressed T cell membrane to deliver a photothermal agent and a STING agonist is thus fabricated. Comparing with normal membrane, this engineered membrane increases tumor accumulation by ~2-fold. In a melanoma model in male mice, tumors are eliminated with no recurrence in >80% mice after intravenous injection and laser irradiation; while in a colon cancer model in male mice, ~40% mice are cured without laser irradiation. Data suggest that the engineered membranes escape immune surveillance to avoid blood clearance while keeping functional surface molecules exposed. In summary, we develop a simple, effective, safe and widely-applicable biological membrane modification strategy. This "subtractive" strategy displays some advantages and is worth further development.
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