Synthesis of Paclitaxel Derivatives for Remote Loading into Liposomes and Improved Therapeutic Effect.

A series of novel paclitaxel derivatives modified by boronic acid according to the characteristics of the interaction between RB(OH)2 and different strapping agents of intraliposomal aqueous phase were designed and synthesized, which were then used to develop remote poorly water-soluble drugs loading into liposomes. Meanwhile, we screened nineteen paclitaxel boronic acid derivatives for their cytotoxic activities against three cancer cell lines (A549, HCT-116 and 4T1) and one normal cell line (LO2), and performed liposome formulation screening of active compounds. Among all the compounds, the liposome of 4d, with excellent drug-encapsulated efficiency (>95% for drug-to-lipid ratio of 0.1 w/w), was the most stable. Furthermore, the liposomes of compound 4d (8 mg/kg, 4 times) and higher dose of compound 4d (24 mg/kg, 4 times) showed better therapeutic effect than paclitaxel (8 mg/kg, 4 times) in the 4T1 tumor model in vivo, and the rates of tumor inhibition were 74.3%, 81.9% and 58.5%, respectively. This study provided a reasonable design strategy for the insoluble drugs to improve their drug loading into liposomes and anti-tumor effect in vivo.

Single-ligand dual-targeting irinotecan liposomes: Control of targeting ligand display by pH-responsive PEG-shedding strategy to enhance tumor-specific therapy and attenuate toxicity.

Along with the malignant proliferation of tumor requiring nutrients, the expression of L-type amino acid transporter 1(LAT1) and amino acid transporter B0,+ (ATB0,+) in cancer cells is up-regulated that can be used as new targets for active targeting of tumor. However, since normal cells also express amino acid transporters in small amounts, traditional ligand-exposure drug delivery systems are potentially toxic to the body. Therefore, we designed a smart-response drug delivery system that buries the tyrosine ligand in PEG hydration layer at normal tissues and exposes the ligand by cleaving the pH-sensitive bond of PEG at the tumor site. Irinotecan (CPT-11) is actively loaded into the inner aqueous phase of liposomes via a copper ion gradient mechanism which has high encapsulation efficiency and stable drug release profile. Smart-response liposomes showed the strongest cytotoxicity and the maximum cellular uptake in vitro, the largest amount of tumor site accumulation and the best antitumor effect in vivo, compared with non-targeted liposomes and non-sensitive liposomes. It is worth noting that smart-response liposomes not only achieved enhanced antitumor effect but also attenuated side effects compared to ligand-exposure liposomes. This provides a smart responsive drug delivery system for precise treatment and shows a good application prospect.

Tyrosine modified irinotecan-loaded liposomes capable of simultaneously targeting LAT1 and ATB0,+ for efficient tumor therapy.

As the demand for nutrients in malignant proliferation of tumors increases, the L-type amino acid transporter 1(LAT1) and amino acid transporter B0,+ (ATB0,+) of tumor cells are more highly expressed than normal cells which can be used as new targets for active targeting of cancer. However, drug delivery systems often require multi-target design to achieve simultaneous targeting of different receptors or transporters due to the heterogeneity of the tumor. Here we utilized triethylamine-sucrose octasulfate gradient to actively encapsulate irinotecan into the introliposomal aqueous phase. Targeted ability was achieved through inserting different amino acids modified polyethylene glycol monostearate into the liposomes, and found that glutamate-liposomes can be targeted to LAT1, lysine-liposomes can be targeted to ATB0,+, and inspiringly, tyrosine-liposomes can be simultaneously targeted to LAT1 and ATB0,+. The tyrosine-modified liposomes showed the highest cellular uptake in BxPC-3 and MCF-7 cells which were highly expressed both LAT1 and ATB0,+. Moreover, we validated their targeting capabilities and elucidated the transport mechanism of LAT1 and ATB0,+-mediated endocytosis. The tumor inhibition rate of tyrosine-modified liposomes greatly increased from 39% to 87% compared with commercially available liposomes loaded CPT-11(Onivyde®). Overall, it showed a good application prospect for efficient tumor therapy and industrial production.