A Multifunctional Lipid Incorporating Active Targeting and Dual-Control Release Capabilities for Precision Drug Delivery

Abstract

Active targeting and precise control of drug release based on nanoparticle therapies are urgently required to precisely treat cancer. We have custom-synthesized a functional lipid (termed Fa-ONB) by introducing a folic acid-targeting group into an o-nitro-benzyl ester lipid. As designed, the liposomes formed by Fa-ONB combine active targeting and dual trigger release capabilities, which help to improve drug efficacy and reduce the toxicity of traditional liposomes. We first verified that both pH-induced hydrolysis and light treatment were able to cleave the Fa-ONB lipid. We then prepared a series of liposomes (termed FOBD liposomes) by compounding the Fa-ONB lipid with DOPC at different ratios. After encapsulation of doxorubicin (DOX), we found that the particle size of DOX-loaded FOBD liposomes (DOX/FOBD) first increased (290 to 700 nm) and then decreased again (to 400 nm) under continuous UV irradiation (120 min). The photocatalytic release efficiency under different pH conditions was investigated by dialysis experiments, and it was found that the release efficiency in an acidic environment was significantly increased relative to neutral pH. This pH-triggered release response helps distinguish pathological tissues such as lysosomal compartments and tumors. The light-induced formation of a DOX precipitate increases in efficiency with increasing UV exposure time as well as with increasing environmental acidity or alkalinity. In addition, confocal imaging and flow cytometry showed that the ability of FOBD lipids to actively target HeLa cells increased with increasing Fa-ONB lipid content. Real-time in vivo fluorescence small animal experiments proved targeting to tumors and pH-and photoinduced release properties. Furthermore, therapeutic experiments using a mouse model found a significant tumor inhibitory effect for DOX/FOBD55 liposomes with UV irradiation, clearly demonstrating the benefit of light treatment: the tumor size of the control (PBS) group was 7.59 times that of the light treatment group. Therefore, this research demonstrates the benefits of combining triggerable release functions and effective active tumor targeting in one small lipid molecule for precise cancer treatment.

Recent Advancements in Stimuli Responsive Drug Delivery Platforms for Active and Passive Cancer Targeting

“…pH-responsive lipid-based systems can be engineered with both pH and light trigger release capabilities of the loaded anticancer drugs. This technology has become a very popular approach and recently one of the studies demonstrated that DOX/FOBD55 resulted in a significant anticancer effect using a mouse model compared to the control group [161]. Over the past several decades, pH-responsive drug delivery systems have contributed to the momentous progress regarding tumor targeting and cancer therapy, but still there is a need to develop the understanding of in vitro and in vivo acceptability and behavior, optimum composition and excipients and more importantly the in vivo clinical applications.…”

Recent Trends in Applying Ortho-Nitrobenzyl Esters for the Design of Photo-Responsive Polymer Networks

“…A first adoption of o-nitrobenzyl alcohol moieties as photolabile groups in polymer chemistry is reported in the work of Petropoulos in 1977 [36]. They were initially introduced in polymer networks for the fabrication of UV-sensitive photoresists and progressively adopted as photocleavable crosslinkers for light-triggered drug delivery or as photocleavable junctions in copolymer blocks [37][38][39][40][41][42][43][44][45][46][47][48][49]. Advancing from bulk properties, the photo-sensitive nature of o-NB groups was used to opto-regulate the surface chemistry [50][51][52].…”

“…In order to enhance the stimuli-responsiveness and the level of selectivity in changing polymer properties, some researches have focused on the design of polymer networks with multi-responsive properties [44,107,108].…”

A dual-functional nanovehicle with fluorescent tracking and its targeted killing effects on hepatocellular carcinoma cells

“…However, the poor photostability of organic dye and the toxicity of QDs limit their application in clinic. 23 Gold nanoclusters (Au NCs) of $2 nm in size are attractive in tumour imaging due to the strong luminescence, stable photostability, low toxicity and surface functionalities. 24,25 It has been proved that the hydrodynamic size (<3 nm) is relatively small which could be effectively eliminated through renal.…”