CN-121987824-A - Liposomes and compositions with synergistic oxygen release kinetics and synergistic photodynamic therapy system

CN121987824ACN 121987824 ACN121987824 ACN 121987824ACN-121987824-A

Abstract

The invention discloses a liposome and a composition with cooperative oxygen release kinetics and a cooperative acoustic power treatment system. The composition comprises at least two targeted oxygen-enriched phase-change liposomes with different average particle sizes, wherein each liposome comprises a carrier framework, a sound-sensitive agent, a perfluorocarbon ultrasonic response phase-change agent which is encapsulated in the interior and loads oxygen, and a targeting ligand which is modified on the surface. Liposomes of different particle sizes can be obtained by controlling the time of ultrasonication during the preparation process. Based on Laplace pressure difference principle, liposomes with different particle sizes have different phase change thresholds under the same ultrasonic condition, so that phase change and oxygen release can be sequentially carried out in time sequence under therapeutic ultrasonic irradiation, and continuous and controllable oxygen supply is realized. The composition can form a cooperative treatment system with an ultrasonic generating device, and the released oxygen is used as a substrate for the reaction of the sound-sensitive agent, so that the tumor hypoxia is effectively relieved, the generation of active oxygen is obviously enhanced, and the sound power treatment effect is improved.

Inventors

WANG ZHENYU
CHEN HAIXIANG
LI JIE
TANG LIANG
You Yaran
WANG MEILI

Assignees

重庆医科大学

Dates

Publication Date: 20260508
Application Date: 20260212

Claims (10)

1. The targeted oxygen-enriched phase-change liposome with the synergistic oxygen release kinetics is characterized by comprising a carrier framework, a sound sensitizer, an oxygen-enriched and ultrasonic response phase-change agent and a targeted ligand; The sound sensitive agent is loaded in a hydrophobic area of the carrier framework or an internal water phase wrapped by the carrier framework; The oxygen-enriched and ultrasonic response phase change agent is encapsulated in the carrier framework; The targeting ligand is modified on the outer surface of the carrier framework; and under the condition of ultrasonic irradiation, the oxygen-enriched and ultrasonic response phase change agent changes phase and releases oxygen, and simultaneously the sound sensitive agent is activated, so that the released oxygen is used as a substrate for the sound sensitive agent reaction, thereby promoting the generation of active oxygen.
2. A liposome composition having coordinated oxygen release kinetics, comprising the targeted oxygen-enriched phase-change liposome composition having coordinated oxygen release kinetics according to claim 1, wherein the liposome composition having coordinated oxygen release kinetics comprises at least two targeted oxygen-enriched phase-change liposomes having different particle sizes; And under the condition of ultrasonic irradiation, the targeted oxygen-enriched phase-change liposome sequentially changes phase according to the particle size sequence, so that the total oxygen release time is longer than the oxygen release time of any liposome with single particle size.
3. The liposome composition with synergistic oxygen release kinetics as claimed in claim 2, wherein the at least two liposomes of different average particle sizes comprise: A first particle size fraction configured for oxygen release at an initial stage of ultrasound triggering; a second particle size fraction configured to undergo a delay period following ultrasound triggering, followed by oxygen release.
4. The liposome composition with synergistic oxygen release kinetics as claimed in claim 2, wherein the targeted oxygen-enriched phase change liposomes of different particle size are mixed in equiconcentration.
5. The liposome composition with synergistic oxygen release kinetics as claimed in claim 2, wherein the targeted oxygen-enriched phase change liposomes of different particle sizes are obtained by controlling the sonication time during liposome preparation, wherein shorter sonication time corresponds to larger particle size and longer sonication time corresponds to smaller particle size.
6. The liposome composition with coordinated oxygen release kinetics of claim 2, wherein the targeted oxygen-enriched phase change liposome comprises a staged or sustained oxygen release process in a manner that sequentially changes phase in order of particle size.
7. A method for preparing a liposome composition having synergistic oxygen release kinetics, comprising the steps of: s1, mixing phospholipid, cholesterol, a sound-sensitive agent and a targeting ligand derivative to form a lipid film, and hydrating to obtain a liposome primary suspension; S2, carrying out ultrasonic treatment on the liposome primary suspension under ice bath condition, and adding perfluorocarbon in the treatment process to ensure that the perfluorocarbon is encapsulated in the liposome, wherein liposome groups with at least two different average particle diameters are prepared by adopting different ultrasonic crushing times; S3, carrying out oxygen enrichment treatment on the liposome encapsulated with the perfluorocarbon to enable oxygen to be loaded in the perfluorocarbon; wherein, the at least two liposomes with different average particle sizes have different phase transition threshold values and oxygen release kinetics due to internal Laplace pressure difference under the same ultrasonic condition.
8. The method of claim 7, wherein the mass ratio of phospholipid, cholesterol, sonosensitizer to targeting ligand derivative is (15-25): 8-12): 1-3): 0.5-1.5.
9. A synergistic photodynamic therapy system for the treatment of tumours using a liposomal composition having synergistic oxygen release kinetics as claimed in any one of claims 2 to 6, the system comprising: (a) A liposome composition having synergistic oxygen release kinetics, comprising: at least two targeted oxygen-enriched phase change liposomes according to any one of claims 1 to 5 of different particle sizes; (b) An ultrasound generating device for applying therapeutic ultrasound irradiation to the target site to trigger the composition to effect oxygen release; During treatment, the nano carrier is combined and enriched at a tumor part through the targeting ligand, then the ultrasonic generating device is used for irradiation, and liposomes with different particle sizes are triggered to sequentially generate phase change and release oxygen, so that oxygen supply is realized, and the tumor hypoxia is relieved and active oxygen generated by the sound sensitizer is synergistically enhanced.
10. The collaborative photodynamic therapy system of claim 9 wherein the ultrasound generating means is configured to output ultrasound of adjustable intensity or adjustable frequency and the intensity or frequency adjustment of the ultrasound is programmed to match the onset of phase change oxygen release of the liposomes of the at least two different particle sizes.

Description

Liposomes and compositions with synergistic oxygen release kinetics and synergistic photodynamic therapy system Technical Field The invention relates to the technical field of biomedical nano-and micro-fluidic, in particular to a liposome and a composition with synergistic oxygen release kinetics and a synergistic acoustic power treatment system. Background Sonodynamic therapy (Sonodynamic Therapy, SDT) is a non-invasive therapeutic strategy that utilizes ultrasound to activate sonosensitizers to generate reactive oxygen species (Reactive Oxygen Species, ROS) to selectively kill tumor cells. Ultrasound has good tissue penetration, making SDT a great potential in the treatment of deep solid tumors. However, its clinical efficacy is still limited by the following key bottlenecks from the exterior to the interior: 1. Limiting ROS production in tumor hypoxia microenvironment The generation of ROS, especially singlet oxygen generated by a type II reaction, is highly dependent on oxygen as a reaction substrate. The ubiquitous abnormal vascular structure and vigorous metabolic consumption of solid tumors lead to the microenvironment in a continuous hypoxia state, so that the sound sensitizer reacts with insufficient substrate, and the therapeutic efficacy of SDT is severely restricted. 2. The existing oxygen-carrying nano-carrier has single oxygen release kinetics and is not sustainable In order to alleviate hypoxia, perfluorocarbons (such as perfluorohexane and perfluoropentane) with high oxygen dissolution capacity are often encapsulated in nano-carriers such as liposome to realize oxygen transportation. However, such carriers often employ a single particle size design, resulting in internal perfluorocarbon droplets having similar phase transition thresholds at given ultrasonic conditions, and oxygen release behavior often exhibiting "explosive" unimodal curves. Oxygen is difficult to follow after rapid release in the early stage of treatment, and cannot be matched with continuous sound-sensitive reaction, so that the curative effect is reduced again due to hypoxia in the later stage of treatment. 3. Carrier particle size uniformity is a physical source that leads to uncontrollable oxygen release The oxygen release kinetics of the nanocarriers are regulated by the internal Laplace pressure, which is directly related to the carrier particle size. The existing carrier system with uniform particle size can not realize time sequence differential regulation and control of oxygen release behavior, so that oxygen supply and ROS generation are disjointed in time, the continuous and stable oxygen supply capability is lacked, and the whole ultrasonic treatment period is difficult to cover. 4. The internal cooperative mechanism of the multifunctional nano-carrier is insufficient Although research has been carried out on integrating the sound-sensitive agent, perfluorocarbon and targeting ligand into the same nano-carrier, each functional module stays at the physical coexistence level, and the precise coordination of oxygen release and sound-sensitive agent activation in time and space cannot be realized through the active design of the physical properties of the carrier. How to realize the dynamic matching of oxygen release and sound-sensitive reaction through particle size regulation and control is still an insufficiently solved technical problem. Disclosure of Invention In view of the above, the present invention aims to provide a liposome and a composition with synergistic oxygen release kinetics and a synergistic sonodynamic therapeutic system, wherein the method uses Laplace pressure difference to enable liposomes with different particle sizes to sequentially release oxygen in a phase-change manner under the same ultrasound by means of multi-particle-size liposome combination and ultrasonic control of particle sizes, so as to solve the technical problem of insufficient ROS generation caused by uncontrollable tumor hypoxia and oxygen supply in sonodynamic therapy. In order to achieve the above purpose, the present invention provides the following technical solutions: the invention provides a targeted oxygen-enriched phase-change liposome with synergistic oxygen release kinetics, which comprises a carrier framework, a sound sensitizer, an oxygen-enriched and ultrasonic response phase-change agent and a targeted ligand; The sound sensitive agent is loaded in a hydrophobic area of the carrier framework or an internal water phase wrapped by the carrier framework; The oxygen-enriched and ultrasonic response phase change agent is encapsulated in the carrier framework; The targeting ligand is modified on the outer surface of the carrier framework; and under the condition of ultrasonic irradiation, the oxygen-enriched and ultrasonic response phase change agent changes phase and releases oxygen, and simultaneously the sound sensitive agent is activated, so that the released oxygen is used as a substrate for the sound sensitive