Targeted (brain targeted and tumor targeted) drug delivery and evaluation techniques

1.1 Brain targeted drug delivery and evaluation techniques

It has a molecular design technology platform for targeting polypeptides, and has obtained a variety of brain targeting molecules mediated by the blood brain barrier (BBB), such as acetylcholine receptor, low-density lipoprotein receptor, dopamine receptor, etc. with independent intellectual property rights, as well as multi-level targeting polypeptides, multifunctional targeting polypeptides and whole process targeting polypeptides for brain tumors. On this basis, functional polymer materials modified by target molecules have been developed, and a series of brain targeted and brain tumor targeted nano drug delivery systems have been constructed, which can be used for efficient delivery of various drugs in the brain or brain tumor. At the same time, it has an advanced evaluation technology platform for brain targeted and brain tumor targeted drug delivery, including: evaluation of interaction between target molecules and receptors on BBB and brain tumor related cells, characterization of targeted drug delivery system, investigation of uptake efficiency and mechanism of brain capillary endothelial cells and brain tumor related cells, evaluation of targeting efficiency of BBB model and brain tumor model in vitro, evaluation of pharmacokinetics and tissue distribution in vivo, pharmacodynamics evaluation of model animals, etc. 

Example: CDX mediated brain targeted micelle delivery across BBB

By utilizing the high affinity between the Loop II region of snake neurotoxin and nicotinic acetylcholine receptors (nAChRs) on BBB, a peptide CDX with cross BBB function was screened using computer-aided design and solid-phase peptide synthesis technology. After modification on the surface of PEG-PLA polymer micelle delivery system, it can promote the brain transport of insoluble drugs and increase drug concentration in the brain, Significantly improved the therapeutic effect of paclitaxel (PTX) on glioma (Figure 4).

Figure 4. Characterization and efficacy of CDX and its modified PTX loaded polymer micelle delivery system

Related patents:

1. Lu Weiyue, Zhang Zhixin, Xie Cao, Wei Xiaoli, Li Jin, Meng Qinggang; A brain targeted polymer micelle delivery system mediated by p-hydroxybenzoic acid (2013100500845, authorized on February 8, 2017), transferred in September 2019 with a transfer amount of 1 million yuan

2. Lu Weiyue, Meng Qinggang, Li Jin, Gu Bing, Yu Mei; Brain targeted drug delivery system mediated by benzamide analogues (2010101119607, authorized on February 27, 2013), transferred in September 2019 with a transfer amount of 1 million yuan

3. Lu Weiyue, Zhang Zhixin, Xie Cao, Wei Xiaoli, Li Jin, Meng Qinggang; A Myristic Acid Mediated Brain Targeted Polymer Micelle Delivery System and Its Preparation Method and Application (2013101895851, Authorization Date December 1, 2017)

4. Lu Weiyue, Zhaqiya, Xie Cao, Hu Xuefeng; A multifunctional targeted molecule and its use (2016100776577, authorized on January 2, 2020)

5. Lu Weiyue, Zhan Changyou, Xie Cao, Meng Qinggang, Gu Bing; An Active Targeted Drug Delivery System Mediated by Acetylcholine Receptors Across the Blood Brain Barrier (201010110665X; Authorization Date May 29, 2013)

6. Lu Weiyue, Ran Danni, Mao Jiani, Xie Cao, Zhan Changyou; Population sensing peptides and their use in the preparation of tumor targeted diagnosis and treatment delivery systems (2017103475504, authorization date November 2, 2021)

7. Lu Weiyue, Meng Qinggang, Gu Bing, Yu Mei, Li Jin, Xie Cao; A Brain Targeted Drug Delivery System (2009100519703, Authorization Date February 1, 2012)

8. Lu Weiyue, Zhou Jianfen, Chai Zhilan, Xie Cao; A Whole Process Targeted Molecule and Its Application in Constructing Drug Delivery Systems (2020100781533, App. February 3, 2020; PCT/CN2021/072910, App. January 20, 2021)

9. Lu Weiyue, Shen Jie, Xie Cao, Wei Xiaoli, Zhan Changyou, Li Chong; A pH sensitive brain tumor two-stage targeted nanodrug delivery system, preparation method and application (2012103204177, authorized on December 9, 2015)

1.2、Tumor Targeted Drug Delivery and Evaluation Techniques

We have a targeted peptide molecular design technology platform and have constructed a series of tumor targeted nano drug delivery systems that can be used for efficient tumor delivery of various drugs by obtaining various functional polymer materials with independent intellectual property rights, such as folate receptors, integrins, p32 receptors, and their modifications. At the same time, there is an advanced evaluation technology platform for tumor targeted drug delivery, including: evaluation of receptor interactions between target molecules and tumor related cells, characterization of targeted nanodrug delivery systems, investigation of tumor related cell uptake efficiency and mechanism, evaluation of in vitro tumor tissue targeting efficiency (tumor balls), evaluation of in vivo pharmacokinetics and tissue distribution, and pharmacodynamic evaluation of model animals.

1.2.1、Intravenous administration

Targeted drug delivery through intravenous pathways can achieve precise delivery of solid tumors and tumor metastases, achieving efficient and low toxicity tumor treatment effects.

Example: RGD mediated tumor targeting lipid disc delivery

RGD modified lipid nanodiscs were constructed by regulating the ratio of PEG-DSPE and loaded with melittin (RGD-ND/millitin). RGD-ND can not only protect melittin from hydrolysis by proteases in the body, but also reduce its hemolytic toxicity to red blood cells. By utilizing the high affinity between RGD and integrin, RGD-ND/melitin can actively target tumor sites and internalize into cells, releasing melitin, damaging mitochondrial membranes, promoting tumor cell apoptosis, and exerting good targeted anti-tumor effects (Figure 5). 

Figure 5. Characterization and efficacy of cRGD modified melittin loaded lipid discs

Related patents:

1. Lu Weiyue, Han Xue, Liu Jing, Liu Min, Xie Cao; A folate mediated targeted polymer micelle (2008102010750, authorized on July 22, 2011)

2. Lu Weiyue, Xu Wen, Han Huilan, Liu Min, Xie Cao, Pan Jun, Zhong Gaoren, Chen Shaoliang, Yao Ming; Folic acid polyglycol compounds and their drug complexes (031295622, authorized on September 14, 2005)

3. Lu Weiyue, Li Jinyang, Xie Cao; Polypeptide mn targeting integrin and its application in the preparation of tumor targeting drugs (2018114334909; application date November 28, 2018)

4. Lu Weiyue, Mao Jiani, Ran Danni, Xie Cao; AE peptides and their use in the preparation of tumor targeted diagnosis and treatment delivery systems (2017101447124; application date March 13, 2017)

5. Lu Weiyue, Pan Hong, Yao Ming, Zhong Gaoren, Zhou Guangxing; A tumor necrosis targeting monoclonal antibody targeted liposome delivery system and its application (2006100272251, application date June 1, 2006)

6. Lu Weiyue, Wang Chenyu, Feng Linglin, Yang Xiangkun, Wang Fei; A targeted liposome delivery system for multidrug resistant tumors (2012101699372, application date: May 28, 2012)

7. Lu Weiyue, Yan Zhiqiang, Gu Bing, Meng Qinggang, Zhan Changyou, Xie Cao; A Liposome Carrier System for Targeted Drug Delivery in Tumors (2010101743446, Application Date May 14, 2010)

1.2.2、Subcutaneous injection route administration

By utilizing the characteristic that large molecules or nanoparticles can selectively enter the lymphatic vessels after being administered through tissue gaps, targeted nanomedicines can be administered subcutaneously to achieve precise medication for lymphatic metastatic tumors.

Example: LyP-1 Mediated Lymphatic Metastasis Tumor Targeted Liposome Delivery

To address the issue of tumor metastasis through the lymphatic system, LyP-1 peptides that can target newly formed lymphatic vessels and tumor cells with high expression of p32 receptors were introduced into the liposome delivery system to construct LyP-1 liposomes (LyP-1-PEG-LS), endowing them with dual targeting functions towards tumor cells and related lymphatic vessels. The results show (Figure 6) that LyP-1-PEG-LS has a good targeting effect on lymph metastasis of melanoma cells (MDA-MB-435), and the uptake of LyP-1-PEG-LS/FAM by tumor cells is significantly higher; The pharmacokinetics of metastatic popliteal lymph nodes after subcutaneous injection showed that the AUC of DiR in the LyP-1-PEG-LS group was 1.39 times higher than that in the PEG-LS group; After loading chemotherapy drug DOX, the tumor inhibitory effect of lymphatic metastasis was characterized by the weight ratio of left and right lymph nodes (popliteal lymph nodes (P) and iliac lymph nodes (Il)), indicating that LyP-1-PEG-liposomes/DOX has significant anti lymphatic metastasis tumor efficacy.

图6. LyP-1脂质体的体内外靶向性和载药脂质体药效

Related patents:

1. Pan Hong, Pan Jun, Lu Weiyue, Zhang Jing, Zhang Lei, Liu Min, Zhong Gaoren; A Method for Promoting Liposome Lymphatic Absorption and Reducing Normal Lymph Node Accumulation (2005100240468, Authorization Date October 15, 2008)

2. Lu Weiyue, Yan Zhiqiang, Wang Fei, Gu Bing, Meng Qinggang, Zhan Changyou, Xie Cao; An Active Targeting Liposome Carrier System for in situ Tumor and Lymphatic Metastatic Tumor (2010101923985, App. Date June 3, 2010)

1.2.3. Adjacent injection route for drug administration

In clinical practice, some tumors require medication to reduce the tumor volume before surgical resection in order to meet the clinical surgical criteria. Injecting tumor targeted nanomedicine into this type of tumor can achieve better preoperative drug efficacy and better meet clinical needs.

Example: Folic acid mediated tumor targeting phospholipid coated paclitaxel nanocrystal delivery system

A folate modified phospholipid coated paclitaxel nanocrystal delivery system (PTX) was designed to meet the clinical needs of preoperative chemotherapy for gastric cancer to reduce tumor volume and infiltration range NC@FA ）. The drug delivery system is administered through local injection within and around gastric cancer lesions, and through folate mediated targeted drug delivery to tumors and the high drug loading advantage of nanocrystals, it ensures that the tumor volume can still be significantly reduced even in small doses (limited injection volume for clinical gastric cancer lesions) (Figure 7).

Figure 7. Characterization and efficacy of folate modified phospholipid coated paclitaxel nanocrystal delivery system

Related patents:

Lu Weiyue, Liu Yu, Wang Jun, Huang Guangjian; A tumor targeted nanocrystal delivery system (2019107923212, application date August 27, 2019)