Mechanisms of chemotherapeutic resistance and the application of targeted nanoparticles for enhanced chemotherapy in colorectal cancer

Abstract

Colorectal cancer is considered one of the major malignancies that threaten the lives and health of people around the world. Patients with CRC are prone to post-operative local recurrence or metastasis, and some patients are advanced at the time of diagnosis and have no chance for complete surgical resection. These factors make chemotherapy an indispensable and important tool in treating CRC. However, the complex composition of the tumor microenvironment and the interaction of cellular and interstitial components constitute a tumor tissue with high cell density, dense extracellular matrix, and high osmotic pressure, inevitably preventing chemotherapeutic drugs from entering and acting on tumor cells. As a result, a novel drug carrier system with targeted nanoparticles has been applied to tumor therapy. It can change the physicochemical properties of drugs, facilitate the crossing of drug molecules through physiological and pathological tissue barriers, and increase the local concentration of nanomedicines at lesion sites. In addition to improving drug efficacy, targeted nanoparticles also reduce side effects, enabling safer and more effective disease diagnosis and treatment and improving bioavailability. In this review, we discuss the mechanisms by which infiltrating cells and other stromal components of the tumor microenvironment comprise barriers to chemotherapy in colorectal cancer. The research and application of targeted nanoparticles in CRC treatment are also classified.

Keywords: Chemotherapeutic resistance; Colorectal cancer; Targeted nanoparticles.

Fig. 1

The complex microenvironment of tumors and its role in tumor progression

Fig. 2

Classification and mechanisms of targeting nanoparticles

Fig. 3

Effects of oxaliplatin and retinoic acid loaded in cholesterol-coated PLGA NPs on tumor cells. a AFM images of Control group, NPs 1 group and NPs 2 group; fluorescence images display the internalization of NPs by CT26 cells, with monitored NPs in yellow; b Cell viability of SW-480 cells after treatment with different concentrations of OXA and PLGA NPs for 24 h; c Changes in tumor volume after treatment with different concentrations of OXA and PLGA NPs in a subcutaneous transplantation tumor model in mice; d Tumor growth curves for each group were compared with the negative control group (Reproduced with permission from [133]. © 2020 by Ana Luiza C. de S. L. Oliveira et al.)

Fig. 4

pH-sensitive hydrazone bonds attached doxorubicin to mPEG-based diblock copolymers. a Rates of Doxo release from different ratios of Leu and Glu copolymers bound to mPEG at varying pH conditions; Doxo release profile of mPEG_5kDa-(Doxo-hydGlu)₁₆; b Doxo release profile of mPEG_5kDa-b-[(Dox-hydGlu)₆-r-Leu₁₀]; c Confocal microscopy images of CT26 cells and nanodrug after 2 h incubation and a further 4 h incubation. Nanodrug delivery into the cells and cleavage of the hydrazone bond in an acidic lysosomal environment resulted in Doxo release (Reproduced with permission from [146]. © 2021 Elsevier B.V. All rights reserved)

Fig. 5

Redox-responsive NPs prepared on the basis of xylan-lipoic acid for the delivery of niclosamide for the treatment of CRC. a Schematic diagram of the preparation of Xyl-LA/Nic NPs; b stability and degradation of Xyl-LA/Nic NPs at different pH; c drug release rate of Xyl-LA/Nic NPs at different pH and in the presence or absence of GSH (Reproduced with permission from [150]. © 2020 Elsevier Ltd)

Fig. 6

Folic acid modification of PLGA NPs containing oxaliplatin enhances its targeting and antitumor capacity. a Schematic of the formulation of PLGA-PEG-FA NPs; b: analysis of cell binding and uptake of NPs under fluorescence microscopy after incubation of PLGA-PEG and PLGA-PEG-FA NPs on CT26 cells for different times; c changes in tumor volume and weight of CT26 tumor-bearing mice under different treatment groups (Reproduced with permission from [156]. © 2021 by Ana Luiza C. de S.L.Oliveira et al.)

Fig. 7

EpCAM aptamer-functionalized cationic liposome NPs loaded with miR-139-5p inhibited CRC cells. a Schematic diagram of the preparation method of NPs and ANPs; b fluorescence images of HCT116 subcutaneously transplanted tumor-bearing mice after tail vein injection of free DiR, DiR-NPs and DiR-ANPs, revealing the in vivo targeting and distribution of ANPs; c tumor volume changes after group treatment in HCT8 tumor-bearing mice (Reproduced with permission from [168]. © 2019 American Chemical Society)

Fig. 8

Anti-EGFR-coated AuNPs target 5-Fu delivery to CRC cells. a Morphological and physical characterization of AuNPs by transmission electron microscopy; b toxicity of different concentrations of NPs on HT-29 cells after treatment for 24 and 48 h, respectively (Reproduced with permission from [170]. © 2020 by Raquel B. Liszbinski et al.)

Fig. 9

The composition of PLP-NPs with pH responsive PHis, ROS responsive thioketal and paclitaxel prodrugs can be targeted to treat multi-drug resistant CRC. a Size change ratio (SCR) and Lapa release level (LRL) of PLP-NPs after 8 h incubation at different pH conditions; b the curve of Lapa released from PLP-NPs at different pH conditions and that of PTX released from PLP-NPs at different concentrations of H₂O₂; c tumor weights and PTX levels in major tissues of HCT-8 tumor-bearing mice after 21 days of treatment in different groups. d Relative tumor volumes and survival rates of mice in different treatment groups (Reproduced with permission from [174]. © 2020 by Na Chang et al.)