Abstract
ObjectivesNano-drug delivery system is an interesting field in precise cancer treatment, but few study has reported the microenvironmental changes after such treatment. This study aimed to detect the hemodynamic and microenvironmental changes in a lung cancer xenograft model after treated with doxorubicin (DOX) encapsulated by a cyclic arginine-glycine-aspartic acid polypeptide modified poly-(lactic-co-glycolic acid) nanosystem (cRGD-PLGA@DOX) using functional magnetic resonance imaging.Materials and MethodsThirty-two tumor-bearing mice were randomly divided into four groups. Group A was treated with 0.9% saline, Group B with 4 mg/kg of doxorubicin, Group C with 2 mg/kg of cRGD-PLGA@DOX, and Group D with 4 mg/kg of cRGD-PLGA@DOX. Intravoxel incoherent motion diffusion-weighed imaging (IVIM-DWI) and R2∗ mapping were performed, and D∗, f, D, and R2∗ values were obtained before and1, 2, and 3 weeks after treatment. They were sacrificed for pathological examination after examinations.ResultsThe reconstructed cRGD-PLGA@DOX was homogeneous, well-dispersed, and spherical in shape, with an average size of 180 nm. Group D demonstrated the smallest tumor volume and highest tumor inhibition rate in 3 weeks. D value of Group B, C, and D manifested an upward trend in 3 weeks with the highest increase in Group D. D∗ values shared a similar increased trends with f values in Group A, B, and C in 3 weeks, except Group D. R2∗ value of Group A gradually increased in 3 weeks, but the trends were reversed in the treatment groups. D value was significantly negative with Ki-67 expression (r = −0.757, P < 0.001) but positive with TUNEL (r = 0.621, P < 0.001), and phosphate and tension homology deleted on chromosome ten (PTEN) staining (r = 0.57, P = 0.004). R2∗ value was closely correlated with HIF-1a (r = 0.721, P < 0.001).ConclusionThe nano-drug demonstrated an enhanced anti-tumor effect without the need of increased chemotherapeutic dosage. The tumor microenvironment such as cellular and perfusion changes during treatment can be non-invasively detected by two functional MRI including IVIM-DWI and R2∗ mapping.
Highlights
Lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths) in 2018 around the world [1]
CRGD was conjugated with polyethylene glycol (PEG)–polyetherimide–lactic acid–hydroxyacetic acid to establish the basic frame of the copolymer, doxorubicin was dissolved into the multipolymer using emulsification and solvent evaporation techniques
The DOX concentration of nanosystem needed to kill 50% of the cells (IC50) was 0.25 ± 0.06 vs 0.85 ± 0.10 μM for A549 cells, and 0.35 ± 0.05 vs 0.65 ± 9.3 μM for HeLa cells. These results indicate that Cyclic arginine-glycine-aspartic acid polypeptide (cRGD)-poly-(lactic-co-glycolic acid) (PLGA)@DOX nanoparticles satisfied the conditions for sustainably and effectively delivering drugs into tumor tissues, which would reduce its toxic side effects against the normal tissues
Summary
Lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths) in 2018 around the world [1]. The incidence and mortality of lung cancer still increased in recent 30 years. A variety of side-effects may arise due to the low targeted characteristics and high tissue toxicity, reducing the tolerance of receiving further therapy. More specific agents are needed to reduce the side effect and improve therapeutic efficacy [2]. The rapid development of nanotechnology has provided new opportunities for cancer treatment with nanomedicine. There are abundant immature blood vessels with incontinuous endothelial cells, as well as blocked lymphatic reflux, causing an enhanced permeability and retention effect for nanoparticles, which are the most commonly used mechanisms for passively targeting the tumors in nanomedicine [3]. How to effectively monitor the tumor microenvironment is an important key to reflect the therapeutic efficacy of nanomedicine during antitumor treatment
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