Cancer nanomedicine in preoperative therapeutics: Nanotechnology-enabled neoadjuvant chemotherapy, radiotherapy, immunotherapy, and phototherapy

Abstract

Surgical resection remains a mainstay in the treatment of malignant solid tumors. However, the use of neoadjuvant treatments, including chemotherapy, radiotherapy, phototherapy, and immunotherapy, either alone or in combination, as a preoperative intervention regimen, have attracted increasing attention in the last decade. Early randomized, controlled trials in some tumor settings have not shown a significant difference between the survival rates in long-term neoadjuvant therapy and adjuvant therapy. However, this has not hampered the increasing use of neoadjuvant treatments in clinical practice, due to its evident downstaging of primary tumors to delineate the surgical margin, tailoring systemic therapy response as a clinical tool to optimize subsequent therapeutic regimens, and decreasing the need for surgery, with its potential for increased morbidity. The recent expansion of nanotechnology-based nanomedicine and related medical technologies provides a new approach to address the current challenges of neoadjuvant therapy for preoperative therapeutics. This review not only summarizes how nanomedicine plays an important role in a range of neoadjuvant therapeutic modalities, but also highlights the potential use of nanomedicine as neoadjuvant therapy in preclinical and clinic settings for tumor management.

Keywords: Nanotechnology; Neoadjuvant treatment; Preoperative preparation; Surgical resection.

Graphical abstract

Fig. 1

Scheme of nanotechnology-assisted preoperative therapeutic strategies, including neoadjuvant chemotherapy, neoadjuvant radiotherapy, neoadjuvant immunotherapy, and neoadjuvant phototherapy, as singular as well as combination therapies. Created with permission by BioRender.com.

Fig. 2

Three-in-one nano-micelle-mediated tumor priming, tumor optical imaging and neoadjuvant chemotherapy. a. Scheme of 3-in-1 PEG-b-PLA nanoparticles containing PTX/17-AAG/RAPA, and diagram of DIR containing PEC-b-PCL micelles. b. Schematic illustration of PTX/17-AAG/RAPA nano-micelle-mediated tumor priming and subsequently promoted NIR optical imaging of tumor by DiR loaded PEC-b-PCL micelles. c. In vivo NIR imaging of tumor bearing mice after administering DiR-containing PEG-b-PCL micelles following vehicle, PTX, and PTX/17-AAG/RAPA injection for 48 h. d. Intratumoral distribution of DiR-containing PEG-b-PCL micelles in different treatment groups. e. Apoptotic cells in tumor tissue of different treatment groups. f. Tumor growth curve in different treatment groups. g. Mice body weight in different treatment groups [32]. Copyright 2011. American Chemical.

Fig. 3

Nanomedicine-dominated neoadjuvant-therapy-mediated tumor microenvironment remodeling and metastasis suppression. a. Scheme of the synthesis of T-CeNP and the remodeling of the tumor microenvironment. b. The TEM of T-CeNP. c. Diagrammatic illustration of T-CeNP-dominated cancer-associated fibroblast reprogramming. d. Representative morphological images of fibroblasts, cancer-associated fibroblasts, and reprogrammed fibroblasts. e. Validation of fibroblasts, cancer-associated fibroblasts, and reprogrammed fibroblasts by western blotting. f. T-CeNP-mediated cancer-associated fibroblast reprogramming promoted growth suppression of tumor spheroid in 3D cocultures of fibroblast and tumor cells. g. Diagram illustrating the therapy regimen of neoadjuvant therapy, surgery, and therapeutic evaluation. h. In vivo fluorescence imaging of nanoparticle distribution in tumors with or without neoadjuvant treatment. i. Ex vivo fluorescence imaging of nanoparticle distribution with or without neoadjuvant treatment. j. Fluorescence images of different nanoparticles in frozen tumor sections with or without neoadjuvant treatment. k. Ex vivo bioluminescence imaging for micrometastases in the lung of different treatment groups. l. Ex vivo bioluminescence imaging for micrometastases in the liver of different treatment groups. The red X represents animals that died during tumor removal surgery [20]. Copyright 2021, John Wiley and Sons.

Fig. 4

Deep-penetrating triple-responsive prodrug nanosensitizer Actuates Efficient CRT in PDAC a. Efficient PDAC tumor accumulation, b. GGT-triggered tumor penetration, c. The potential mechanism of GSH/hypoxia dual-responsive drug release and hypoxic chemo-radio sensitization, and d. Representative in vivo bioluminescence images of orthotopic PDAC models treated as indicated [78]. Copyright 2022, John Wiley and Sons.

Fig. 5

Schematic combining systemic dual agonists (STING and TLR4) formulated in immunostimulatory lipid NPs (immuno-NP) with anti-PD1, as a powerful neoadjuvant immunotherapy [119]. Copyright 2009, Royal Society of Chemistry.

Fig. 6

CoG-NS-mediated MR-guided neoadjuvant phototherapy for oral squamous cell carcinoma. a. Scheme of the synthesis of CoG-NSs and its MR-guided preoperative phototherapy for oral squamous cell carcinoma. b. TEM image of CoG-FSs. c. TEM image of CoG-NSs. d. Elemental mapping of CoG-NSs (EDS). e. Concentration dependent photothermal effect of CoG-NSs. f. Photothermal stability of CoG-NSs over laser on/off cycles. g. Uptake of CoG-NSs by CAL-27 cells (scale bar: 20 μm). h. Live/dead cells staining of CAL-27 cells with Calcein–AM (green: live cells) and PI (red: dead cells) after treatment with various concentration of CoG-NSs with or without laser (scale bar: 100 μm). i. Phantom T2-weighted MR images of different concentrations of CoG-NSs suspensions. j. Phantom T1-weighted MR images of different concentrations of CoG-NSs suspensions. k. In vivo axial T1 and T2 MR imaging of tumor at different time point post injection of CoG-NSs. l. In vivo infrared photothermal imaging of CAL-27 tumor. m. Immunofluorescence of HIF-1a expression in the tumor after different treatments (scale bar: 100 μm). n. DHE staining of ROS in tumor tissue in different groups (scale bar: 100 μm). o. The schedule of CoG-NS-mediated MR-guided neoadjuvant photo-therapy anticancer recurrence. p. Representative photos of CAL-27 tumor-bearing BALB/c nude mice in different treatment groups at different time. q. Survival curve of CAL-27 tumor-bearing BALB/c nude mice in different treatment groups. r. The recurrence of CAL-27 tumor-bearing BALB/c nude mice in different treatment groups [139]. Copyright 2022, Elsevier.