Development of Stimuli-Responsive Polymeric Nanomedicines in Hypoxic Tumors and Their Therapeutic Promise in Oral Cancer

Abstract

Hypoxic tumors pose considerable obstacles to cancer treatment, as diminished oxygen levels can impair drug effectiveness and heighten therapeutic resistance. Oral cancer, a prevalent malignancy, encounters specific challenges owing to its intricate anatomical structure and the technical difficulties in achieving complete resection, thereby often restricting treatment efficacy. The impact of hypoxia is particularly critical in influencing both the treatment response and prognosis of oral cancers. This article summarizes and examines the potential of polymer nanomedicines to address these challenges. By engineering nanomedicines that specifically react to the hypoxic tumor microenvironment, these pharmaceuticals can markedly enhance targeting precision and therapeutic effectiveness. Polymer nanomedicines enhance therapeutic efficacy while reducing side effects by hypoxia-targeted accumulation. The article emphasizes that these nanomedicines can overcome the drug resistance frequently observed in hypoxic tumors by improving the delivery and bioavailability of anticancer agents. Furthermore, this review elucidates the design and application of polymer nanomedicines for treating hypoxic tumors, highlighting their transformative potential in cancer therapy. Finally, this article gives an outlook on stimuli-responsive polymeric nanomedicines in the treatment of oral cancer.

Keywords: hypoxic tumors; oral cancer; polymeric nanomedicines; stimulus response.

Figure 9

(A) Schematic illustration of tumor acidity-mediated activation of iPAPD nanoparticles with iRGD-enhanced tumor penetration and imaging-guided combination cancer therapy [122], Copyright 2017, American Chemical Society; (B) schematic diagram of in situ synthesized LA-targeted NMOFs for bioimaging and targeted drug delivery application [125], Copyright 2019, Elsevier; (C) fluorescent quantification of Cy5 in tumor and major healthy organs ex vivo 24 h post mPEG-OA administration [131], Copyright 2018, American Chemical Society; (D) in vivo MR images of EMT6 tumor-bearing mice after intravenous injection of SPNs, IPNs, and DTPA(Gd), respectively [132], Copyright 2020, American Chemical Society.

Scheme 1

Full–text schematic diagram.

Figure 1

(A) Schematic illustration of Ce6-loaded cHDEA nanogels [21], Copyright 2023, Wiley; (B) cumulative release profile of Ce6 from the nanogels at pH 7.4 or pH 6.8 over a 24 h period [21], Copyright 2023, Wiley; (C) immunofluorescence analysis of HIF-1α level in 4T1 cells after different treatments [22], Copyright 2022, American Chemical Society; (D) flow cytometry analysis of apoptosis in 4T1 cells treated with PBS, DOX, iCPN, iCPN, or iCPDN [22], Copyright 2022, American Chemical Society.

Figure 2

(A) Schematic illustration of the possible reaction between M3a and GSH [23], Copyright 2022, Wiley; (B) NIR-II fluorescence bioimaging of mice injected with NP@PEDOX/PSP after various time points in vivo [23], Copyright 2022, Wiley; (C) the relative tumor volume change curve during treatment. (* p < 0.05) Copyright 2022, Wiley [23]. Copyright 2022, Wiley.

Figure 3

(A) Schematic diagram of the working principle of DSNs [27], Copyright 2016, American Chemical Society; (B) in vivo and ex vivo fluorescence imaging of tumor-bearing A549 mice at predetermined time intervals postinjection of DiR solution and DSNs [27], Copyright 2016, American Chemical Society; (C) schematic of drug delivery and release strategy of SynB3-PVGLIG-PTX [28], Copyright 2020, Wiley.

Figure 4

(A) The proposed framework for utilizing LDGI-loaded mesenchymal stem cells (MSCs) aims to augment the migratory capacity of tumors, as well as to improve the effectiveness of photothermal therapy (PTT) and chemotherapy in the treatment of triple-negative breast cancer (TNBC) [30], Copyright 2018, Wiley; (B) relative tumor volume of being intratumorally injected with DOX, PBS, LDGI, MSCs-LGI, and MSCs-LDGI with and without NIR laser irradiation within 15 days [30], (** p < 0.01, and *** p < 0.001) Copyright 2018, Wiley; (C) images of the excised tumors at the end of different treatments [31], Copyright 2021, American Chemical Society.

Figure 5

(A) The mechanism of nanoparticles (Br NP2) for enhancing DOX delivery by the degradation of tumor ECM [33], Copyright 2020, Elsevier; (B) schematic displaying pH-responsive DOX delivery using STBs for localized melanoma treatment [34], Copyright 2022, The Royal Society of Chemistry; (C) body and tumor temperature of the mice injected with PBS, Mo154Gel, and Mo154GelDOX upon 10 min of NIR irradiation [35], Copyright 2021, Wiley.

Figure 6

(A) Schematic diagram of the formation of HR-NPs and the in vivo tumor targeting pathway [38], Copyright 2013 Elsevier; (B) functionalized hypoxia-responsive polymeric micelles for targeted therapy of bone metastatic prostate cancer [39], Copyright 2021 Elsevier; (C) a novel bioinduced linker based on 2-nitroimidazole. -nitroimidazole is used for three paclitaxel (PTX) prodrugs, the 2-nitroimidazole linker can accelerate the release of prodrugs under hypoxic conditions [40], Copyright 2018 American Chemical Society.

Figure 7

(A) Hollow mesoporous manganese dioxide (H-MnO₂) nanoshells loaded with chemotherapeutic drugs docetaxel and cisplatin (TP), forming H-MnO₂-PEG/TP nanoshells [41], Copyright 2021 BMC; (B) changes in O₂ concentration in hydrogen peroxide solution (100 μM) [41], Copyright 2021 BMC; (C) a novel nanoparticle, this polymer is synthesized by coupling the hydrophobic small molecule 4-nitrobenzyl (3-azidopropyl) carbamate to the side chain of mPEG-PPLG copolymer [42], Copyright 2020 American Chemical Society.

Figure 8

(A) Drug release via polymer–drug conjugates bound to human carboxylesterase 2 for targeted drug activation [47], Copyright 2023 American Chemical Society; (B) schematic diagram of the multi-stage drug delivery mechanism of pNG-DOX [86], Copyright 2020 Ivyspring International Publisher; (C) changes in tumor volume of mice during the treatment with HRM NPs [48], Copyright 2024 American Chemical Society; (D) schematic diagram of the self-assembly of PEGylated PTX prodrug, tumor hypoxia-specific drug release, and anti-tumor activity [87], Copyright 2022 American Chemical Society.

Figure 10

(A) The illustration of the charge-reversal and intracellular ROS generation of PVD-NPs in tumor tissue [163], Copyright 2020, DOVE Medical Press; DOVE MEDICAL PRESS LTD; Dove; (B) tumor inhibition rate of mice after treatment with different formulations [163], Copyright 2020, DOVE Medical Press; DOVE MEDICAL PRESS LTD; Dove; (C) mouse body weight after treatment with different formulations [163], Copyright 2020 DOVE Medical Press; DOVE Medical Press Ltd.; Dove.

Figure 11

(A) In vitro tumor penetration of RLPA-NPs and LPA-NPs into 4T1 3D TSs after 8 h incubation. Green represents FITC. scale bar: 50 µm (reproduced from [185]). (B,C) In vivo (B) and ex vitro (C) images of 4T1 tumor-bearing mice following the systemic administration of Cy5.5-loaded RLPA-NPs and LPA-NPs for indicated times (reproduced from [185]).