Targeted delivery and controlled release of polymeric nanomedicines for tumor therapy

Abstract

Drug therapy, including chemotherapy and immunotherapy, remains a cornerstone of cancer treatment; however, significant toxic side effects are often unavoidable, inhibiting tumor growth while causing damage to multiple organ systems. Polymeric nanomedicines have shown substantial promise in addressing the limitations of small-molecule drugs, such as poor solubility, rapid clearance, low tumor retention, and adverse effects, thereby enhancing the therapeutic index. Despite these advances, clinical outcomes indicate that the overall survival rates of cancer patients post-treatment are often not significantly higher than those achieved with standard small-molecule drugs. This is largely due to the inadequate tumor targeting and limited tumor penetration of polymeric drugs despite their drug release and targeting capabilities. While actively tumor-targeted and selectively activated drug strategies can potentially improve drug targeting, traditional approaches have yielded unsatisfactory results due to insufficient differences in targets, such as markers and stimuli, between tumor and normal tissues. Recent innovations focus on utilizing drug or external stimuli, such as light, radiation, and ultrasound, to amplify tumor-associated markers or stimuli, enabling more precise tumor targeting and selective drug activation. Based on these innovations, actively targeted or selectively activated polymeric nanomedicines can further enhance drug accumulation within tumors and improve therapeutic outcomes. Moreover, the integration of actively tumor-targeting and tumor-selectively activated strategies represents a significant advancement, which achieves simultaneously enhanced drug accumulation and selective activation within the tumors. This review highlights the significant potential, challenges, and advanced strategies of polymeric nanomedicines in targeted tumor therapy, emphasizing the need for ongoing research to optimize their effectiveness and ultimately improve patient outcomes, paving the way for more effective and less toxic cancer treatment options.

Keywords: Controlled release; Drug delivery; Polymeric nanomedicines; Selective activation; Tumor targeting.

Fig. 1

An Fc binding peptide-based multi-specific antibody (MsAb) and antibody-drug conjugate building platform. (A-C) An Fc binding peptide-based platform for MsAb. (A) Synthesis approach of PGLU-Fc-III-4C. (B) Fc binding peptide-based platform for the generation of multispecific antibodies. (C) The underlying mechanisms, tumor growth curve and mice body weight change in the tumor inhibition experiment of PDL1/CD3e/4–1BB TsAb treated MC38 mice. Reproduced under terms of the CC-BY license. [56] Copyright 2023, American Society for Clinical Investigation.

Fig. 2

Different antibody-polymer-drug conjugates (APDCs) were prepared using polymer linkers based on a “Lego-like” assembly.(A-B) Schematic illustration of APDC. (C-E) The tumor growth curves in the tumor inhibition experiments of (C) aHER2-P-MMAE treated SKOV-3 tumor bearing mice (Reproduced with permission. [57] Copyright 2023, Wiley-VCH Verlag GmbH & Co.), (D) aHER-2-NPLG-DM1 treated SKOV-3 tumor bearing mice (Reproduced with permission. [58] Copyright 2024, Elsevier Ltd.), and (E) aPDL1-NPLG-SN38 treated MC38 bearing mice (Reproduced with permission. [59] Copyright 2023, Elsevier Ltd.).

Fig. 3

Self-amplifying nanotherapeutic drugs targeting tumors via a chain reaction mechanism. (A) Synthesis and preparation of the A15-PLG-CA4 drug delivery platform. (B) Schematic representation of the self-amplifying tumor coagulation targeting mechanism of A15-PLG-CA4. (C-D) Tumor growth curves in C26 tumor-bearing mice treated with A15-PLG-CA4 (C) and A15-PLG-CA4/BLZ945 (D) in tumor inhibition experiments. (E) Biodistribution of the drug in mice following A15-PLG-CA4 treatment. Reproduced with permission. [72] Copyright 2020, Wiley-VCH Verlag GmbH & Co.

Fig. 4

Tumor selective activation strategies. (A) Schematic illustration of ROS-responsive TLR7/8 nanoagonists R848 NPs. (B) Treatment schedule, tumor growth curves, and representative tumor images at the end of the in vivo antitumor experiment on BALB/c mice bearing CT26 tumors. Reproduced with permission. [79] Copyright 2024, Elsevier B.V. (C) Redox-sensitive drug release mechanism of PTX-S-OA triggered by GSH/ROS. Reproduced under terms of the CC-BY license. [81] Copyright 2016, American Society for Clinical Investigation. (D) Schematic illustration of the cascade of ROS generation and drug release. Reproduced with permission. [83] Copyright 2019, Wiley-VCH Verlag GmbH & Co.

Fig. 5

Self-activated drug deliveries. (A) Synthesis and preparation of the AzoP-NPs. (B) Schematic image for release of AmP in hypoxic tumor microenvironment. Reproduced under terms of the CC-BY license. [91] Copyright 2022, Elsevier B.V. (C) Chemical structure and benefits of esterase- and hypoxia-responsive prodrugs PSM, TPZHex, and PT-NPs. Reproduced under terms of the CC-BY license. [92] Copyright 2024, Elsevier B.V.

Fig. 6

Ultrasound irradiation-induced superoxide anion radical mediates the reduction of tetravalent platinum prodrug for anti-tumor therapy. (A) Structure and ultrasound induced cisplatin release of polymeric tetravalent platinum P-Rf/cisPt(IV). (B) In vitro evidences of ultrasound induced cisplatin release of polymeric tetravalent platinum P-Rf/cisPt(IV). (C) Mechnism evaluation for ultrasound induced cisplatin release of polymeric tetravalent platinum P-Rf/cisPt(IV). (D) In vivo evidences of ultrasound induced cisplatin release,biodistribution, and tumor inhibition of polymeric tetravalent platinum P-Rf/cisPt(IV). [96] COPYRIGHT & PERMISSIONS © 2024 Chinese Chemical Society.

Fig. 7

Multiple tumor-targeted delivery strategies. (A) Schematic illustration of pH-responsive cRGD-Dex-DOX/HDZ nanoparticles. Reproduced under terms of the CC-BY license. [97] Copyright 2023, Wiley-VCH Verlag GmbH & Co. (B) Schematic illustration of the RA-S-S-Cy@PLGA NPs structure. Reproduced under terms of the CC-BY license. [98] Copyright 2019, Ivyspring International. (C) Schematic illustration of synthesis and self-assembly of mAb-CD163-PDNPs nanoparticles modified by CD163 monoclonal antibody. (D) Tumor volume, changes in mouse body weight during mAb-CD163-PDNPs treatment and representative picture of tumor after treatment on day 14. Reproduced under terms of the CC-BY license. [99] Copyright 2023, MDPI. Co. (E) Chemical structure of TPZP and schematic diagram of CA4-NPs, FT11-TPZP-NPs combined therapy. Reproduced under terms of the CC-BY license. [102] Copyright 2024, China Science Publishing & Media Ltd,.

Fig. 8

Tumor microenvironment remodeling-mediated sequential drug delivery potentiates treatment efficacy. (A) Synthesis of IMDQ-N₃, PLG-IMDQ-N₃ and apcitide-PLG-IMDQ-N₃. (B) Schematic illustration for CA4-NPs induced coagulation cascade, active recognition and binding of apcitide on apcitide-PLG-IMDQ-N₃ and active GPIIa-IIIb in active platelet, and activation of apcitide-PLG-IMDQ-N₃ under hypoxia. (C) Schematic of the sequential drug delivery strategy with tumor microenvironment remodeling. (D) Biodistribution of active IMDQ of tumor-bearing mice post different treatment. (E) Tumor growth curves of mice post treatment in the tumor inhibition experiment and re-challenge experiment. Reproduced with permission. [103] Copyright 2024, Wiley-VCH Verlag GmbH & Co.

Fig. 9

Schematic illustration of advanced tumor-targeted delivery and release strategies of polymeric nanomedicines, including actively tumor-targeted delivery, tumor selective drug activation and multiple tumor-targeted delivery.