Tumor microenvironment responsive drug delivery systems

Abstract

Conventional tumor-targeted drug delivery systems (DDSs) face challenges, such as unsatisfied systemic circulation, low targeting efficiency, poor tumoral penetration, and uncontrolled drug release. Recently, tumor cellular molecules-triggered DDSs have aroused great interests in addressing such dilemmas. With the introduction of several additional functionalities, the properties of these smart DDSs including size, surface charge and ligand exposure can response to different tumor microenvironments for a more efficient tumor targeting, and eventually achieve desired drug release for an optimized therapeutic efficiency. This review highlights the recent research progresses on smart tumor environment responsive drug delivery systems for targeted drug delivery. Dynamic targeting strategies and functional moieties sensitive to a variety of tumor cellular stimuli, including pH, glutathione, adenosine-triphosphate, reactive oxygen species, enzyme and inflammatory factors are summarized. Special emphasis of this review is placed on their responsive mechanisms, drug loading models, drawbacks and merits. Several typical multi-stimuli responsive DDSs are listed. And the main challenges and potential future development are discussed.

Keywords: Cancer therapy; Controlled release; Drug delivery system; Dynamic targeting; Stimuli responsive.

Graphical abstract

Fig. 1

Tumor microenvironment-activatable targeting and self-controlled drug release (Reproduced with permission from . Copyright 2016 The Authors).

Fig. 2

Summary of the 3S transitions in the CAPIR cascade for a nano-formulation to achieve optimal drug-delivery (Reproduced with permission from . Copyright 2017 Wiley-VCH.).

Fig. 3

Dynamic targeting strategies for enhanced drug delivery. (A) Size shrinkage targeting (Reproduced with permission from reference . Copyright 2016 National Academy of Sciences); (B) Surface charge conversion targeting (Reproduced with permission from . Copyright 2016 Ivyspring) (C) TAT CPPs targeting ligand exposure strategy (Reproduced with permission from . Copyright 2015, American Chemical Society).

Fig. 4

pH responsive DDSs. (A) Encapsulation of small molecules into the ZIF-8 frameworks during synthesis, and acidic responsive release of drugs or NPs at tumor microenvironments (Reproduced with permission from . Copyright 2014, American Chemical Society). (B) Recombinant of DOPA-containing MAP and Fe (III)-DOPA complexation for pH-triggered drug release (Reproduced with permission from . Copyright 2015 Wiley-VCH). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 5

GSH responsive DDSs. (A) Illustration of the gluthione-triggered nanoplatform, comprising Pt (IV) prodrug, poly (disulfide amide) polymers and lipid-PEG for treatment of cisplatin-resistant tumors; Intracellular delivery of Pt and reversal of tumor cisplatin resistance (Reproduced with permission from . Copyright 2018, American Chemical Society). (B) Chemical structure of the redox-responsive block copolymer PEG-SS-PS used for the stomatocyte assembly; Self-assembly and GSH-triggered disassembly of the redox-sensitive stomatocyte nanomotor (Reproduced with permission from . Copyright 2017 The Authors). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 6

Chemical structures of the disulfide-containing PTX-CIT prodrugs: (A) α-PTX-SS-CIT, (B) β-PTX-SS-CIT, and (C) γ-PTX-SS-CIT (Reproduced with permission from . Copyright 2018 American Chemical Society). (D) Drug release of carbonate- and carbamate-linkers bearing albumin-prodrug conjugates after intravenous administration (Reproduced with permission from . Copyright 2018 American Chemical Society).

Fig. 7

GSH responsive DDSs. (A) Preparation of PEGylated prodrug NPs of PTX-S-OA; (B) Redox-sensitive drug release of PTX-S-OA triggered by GSH/ROS; PTX release from PTX-S-OA/TPGS_2k NPs, PTX-2S-OA/TPGS2k NPs and PTX-OA/TPGS2k NPs after treatment with (C) 10 mM DTT and (D) 10 mM H₂O₂ (Reproduced with permission from . Copyright 2018 American Chemical Society). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 8

ROS responsive drug DDSs. (A) ROS generation based on photodynamic therapy: the construction of Pros-PDC NPs with prolonged circulation time and enhanced cellular internalization, and light-triggered ROS generation and the newly generated ROS activated anticancer drug release of the DOX and IR780 co-loaded Pros-PDC NPs with a spatially and temporally precise profile, adapted from reference (Reproduced with permission from . Copyright 2017 Elsevier). (B) ROS generation based on ROS producing agent administration: structure of T/D@RSMSNs nano-system and its positive feedback mechanism for ROS-responsive self-accelerating drug release (Reproduced with permission from . Copyright 2017 Elsevier). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 9

ATP triggered drug release. (A) Nanogel composed of an ATP-responsive DNA motif, protamine and a HA crosslinked shell for cellular delivery of DOX (Reproduced with permission from . Copyright 2014 Springer Nature). (B) ATP-responsive charge reversal crosslinked polyplex for tumor-targeted siRNA delivery (Reproduced with permission from . Copyright 2018 Ivyspring).

Fig. 10

ATP triggered drug release. (A) ATP responsive GroEL_CM protein based on chemomechanical conformational changes for promotion of intelligent drug release (Reproduced with permission from . Copyright 2013 Springer Nature). (B) TDPA-Zn²⁺-UCNP@MSNs wrapped with polypeptide for real-time monitoring of ATP-responsive drug release (Reproduced with permission from . Copyright 2015 American Chemical Society). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 11

Enzyme responsive drug delivery platform. (A) Legumain specific cleavable bioinspired macrophage delivery system for treatment of lung metastasis (Reproduced with permission from . Copyright 2018 American Chemical Society). (B) Cathepsin B-specific cleavable production of Ac₃ManNAz for exogenous generation of chemical receptor on the membrane of cancer cell where specific bioorthogonal click molecule DBCO-Cy5.5 could be actively bound (Reproduced with permission from . Copyright 2016 Wiley-VCH). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 12

Inflammatory mediators activated DDSs. (A) In situ activation of the platelets-based DDSs medicated by inflammatory factors facilitated the release of anti-PDL1 (aPDL1) and cytokines (Reproduced with permission from . Copyright 2017, Springer Nature). (B) TEM images of P-aPDL1 before (left) and after (middle and right) activation (Reproduced with permission from . Copyright 2017, Springer Nature). The red arrowheads refer to the released PMPs from the platelet. (C) Immunofluorescence images of residual tumors showed CD⁴⁺ and CD⁸⁺ T cells infiltration. A higher infiltration of T-cells indicates a stronger immune response with a positive correlation to the amount of the released P-aPDL1 (Reproduced with permission from . Copyright 2017, Springer Nature). (D) Integration of hemato-poietic stem cells and platelets for the delivery of anti-PD-1 antibodies to the leukaemia location site (Reproduced with permission from . Copyright 2018, Springer Nature). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 13

Schematic design of smart nanocarriers coated with pH-/thermal-/GSH-responsive polymer zippers for precision anticancer molecular drug delivery (Reproduced with permission from . Copyright 2017 WILEY-VCH). (A) NIR-/pH-guided cellular uptake and GSH/HAase-controlled release in vivo. (i) Passive accumulation at tumor sites in the PEG state via the EPR effect; (ii) NIR-/pH-activated surface shift to the Gu⁺/CPD-SS-RGD state with positive charge and RGD ligand for selective uptake; (iii) Endosome escape and controlled release by endogenous GSH/HAase; (iv) nonspecific retention and clearance in normal tissues. (B) The surface state variations during drug delivery (the polymer zipper decoding and the sandwich protective shell degradation). (C) The composition of the Gu⁺/CPD-SS-RGD and PY⁻/PTP-PEG polymer zipper with multiple pY⁻/Gu⁺ salt bridges. The Gu⁺/CPD-SS-RGD was prepared with a cyclic peptide with a sequence of arginine-glycine-aspartic acid (RGD) as an initiator. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)