Review ArticleReview

Nanotechnology assisted photo- and sonodynamic therapy for overcoming drug resistance

Rui Li, Zhimin Chen, Zhifei Dai and Yingjie Yu
Cancer Biology & Medicine May 2021, 18 (2) 388-400; DOI: https://doi.org/10.20892/j.issn.2095-3941.2020.0328

Abstract

Drug resistance is considered the most important reason for the clinical failure of cancer chemotherapy. Circumventing drug resistance and improving the efficacy of anticancer agents remains a major challenge. Over the past several decades, photodynamic therapy (PDT) and sonodynamic therapy (SDT) have attracted substantial attention for their efficacy in cancer treatment, and have been combined with chemotherapy to overcome drug resistance. However, simultaneously delivering sensitizers and chemotherapy drugs to same tumor cell remains challenging, thus greatly limiting this combinational therapy. The rapid development of nanotechnology provides a new approach to solve this problem. Nano-based drug delivery systems can not only improve the targeted delivery of agents but also co-deliver multiple drug components in single nanoparticles to achieve optimal synergistic effects. In this review, we briefly summarize the mechanisms of drug resistance, discuss the advantages and disadvantages of PDT and SDT in reversing drug resistance, and describe state-of-the-art research using nano-mediated PDT and SDT to solve these refractory problems. This review also highlights the clinical translational potential for this combinational therapy.

keywords

Introduction

Chemotherapy, a mainstream cancer treatment, plays an important role in tackling cancer1. More than 200 anticancer drugs have been used clinically2. These drugs usually work well at early stages of disease, but more than 90% of patients show drug resistance after relapse3. Even patients treated with immunotherapy almost inevitably develop drug resistance in relatively short periods of time4,5. Because of the low therapeutic indexes of most chemotherapeutic drugs, even slight changes in the sensitivity of tumor cells can result in drug resistance. All these factors make drug resistance a major obstacle in cancer treatment6.

Over the past half-century, progress has been made in understanding drug resistance, thereby facilitating the development of new therapeutic strategies for overcoming this obstacle7. Scientists have proposed 3 major hypotheses underlying drug resistance: (1) pharmacokinetics, in which up-regulating the expression of efflux membrane proteins and detoxification enzymes leads to insufficient accumulation of drugs in tumor regions8; (2) tumor specificity9, in which genetic mutations in cancer cells are the biological basis of drug resistance: after application of chemical drugs, the tumor cells gradually acquire genetic mutations and epigenetic changes, and the elimination of sensitive subtypes leads to the development of drug-resistant tumors; and (3) the tumor micro-environment (TME)10, which regulates the drug sensitivity of tumor cells and promotes the development of drug resistant phenotypes11.

PDT, an invasive treatment for clinical cancer, has been used to reverse chemoresistance12,13. The 3 elements of PDT include a photosensitizer (PS), light, and oxygen. Light-activated PS transfers energy to oxygen and generates cytotoxic reactive oxygen species (ROS)14, which decrease the expression of membrane efflux proteins and anti-apoptotic proteins15. Because of the high tissue penetration of near-infrared light (NIR), various NIR-excited PSs have been developed16. In addition, the unique mechanism of PDT can enhance tumor sensitivity, vascular permeability, and immune responses17,18.

SDT is an emerging therapy, which generates ROS through a combination of low intensity ultrasound (US) (∼1 MHz) and sensitizing drugs19. The main advantage of SDT is that US has deep penetration in mammalian tissue (above 10 cm)20, thus making SDT a promising therapy for deep tumors21–23. Microbubbles, which have been approved as contrast agents for US diagnosis, are used to load and release oxygen under US and regulate the TME24–27. Because drug-resistant cells have a higher clearance rate of ROS than sensitive cells, they are more susceptible to ROS28,29. Hence, combining PDT or SDT with conventional chemotherapy endows conventional chemotherapy with more versatility, thereby providing an effective and facile means of overcoming drug resistance.

Nanotechnology is the manufacturing of materials at atomic and molecular scales. Because of their unique properties, nanomaterials have been the basis for development of numerous drug delivery systems. Although drug-resistant cells are more susceptible to ROS, PDT and SDT still have several limitations that compromise their efficacy30,31. With the development of ideal sensitizers for PDT and SDT, light and US not only sensitize tumor cells but also trigger the release of sensitizers into the cytoplasm, thus bypassing the efflux membrane proteins and inhibiting the escape pathway and significantly enhancing drug accumulation in tumor regions32. The strategies of nanotechnology assisted PDT and SDT to overcome drug resistance are summarized in Figure 1.

Figure 1
Figure 1

Schematic illustration of nanotechnology assisted photo- and sonodynamic therapy for overcoming drug resistance. The drug resistance of cancer cells is closely associated with drug efflux, apoptosis inhibition, DNA repair, tumor heterogeneity, tumor epithelial-mesenchymal transition (EMT), and the tumor microenvironment (TME). The application of PDT and SDT improves the sensitivity of tumors by inhibiting drug resistance-related proteins, thus artificially activating and promoting drug internalization. Nanotechnology is applied not only to bypass efflux proteins but also to facilitate targeted delivery and the controlled release of sensitizers.

Drug resistance remains a major hindrance in cancer therapy

Because drug resistance is a major predictor of patient mortality33,34, understanding the mechanisms of drug resistance is crucial35. Resistance to a wide range of anticancer drugs is attributed to the expression of energy-dependent transporters, which eliminate anticancer drugs from cells. These transporters are called ATP binding cassette (ABC) proteins, which include multidrug resistance protein 1 (MDR-1), multidrug resistance related protein 1 (MRP-1), and ATP-binding cassette subfamily G member 2 (ABCG-2)36. However, other resistance mechanisms, such as insensitivity to drug-induced apoptosis, DNA repair, target alteration, alternative pathway hyperactivation, and induction of drug-detoxification, are likely to lead to anticancer drug resistance (Figure 2A)37,38.

Figure 2
Figure 2

Schematic illustration of the mechanism of cancer drug resistance. (A) Common cell-intrinsic resistance mechanisms. (B) Tumor microenvironment and systemic mechanisms of drug resistance.

Beyond intracellular signals, the TME and systemic factors also affect the development of drug resistance (Figure 2B)39. For example, a hypoxic environment activates hypoxia inducible factor-1 (HIF-1), which regulates the expression of MDR-1. Moreover, epithelial-mesenchymal transition (EMT) cells have similar cellular characteristics to those of cancer stem cells (CSC)40,41. The EMT cells decrease the efficacy of chemotherapy by releasing cytokines42. Importantly, tumors are extremely heterogeneous, and this aspect considerably contributes to primary or acquired resistance43. In a further challenge, some of these resistance pathways may result in multidrug resistance. Improved understanding of the diverse mechanisms of cancer drug resistance would aid in designing various anti-cancer therapeutic strategies to circumvent drug resistance.

Photo- and sonodynamic therapy to overcome drug resistance

The unique mechanisms of action of PDT in overcoming drug resistance

PDT has attracted great attention as a promising therapy for drug-resistant tumors, because of its unique mechanisms44. ROS produced by PDT disrupt the original cytokine balance, transforming the tumor cells from a resistant to a sensitive phenotype (Figure 3A)45. The most effective PSs tend to be lipophilic aromatic ring systems, which are preferentially located on extranuclear organelle membranes46,47. Among them, the PSs located in mitochondria disrupt the membrane structure, thereby leading to a sharp decline in the levels of intracellular 5′-adenosine triphosphate (ATP) and anti-apoptotic protein Bcl-2 family proteins48,49. The activity of ATP-dependent ABC proteins is consequently decreased, and efflux of chemotherapy drugs is inhibited (Figure 3B–3E)50–53. Moreover, lysosomal-PDT selectively destroys the lysosomal membrane, thus bypassing protective autophagy and promoting cytoplasmic drug release54. In terms of the TME, vascular injury is observed after PDT, including enhanced vessel permeability and leakage, thereby improving the therapeutic index of chemotherapeutic drugs55,56. In addition, PDT stimulates tumors to form an inflammatory environment and induces T cells to infiltrate tumors57.

Figure 3
Figure 3

(A) Schematic diagram of PDT overcoming drug resistance at the molecular level. PDT caused decreased expression of ABCG2 protein (green) (B) and increased expression of Caspase-3 (green) (C) in HT-29 cells. The nucleus is stained blue by DAPI. Quantification of the ABCG2 (D) and caspase-3 (E) fluorescence intensity per DAPI area after PDT irradiation50. *Significant difference (P < 0.05). Copyright 2018, American Chemical Society.

In summary, the unique mechanism of PDT includes: (1) reversal of chemo-resistance and sensitization of tumors to molecular inhibitors; (2) modulation of vascular permeability for enhanced drug delivery; and (3) stimulation of anti-tumor immunity. Thus, nanotechnologies to integrate the special features of PDT are promising in clinical treatment of drug resistant cancer.

SDT reversal of drug resistance

Although SDT remains in its infancy, it has nonetheless received tremendous attention in cancer treatment. Similarly to PDT, SDT decreases mitochondrial membrane potential and oxidative phosphorylation, thus down-regulating the expression of ABC proteins58–60. However, the biological effects of SDT differ from those of PDT, because of the mechanical effects of ultrasonic treatment (cavitation, alternating pressure, shear stress, and acoustic current), which themselves can decrease drug resistance even without cytostatics. In drug-resistant cells over-expressing P-gp, the fluidity of the drug-resistant cell membrane decreases, thus increasing sensitivity to US61. Moreover, the introduction of microbubbles allows macromolecules to enter cells via stable cavitation62,63. Hence, better understanding of the ROS production mechanism in SDT would aid in the design of more effective sensitizing drugs to overcome drug resistance.

Limitations of PDT and SDT

PDT and SDT have a strong ability to sensitize tumor cells to chemotherapy, but they nonetheless have many drawbacks, such as sensitizer aggregation, selective enrichment, and endogenous oxygen deficiency. First, the π-π aggregation of the hydrophobic sensitizer results in poor solubility in aqueous solution, thus decreasing the degree of internalization and the quantum yield of singlet oxygen64. Second, the different physiological distributions of sensitizers and chemo-drugs may cause systemic toxicity. Designing an appropriate system to selectively deliver sensitizing agents is urgently needed. Third, oxygen is essential for the development of drug resistance and ROS. However, hypoxia, a characteristic of the TME, not only promotes the proliferation of drug-resistant tumors but also decreases the efficiency of PDT and SDT65. The introduction of nanotechnology provides a new strategy to address these issues.

Nanotechnology approaches enhance the efficacy of PDT/SDT in overcoming drug resistance

Targeted delivery of sensitizers

To overcome the drawbacks of PDT and SDT, nanoparticles (NPs) have been used as drug delivery systems to increase the permeability, stability66, and solubility of sensitizers67 and avoid excessive drug removal68. Because of the lack of lymphatic drainage, tumor tissues, compared with normal tissues, tend to retain more NPs that escape from underdeveloped tumor blood capillaries. This phenomenon is termed the enhanced permeability and retention (EPR) effect69–71. Many studies (Table 1) have found that the EPR effect significantly increases drug levels in the tumor region, thereby preventing drug resistance. In sonodynamic photodynamic therapy, a new type of combination therapy82–85, the application of NPs has also shown excellent performance in improving drug efficacy80,81. Additionally, nanomedicines enter cells through endocytosis, a process independent of the MDR protein-mediated pathway86. After PDT (660 nm, 10 mW/cm2, 5 min) treatment, NPs escape from lysosomes successfully, thereby suggesting that cells absorb NPs through endocytosis and evade ABC-mediated drug resistance87. In comparison to the EPR effect, active targeting offers better selectivity88–90. The targeted cyclic peptide RGD associates with the surfaces of the NPs. As shown in Figure 4B, drug enrichment at tumor sites is clearly observed after injection91. Excitingly, the cell mortality rate has been found to significantly increase to 95.6% (61.3% for apoptosis and 34.3% for necrosis) after 671 nm light irradiation 0.1 W/cm2 for 3 min. These results indicate that nano-design can increase the intracellular content of sensitizers and drugs, and may serve as a convenient method for overcoming drug resistance.

View this table:
Table 1

Nanosystems to overcome drug resistance through the EPR effect

Figure 4
Figure 4

(A) Schematic illustration of nanoparticle structure and tumor site accumulation. Nanoparticles are targeted to tumors through active RGD targeting. (B) In vivo three-peak imaging. The white circle denotes the tumor site. (C) Imaging of U87MG tumor-bearing mice after MNP injection. The enrichment of nanoparticles in tumors can be clearly observed in (B) and (C)91. Copyright 2018, Nature.

NIR/US activation release

Nanotechnology-enabled drug delivery systems can provide spatial and temporal control for drug release. Various controlled release systems based on the TME92, NIR93,94 and US95,96 have been developed97. The NIR response has been confirmed to simultaneously activate PDT and NP disintegration at target sites. Sun et al.98 have synthesized a photoactivated nano-metal prodrug, PolyRu (Figure 5A). PolyRu can be cleaved by NIR to achieve on-demand administration, thus increasing the intracellular concentrations of drugs. PolyRu with red light irradiation (656 nm, 50 mW/cm2, 30 min), as compared with control treatment, has been found to decrease tumor volumes by approximately 55%. As mentioned above, the US response is more conducive to treatment of deep drug-resistant tumors, particularly with the assistance of microbubbles. The collapse of microbubbles due to sonodynamics increases vascular permeability99. Using this feature, Chen et al.50 have constructed porphyrin/camptothecin-fluorouridine triad microbubble (PCF-MB) to treat drug-resistant for breast cancer (Figure 5B). Ultrasound triggers the conversion of PCF-MBs into PCF-NPs, which induce greater internalization and uptake. Shi et al.100 have designed “US-detonated nano bombs” containing DOX, which lead to lysosomal escape and mitochondrial targeting. DOX is released from the nanobombs after US treatment (1 W/cm2, 120 s, at 4 h after incubation), and large amounts of DOX are observed in the nucleus.

Figure 5
Figure 5

(A) The light activation process of PolyRu98. Copyright 2016, Wiley. (B) Ultrasound-mediated microbubble blasting and the nano-particle interaction mechanism50. Copyright 2018, American Chemical Society. (C) Schematic diagram of in situ TK bond fracture caused by ROS103. Copyright 2018, American Chemical Society. (D) ROS-responsive nanoplatform to promote lysosomal drug release105. Copyright 2018, American Chemical Society.

Polyethylene glycol (PEG), which is widely used to modify nanomaterials, decreases the uptake of drugs by non-specific cells and prolongs the blood circulation time. The light-controlled shedding of PEG at desired sites has shown advantages in on-demand drug delivery based on nanocarriers101. The ROS-activatable thioketa (TK) bond has been used in the construction of PEG light-controlled shedding nanosystems102. Cao et al.103 have explored the polymer nanocarrier TK-PPE@ NP Ce6/DOX. Under excitation at 660 nm NIR, ROS generated by encapsulated Ce6 cleave the TK linker in situ, thus achieving drug remote control release through shrinking in size from 154 ± 4 nm to 72 ± 3 nm (Figure 5C). Normally, NPs are predominantly restricted to endocytic vesicles, thus preventing the drugs from exerting their effects. However, the ROS conversion NPs solve this problem through triggering cytosolic release of the chemotherapeutics 104. Wei et al.105 have developed photoconversion NPs that cause photochemical rupture of lysosomal membranes under 635 nm (10 mW/cm2, 5 min) NIR and release drugs into the cytoplasm (Figure 5D). The establishment of intelligent nano-systems thus can improve the low tumor specificity of PDT and SDT.

Co-delivery of multiple therapies

The application of multi-dimensional therapy can be achieved through nano-platforms106–108. Single PDT or SDT cannot completely solve drug-resistance issues and usually must be supplemented with exogenous oxygen, inhibitors, targeting agents, and immunotherapy. Nanotechnology has made this combination possible.

  1. The ABC protein inhibitors have a good effect on reducing drug efflux109. After treatment combining inhibitors with PDT and SDT, drug-resistant cancer cells are limited110,111. Wei et al.105 have used a nano-platform to combine PDT and the ABC protein inhibitor apatinib. In drug-resistant breast cancer, the IC50 for this combination therapy is 17.34 μg/mL, and the apoptotic ratio is 45.34%, a value approximately 3.3-fold higher than that of free DOX.

  2. Hypoxia, one of the main features of TME, increases the resistance of chemotherapy, PDT, and SDT. Nanotechnology provides tools to regulate the TME and re-sensitize tumors112. Yang et al.113 have synthesized oxygen self-sufficient NPs (F/DOX) loaded with oxygen-bearing perfluorocarbon and DOX. Under 808 nm light excitation, this nanocarrier disintegrates (Figure 6A). The release of oxygen decreases the expression of HIF-1, and correspondingly low expression of P-gp has also been observed in CLSM (Figure 6B–C). McEwan et al.114 have developed an oxygen-containing microbubble system for the targeted treatment of pancreatic cancer. When micro-bubbles are exposed to US (1 MHz, 3.0 W/cm2, 50% duty cycle, 1 min), oxygen is released, thus leading to downregulation of HIF-1.

  3. EMT enables cancer cells to invade and metastasize like CSCs, thus contributing to drug resistance115. Some NPs have been designed to target EMT cells and CSCs to hinder tumor escape and drug resistance116,117. Spring et al.118 have synthesized photoactivated nanoliposomes combined with inhibitors, integrating photodynamic and anti-VEGF therapy. This treatment causes blood vessel damage and blocks the EMT pathway. Liu et al.119 have constructed NPs co-loaded with HP and DOX. When combined with US radiation (1.0 MHz, 3 W/cm2, 5 min), this treatment effectively reverses the drug-resistance of CSCs.

  4. Checkpoint-blocked immunotherapy provides a promising strategy for cancer therapy, although its effects on low T cell infiltration tumors remain limited120. PDT and SDT with immunogenicity induce tumor cell sensitivity to PD-L1 immunotherapy by initiating an inflammatory response121,122. He et al.123 have designed core-shell NPs carrying pyropheophorbide and oxaliplatin for enhanced immune checkpoint suppression therapy. Under light (670 nm, 60 mW/cm2, 15 min) irradiation, the apoptosis rate of HT29 cells is 43%, and the necrosis rate is 18.7%. These NPs cause immunogenic cell death and inflammatory responses at the primary tumor location, thus stimulating the proliferation of effector T cells and enhancing the efficacy of PD-L1.

Figure 6
Figure 6

(A) A nanoparticle formulation co-delivers O2 and IR780, thus overcoming resistance of chemotherapy and PDT caused by hypoxia. (B) HIF-1 expression after treatment of MCF-7 cells with different methods. (C) CLSM images of P-gp expression after treatment with F/DOX nanoparticles under hypoxic conditions113. Copyright 2019, Royal Society of Chemistry.

Summary and outlook

The emergence of drug resistance has made inhibiting the proliferation of cancer cells more difficult. PDT and SDT are widely used to combat drug-resistant tumors. First, the ROS produced by PDT and SDT destroy subcellular structural membranes, DNA, and proteins, in contrast to the traditional anti-cancer pathway. Second, ROS inhibit the expression of ABC proteins, thus directly decreasing the efflux of drugs. Finally, PDT and SDT also contribute to overcoming drug resistance by damaging the vasculature and sensitizing tumor cells. However, the low specificity and water solubility of sensitizing agents limit the clinical applications of PDT and SDT.

NPs provide powerful tools to treat drug-resistant tumors on the basis of the EPR effect, owing to their structural designability. Unlike small molecule drugs, NPs enter cells through endocytosis. The combination of smart nanomaterials with PDT and SDT improves the targeted delivery and solubility of sensitizing agents, thus maximizing the therapeutic efficacy of the combinational therapy. For instance, NIR irradiation of the sensitizer generates ROS in situ, thus resulting in PEG de-shielding at the tumor region and significantly enhancing the cellular uptake of the nanocarrier. Light-induced PEG shedding enables precise remote control of drug delivery by de-shielding nanocarriers. In general, the synergy maximizes the effect in overcoming drug resistance. Such nanodrug delivery systems have promising therapeutic efficacy.

Although nanotechnology greatly aids in PDT and SDT, many problems remain to be addressed. (1) The low tissue penetration of NIR and quantum yield because of aggregation remain the main reasons for the poor therapeutic effects; consequently, PS with longer excitation wavelengths and delivery strategies that can avoid aggregation must be developed. (2) Further research on cavitation and the mechanical mechanism of SDT is needed. A more comprehensive understanding of the interaction between the sensitizer and cavitation, and the design of a more appropriate delivery system to enhance cavitation, would be conducive to SDT. (3) The low loading rate, instability, and potential toxicity of nanomaterials remains to be addressed. (4) Currently, we are in the new era of immunotherapy. Antibody-based PD-1/PD-L1 blockaded therapy has achieved dramatic therapeutic responses. However, this therapy is only effective for a subset of patients. Patients who do not respond to immunotherapy are referred to “primary resistance”. PDT and SDT provided a powerful toolbox to resolve this issue. Hence, more comprehensive studies related to immunotherapy and PDT/SDT are highly desired. (5) Although a plethora of studies have used nanotechnology to facilitate PDT and SDT and avoid drug resistance, these studies have mainly focused on the inhibitory effects of drug-resistant cancer cells and the synergistic effect of PDT/SDT and chemotherapy. The intracellular mechanism of this therapy in overcoming drug resistance remains unclear. Notably, nanotechnology-assisted PDT and SDT should be advantageous in overcoming long-lasting challenges in drug resistance, although this combination therapy remains in early stages. The comprehensive development of better nano-delivery systems and high-efficiency sensitizers are future directions toward achieving applications in clinical treatment.

Grant support

This work was supported by grants from the National Key Research and Development Program of China (Grant No. 2016YFA0201400), State Key Program of National Natural Science of China (Grant No. 81930047), Projects of International Cooperation and Exchanges NSFC-PSF (Grant No. 31961143003), National Project for Research and Development of Major Scientific Instruments (Grant No. 81727803), Beijing Natural Science Foundation, Haidian, Original Innovation Joint Fund (Grant No. 17 L20170), Foundation for Innovative Research Groups of the National Natural Science Foundation of China (Grant Nos. 81421004 and 52003161), and Shenzhen Science and Technology Project (Grant No. JCYJ20180507183842516).

Acknowledgements

We thank Dr. Qi Zhang at the University of Michigan for linguistic assistance during the preparation of this manuscript.

Footnotes

  • Conflict of interest statement No potential conflicts of interest are disclosed.

  • Received May 16, 2020.
  • Accepted July 21, 2020.
https://creativecommons.org/licenses/by/4.0/

This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY) 4.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.

References

  1. 1.↵
    2. Qin SY,
    3. Cheng YJ,
    4. Lei Q,
    5. Zhang AQ,
    6. Zhang XZ.
    Combinational strategy for high-performance cancer chemotherapy. Biomaterials. 2018; 171: 178–97.
    OpenUrl
  2. 2.↵
    2. Pan ST,
    3. Li ZL,
    4. He ZX,
    5. Qiu JX,
    6. Zhou SF.
    Molecular mechanisms for tumour resistance to chemotherapy. Clin Exp Pharmacol Physiol. 2016; 43: 723–37.
    OpenUrl
  3. 3.↵
    2. Agarwal R,
    3. Kaye SB.
    Ovarian cancer: strategies for overcoming resistance to chemotherapy. Nat Rev Cancer. 2003; 3: 502–16.
    OpenUrlCrossRefPubMed
  4. 4.↵
    2. De Henau O,
    3. Rausch M,
    4. Winkler D,
    5. Campesato LF,
    6. Liu C,
    7. Cymerman DH, et al.
    Overcoming resistance to checkpoint blockade therapy by targeting PI3K-γ in myeloid cells. Nature. 2016; 539: 443–7.
    OpenUrlCrossRefPubMed
  5. 5.↵
    2. Shaffer SM,
    3. Dunagin MC,
    4. Torborg SR,
    5. Torre EA,
    6. Emert B,
    7. Krepler C, et al.
    Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance. Nature. 2017; 546: 431–5.
    OpenUrlCrossRefPubMed
  6. 6.↵
    2. Baguley BC.
    Multiple drug resistance mechanisms in cancer. Mol Biotechnol. 2010; 46: 308–16.
    OpenUrlCrossRefPubMed
  7. 7.↵
    2. Xiao H,
    3. Qi R,
    4. Li T,
    5. Awuah SG,
    6. Zheng Y,
    7. Wei W, et al.
    Maximizing synergistic activity when combining RNAi and platinum-based anticancer agents. J Am Chem Soc. 2017; 139: 3033–44.
    OpenUrl
  8. 8.↵
    2. Wang J,
    3. Seebacher N,
    4. Shi H,
    5. Kan Q,
    6. Duan Z.
    Novel strategies to prevent the development of multidrug resistance (MDR) in cancer. Oncotarget. 2017; 8: 84559–71.
    OpenUrl
  9. 9.↵
    2. Turajlic S,
    3. Swanton C.
    Implications of cancer evolution for drug development. Nat Rev Drug Discov. 2017; 16: 441–2.
    OpenUrl
  10. 10.↵
    2. Burgos-Panadero R,
    3. Lucantoni F,
    4. Gamero-Sandemetrio E,
    5. Cruz-Merino L,
    6. Álvaro T,
    7. Noguera R.
    The tumour microenvironment as an integrated framework to understand cancer biology. Cancer Lett. 2019; 461: 112–22.
    OpenUrl
  11. 11.↵
    2. Wu C-P,
    3. Ohnuma S,
    4. Ambudkar SV.
    Discovering natural product modulators to overcome multidrug resistance in cancer chemotherapy. Curr Pharm Biotechnol. 2011; 12: 609–20.
    OpenUrlCrossRefPubMed
  12. 12.↵
    2. Chen J,
    3. Fan T,
    4. Xie Z,
    5. Zeng Q,
    6. Xue P,
    7. Zheng T, et al.
    Advances in nanomaterials for photodynamic therapy applications: status and challenges. Biomaterials. 2020; 237: 119827.
  13. 13.↵
    2. Yu Y,
    3. Xu Q,
    4. He S,
    5. Xiong H,
    6. Zhang Q,
    7. Xu W, et al.
    Recent advances in delivery of photosensitive metal-based drugs. Coord Chem Rev. 2019; 387: 154–79.
    OpenUrl
  14. 14.↵
    2. Caesar L,
    3. van Doeveren TEM,
    4. Tan IB,
    5. Dilci A,
    6. van Veen RLP,
    7. Karakullukcu B.
    The use of photodynamic therapy as adjuvant therapy to surgery in recurrent malignant tumors of the paranasal sinuses. Photodiagnosis Photodyn Ther. 2015; 12: 414–21.
    OpenUrl
  15. 15.↵
    2. Perillo B,
    3. Di Donato M,
    4. Pezone A,
    5. Di Zazzo E,
    6. Giovannelli P,
    7. Galasso G, et al.
    ROS in cancer therapy: the bright side of the moon. Exp Mol Med. 2020; 52: 192–203.
    OpenUrlCrossRefPubMed
  16. 16.↵
    2. Deng K,
    3. Li C,
    4. Huang S,
    5. Xing B,
    6. Jin D,
    7. Zeng Q, et al.
    Recent progress in near infrared light triggered photodynamic therapy. Small. 2017; 13: 1702299.
  17. 17.↵
    2. Falk-Mahapatra R,
    3. Gollnick SO.
    Photodynamic therapy and immunity: an update. Photochem Photobiol. 2020; 96: 550–9.
    OpenUrl
  18. 18.↵
    2. Huang H-C,
    3. Rizvi I,
    4. Liu J,
    5. Anbil S,
    6. Kalra A,
    7. Lee H, et al.
    Photodynamic priming mitigates chemotherapeutic selection pressures and improves drug delivery. Cancer Res. 2018; 78: 558.
    OpenUrlAbstract/FREE Full Text
  19. 19.↵
    2. Choi V,
    3. Rajora MA,
    4. Zheng G.
    Activating drugs with sound: mechanisms behind sonodynamic therapy and the role of nanomedicine. Bioconj Chem. 2020; 31: 967–89.
    OpenUrl
  20. 20.↵
    2. Mitragotri S.
    Healing sound: the use of ultrasound in drug delivery and other therapeutic applications. Nat Rev Drug Discov. 2005; 4: 255–60.
    OpenUrlCrossRefPubMed
  21. 21.↵
    2. Costley D,
    3. Mc Ewan C,
    4. Fowley C,
    5. McHale AP,
    6. Atchison J,
    7. Nomikou N, et al.
    Treating cancer with sonodynamic therapy: a review. Int J Hyperther. 2015; 31: 107–17.
    OpenUrl
  22. 22.
    2. Wan G-Y,
    3. Liu Y,
    4. Chen B-W,
    5. Liu Y-Y,
    6. Wang Y-S,
    7. Zhang N.
    Recent advances of sonodynamic therapy in cancer treatment. Cancer Biol Med. 2016; 13: 325–38.
    OpenUrlAbstract/FREE Full Text
  23. 23.↵
    2. McEwan C,
    3. Nesbitt H,
    4. Nicholas D,
    5. Kavanagh ON,
    6. McKenna K,
    7. Loan P, et al.
    Comparing the efficacy of photodynamic and sonodynamic therapy in non-melanoma and melanoma skin cancer. Bioorg Med Chem. 2016; 24: 3023–8.
    OpenUrl
  24. 24.↵
    2. Chen M,
    3. Liang X,
    4. Dai Z.
    Manganese(III)-chelated porphyrin microbubbles for enhanced ultrasound/MR bimodal tumor imaging through ultrasound-mediated micro-to-nano conversion. Nanoscale. 2019; 11: 10178–82.
    OpenUrl
  25. 25.
    2. Yan P,
    3. Liu L-H,
    4. Wang P.
    Sonodynamic therapy (SDT) for cancer treatment: advanced sensitizers by ultrasound activation to injury tumor. ACS Appl Bio Mater. 2020; 3: 3456–75.
    OpenUrl
  26. 26.
    2. Zhang N,
    3. Yan F,
    4. Liang X,
    5. Wu M,
    6. Shen Y,
    7. Chen M, et al.
    Localized delivery of curcumin into brain with polysorbate 80-modified cerasomes by ultrasound-targeted microbubble destruction for improved Parkinson’s disease therapy. Theranostics. 2018; 8: 2264–77.
    OpenUrl
  27. 27.↵
    2. McEwan C,
    3. Owen J,
    4. Stride E,
    5. Fowley C,
    6. Nesbitt H,
    7. Cochrane D, et al.
    Oxygen carrying microbubbles for enhanced sonodynamic therapy of hypoxic tumours. J Control Release. 2015; 203: 51–6.
    OpenUrl
  28. 28.↵
    2. Lin X,
    3. Zhang X,
    4. Wang S,
    5. Liang X,
    6. Xu Y,
    7. Chen M, et al.
    Intraoperative identification and guidance of breast cancer microfoci using ultrasound and near-infrared fluorescence dual-modality imaging. ACS Appl Bio Mater. 2019; 2: 2252–61.
    OpenUrl
  29. 29.↵
    2. Cui Q,
    3. Wang J-Q,
    4. Assaraf YG,
    5. Ren L,
    6. Gupta P,
    7. Wei L, et al.
    Modulating ROS to overcome multidrug resistance in cancer. Drug Resist Update. 2018; 41: 1–25.
    OpenUrl
  30. 30.↵
    2. Lovell JF,
    3. Jin CS,
    4. Huynh E,
    5. Jin H,
    6. Kim C,
    7. Rubinstein JL, et al.
    Porphysome nanovesicles generated by porphyrin bilayers for use as multimodal biophotonic contrast agents. Nat Mater. 2011; 10: 324–32.
    OpenUrlCrossRefPubMed
  31. 31.↵
    2. Wang S,
    3. Shang L,
    4. Li L,
    5. Yu Y,
    6. Chi C,
    7. Wang K, et al.
    Metal–organic-framework-derived mesoporous carbon nanospheres containing porphyrin-like metal centers for conformal phototherapy. Adv Mater. 2016; 28: 8379–87.
    OpenUrl
  32. 32.↵
    2. Nidal M,
    3. Harley HLC,
    4. Jason LT,
    5. Cheng SJ,
    6. Lili D,
    7. Michael SV, et al.
    Photodynamic therapy enables tumor-specific ablation in preclinical models of thyroid cancer. Endocr-Relat Cancer. 2020; 27: 41–53.
    OpenUrl
  33. 33.↵
    1. Sosnik A,
    2. Bendayan R
    2. Whitlock BD,
    3. Leslie EM.
    Chapter 2 - Efflux transporters in anti-cancer drug resistance: molecular and functional identification and characterization of multidrug resistance proteins (MRPs/ABCCs). In: Sosnik A, Bendayan R Drug efflux pumps in cancer resistance pathways: from molecular recognition and characterization to possible inhibition strategies in chemotherapy. London: Academic Press; 2020. p. 31–65.
  34. 34.↵
    2. Yang X,
    3. Yu Y,
    4. Huang X,
    5. Chen Q,
    6. Wu H,
    7. Wang R, et al.
    Delivery of platinum (II) drugs with bulky ligands in trans-geometry for overcoming cisplatin drug resistance. Mat Sci Eng C-Mater. 2019; 96: 96–104.
    OpenUrl
  35. 35.↵
    2. Vasan N,
    3. Baselga J,
    4. Hyman DM.
    A view on drug resistance in cancer. Nature. 2019; 575: 299–309.
    OpenUrlCrossRefPubMed
  36. 36.↵
    2. Housman G,
    3. Byler S,
    4. Heerboth S,
    5. Lapinska K,
    6. Longacre M,
    7. Snyder N, et al.
    Drug resistance in cancer: an overview. Cancers (Basel). 2014; 6: 1769–92.
    OpenUrl
  37. 37.↵
    2. Zhao C,
    3. Li H,
    4. Lin H-J,
    5. Yang S,
    6. Lin J,
    7. Liang G.
    Feedback activation of STAT3 as a cancer drug-resistance mechanism. Trends Pharmacol Sci. 2016; 37: 47–61.
    OpenUrlCrossRefPubMed
  38. 38.↵
    2. García-Aranda M,
    3. Pérez-Ruiz E,
    4. Redondo M.
    Bcl-2 inhibition to overcome resistance to chemo- and immunotherapy. Int J Mol Sci. 2018; 19: 3950.
    OpenUrl
  39. 39.↵
    2. Farquhar KS,
    3. Charlebois DA,
    4. Szenk M,
    5. Cohen J,
    6. Nevozhay D,
    7. Balázsi G.
    Role of network-mediated stochasticity in mammalian drug resistance. Nat Commun. 2019; 10: 2766.
    OpenUrl
  40. 40.↵
    2. Du B,
    3. Shim JS.
    Targeting epithelial-mesenchymal transition (EMT) to overcome drug resistance in cancer. Molecules. 2016; 21: 965.
    OpenUrlCrossRef
  41. 41.↵
    2. Agliano A,
    3. Calvo A,
    4. Box C.
    The challenge of targeting cancer stem cells to halt metastasis. Semin Cancer Biol. 2017; 44: 25–42.
    OpenUrl
  42. 42.↵
    2. Katsuno Y,
    3. Meyer DS,
    4. Zhang Z,
    5. Shokat KM,
    6. Akhurst RJ,
    7. Miyazono K, et al.
    Chronic TGF-β exposure drives stabilized EMT, tumor stemness, and cancer drug resistance with vulnerability to bitopic mTOR inhibition. Sci Signal. 2019; 12: eaau8544.
  43. 43.↵
    2. Kibria G,
    3. Hatakeyama H,
    4. Akiyama K,
    5. Hida K,
    6. Harashima H.
    Comparative study of the sensitivities of cancer cells to doxorubicin, and relationships between the effect of the drug-efflux pump P-gp. Biol Pharm Bull. 2014; 37: 1926–35.
    OpenUrl
  44. 44.↵
    2. Imran R,
    3. Shubhankar N,
    4. Girgis O,
    5. Huang-Chiao H,
    6. Mans B,
    7. Anne-Laure B, et al.
    Photodynamic therapy-based combinations to overcome molecular, cellular and stromal resistance mechanisms in ovarian and pancreatic cancer (conference presentation). Proc SPIE. 2018; 10476.
  45. 45.↵
    2. Pramual S,
    3. Lirdprapamongkol K,
    4. Jouan-Hureaux V,
    5. Barberi-Heyob M,
    6. Frochot C,
    7. Svasti J, et al.
    Overcoming the diverse mechanisms of multidrug resistance in lung cancer cells by photodynamic therapy using pTHPP-loaded PLGA-lipid hybrid nanoparticles. Eur J Pharm Biopharm. 2020; 149: 218–28.
    OpenUrl
  46. 46.↵
    2. Lindsay J,
    3. Esposti MD,
    4. Gilmore AP.
    Bcl-2 proteins and mitochondria–specificity in membrane targeting for death. BBA-Mol Cell Res. 2011; 1813: 532–9.
    OpenUrl
  47. 47.↵
    2. Spring BQ,
    3. Rizvi I,
    4. Xu N,
    5. Hasan T.
    The role of photodynamic therapy in overcoming cancer drug resistance. Photochem Photobiol Sci. 2015; 14: 1476–91.
    OpenUrlCrossRefPubMed
  48. 48.↵
    2. Han K,
    3. Zhu J-Y,
    4. Jia H-Z,
    5. Wang S-B,
    6. Li S-Y,
    7. Zhang X-Z, et al.
    Mitochondria-targeted chimeric peptide for trinitarian overcoming of drug resistance. ACS Appl Mater Interfaces. 2016; 8: 25060–8.
    OpenUrl
  49. 49.↵
    2. Wang H,
    3. Gao Z,
    4. Liu X,
    5. Agarwal P,
    6. Zhao S,
    7. Conroy DW, et al.
    Targeted production of reactive oxygen species in mitochondria to overcome cancer drug resistance. Nat Commun. 2018; 9: 562.
    OpenUrlCrossRefPubMed
  50. 50.↵
    2. Chen M,
    3. Liang X,
    4. Gao C,
    5. Zhao R,
    6. Zhang N,
    7. Wang S, et al.
    Ultrasound triggered conversion of porphyrin/camptothecin-fluoroxyuridine triad microbubbles into nanoparticles overcomes multidrug resistance in colorectal cancer. ACS Nano. 2018; 12: 7312–26.
    OpenUrl
  51. 51.
    2. Yang L,
    3. Jing C,
    4. Meng S,
    5. Dawei Z,
    6. Mingfeng B.
    Overcoming chemoresistance using tumor mitochondria-targeted photodynamic therapy. San Francisco, CA, USA: Proc SPIE. 2019; 10860.
  52. 52.
    2. Li Z,
    3. Cai Y,
    4. Zhao Y,
    5. Yu H,
    6. Zhou H,
    7. Chen M.
    Polymeric mixed micelles loaded mitoxantrone for overcoming multidrug resistance in breast cancer via photodynamic therapy. Int J Nanomed. 2017; 12: 6595–604.
    OpenUrl
  53. 53.↵
    2. Guo D,
    3. Xu S,
    4. Huang Y,
    5. Jiang H,
    6. Yasen W,
    7. Wang N, et al.
    Platinum(IV) complex-based two-in-one polyprodrug for a combinatorial chemo-photodynamic therapy. Biomaterials. 2018; 177: 67–77.
    OpenUrl
  54. 54.↵
    2. Liu Y,
    3. Bai H,
    4. Wang H,
    5. Wang X,
    6. Liu Q,
    7. Zhang K, et al.
    Comparison of hypocrellin B-mediated sonodynamic responsiveness between sensitive and multidrug-resistant human gastric cancer cell lines. J Med Ultrason. 2019; 46: 15–26.
    OpenUrl
  55. 55.↵
    2. Bryan QS.
    Photodynamic therapy of brain tumor stem cells overcomes drug-resistance in preclinical models (conference presentation). San Francisco, CA, USA: Proc SPIE. 2019; 11070.
  56. 56.↵
    2. Guo Z,
    3. Zheng K,
    4. Tan Z,
    5. Liu Y,
    6. Zhao Z,
    7. Zhu G, et al.
    Overcoming drug resistance with functional mesoporous titanium dioxide nanoparticles combining targeting, drug delivery and photodynamic therapy. J Mater Chem B. 2018; 6: 7750–9.
    OpenUrl
  57. 57.↵
    2. Duan X,
    3. Chan C,
    4. Guo N,
    5. Han W,
    6. Weichselbaum RR,
    7. Lin W.
    Photodynamic therapy mediated by nontoxic core–shell nanoparticles synergizes with immune checkpoint blockade to elicit antitumor immunity and antimetastatic effect on breast cancer. J Am Chem Soc. 2016; 138: 16686–95.
    OpenUrl
  58. 58.↵
    2. Wu Y,
    3. Liu X,
    4. Qin Z,
    5. Hu L,
    6. Wang X.
    Low-frequency ultrasound enhances chemotherapy sensitivity and induces autophagy in PTX-resistant PC-3 cells via the endoplasmic reticulum stress-mediated PI3K/Akt/mTOR signaling pathway. Onco Targets Ther. 2018; 11: 5621–30.
    OpenUrl
  59. 59.
    2. Xie L,
    3. Feng X,
    4. Shi Y,
    5. He M,
    6. Wang P,
    7. Wang X, et al.
    Blocking the glycolytic pathway sensitizes breast cancer to sonodynamic therapy. Ultrasound Med Biol. 2018; 44: 1233–43.
    OpenUrl
  60. 60.↵
    2. Kim HM,
    3. Cho BR.
    Small-molecule two-photon probes for bioimaging applications. Chem Rev. 2015; 115: 5014–55.
    OpenUrl
  61. 61.↵
    2. Hassan MA,
    3. Furusawa Y,
    4. Minemura M,
    5. Rapoport N,
    6. Sugiyama T,
    7. Kondo T.
    Ultrasound-induced new cellular mechanism involved in drug resistance. PLoS One. 2012; 7: e48291.
  62. 62.↵
    2. Son S,
    3. Kim JH,
    4. Wang X,
    5. Zhang C,
    6. Yoon SA,
    7. Shin J, et al.
    Multifunctional sonosensitizers in sonodynamic cancer therapy. Chem Soc Rev. 2020; 49: 3244–61.
    OpenUrl
  63. 63.↵
    2. Zhang X,
    3. Liu R,
    4. Dai Z.
    Multicolor nanobubbles for FRET/ultrasound dual-modal contrast imaging. Nanoscale. 2018; 10: 20347–53.
    OpenUrl
  64. 64.↵
    2. Mehraban N,
    3. Freeman HS.
    Developments in PDT sensitizers for increased selectivity and singlet oxygen production. Materials (Basel). 2015; 8: 4421–56.
    OpenUrl
  65. 65.↵
    2. Jing X,
    3. Yang F,
    4. Shao C,
    5. Wei K,
    6. Xie M,
    7. Shen H, et al.
    Role of hypoxia in cancer therapy by regulating the tumor microenvironment. Mol Cancer. 2019; 18: 157.
    OpenUrlCrossRef
  66. 66.↵
    2. Pan X,
    3. Bai L,
    4. Wang H,
    5. Wu Q,
    6. Wang H,
    7. Liu S, et al.
    Metal–organic-framework-derived carbon nanostructure augmented sonodynamic cancer therapy. Adv Mater. 2018; 30: 1800180.
  67. 67.↵
    2. Fang Y,
    3. Zheng G,
    4. Yang J,
    5. Tang H,
    6. Zhang Y,
    7. Kong B, et al.
    Dual-pore mesoporous carbon@silica composite core–shell nanospheres for multidrug delivery. Angew Chem Int Ed Engl. 2014; 53: 5366–70.
    OpenUrl
  68. 68.↵
    2. Kapse-Mistry S,
    3. Govender T,
    4. Srivastava R,
    5. Yergeri M.
    Nanodrug delivery in reversing multidrug resistance in cancer cells. Front Pharmacol. 2014; 5: 159.
    OpenUrl
  69. 69.↵
    2. Gao Z,
    3. Zhang L,
    4. Sun Y.
    Nanotechnology applied to overcome tumor drug resistance. J Control Release. 2012; 162: 45–55.
    OpenUrlPubMed
  70. 70.
    2. Liu Y,
    3. Sun D,
    4. Fan Q,
    5. Ma Q,
    6. Dong Z,
    7. Tao W, et al.
    The enhanced permeability and retention effect based nanomedicine at the site of injury. Nano Res. 2020; 13: 564–9.
    OpenUrl
  71. 71.↵
    2. Dhaliwal A,
    3. Zheng G.
    Improving accessibility of EPR-insensitive tumor phenotypes using EPR-adaptive strategies: designing a new perspective in nanomedicine delivery. Theranostics. 2019; 9: 8091–108.
    OpenUrl
  72. 72.
    2. Ai F,
    3. Sun T,
    4. Xu Z,
    5. Wang Z,
    6. Kong W,
    7. To MW, et al.
    An upconversion nanoplatform for simultaneous photodynamic therapy and Pt chemotherapy to combat cisplatin resistance. Dalton Trans. 2016; 45: 13052–60.
    OpenUrl
  73. 73.
    2. Zhou L,
    3. Zhou L,
    4. Wei S,
    5. Ge X,
    6. Zhou J,
    7. Jiang H, et al.
    Combination of chemotherapy and photodynamic therapy using graphene oxide as drug delivery system. J Photochem Photobiol B. 2014; 135: 7–16.
    OpenUrl
  74. 74.
    2. Park H,
    3. Park W,
    4. Na K.
    Doxorubicin loaded singlet-oxygen producible polymeric micelle based on chlorine e6 conjugated pluronic F127 for overcoming drug resistance in cancer. Biomaterials. 2014; 35: 7963–9.
    OpenUrl
  75. 75.
    2. Liu B,
    3. Li C,
    4. Chen G,
    5. Liu B,
    6. Deng X,
    7. Wei Y, et al.
    Synthesis and optimization of MoS2@Fe3O4-ICG/Pt(IV) nanoflowers for MR/IR/PA bioimaging and combined PTT/PDT/chemotherapy triggered by 808 nm laser. Adv Sci (Weinh). 2017; 4: 1600540.
  76. 76.
    2. Liu L,
    3. Bao Y,
    4. Wang J,
    5. Xiao C,
    6. Chen L.
    Construction of carrier-free porphyrin-based drug self-framed delivery system to reverse multidrug resistance through photodynamic-chemotherapy. Dyes Pigments. 2020; 177: 107922.
  77. 77.
    2. Yu G,
    3. Zhu B,
    4. Shao L,
    5. Zhou J,
    6. Saha ML,
    7. Shi B, et al.
    Host−guest complexation-mediated codelivery of anticancer drug and photosensitizer for cancer photochemotherapy. Proc Natl Acad Sci USA. 2019; 116: 6618–23.
    OpenUrlAbstract/FREE Full Text
  78. 78.
    2. Liang S,
    3. Deng X,
    4. Xu G,
    5. Xiao X,
    6. Wang M,
    7. Guo X, et al.
    A novel Pt–TiO2 heterostructure with oxygen-deficient layer as bilaterally enhanced sonosensitizer for synergistic chemo-sonodynamic cancer therapy. Adv Funct Mater. 2020; 30: 1908598.
  79. 79.
    2. Wan G,
    3. Liu Y,
    4. Shi S,
    5. Chen B,
    6. Wang Y,
    7. Wang H, et al.
    Hematoporphyrin and doxorubicin co-loaded nanomicelles for the reversal of drug resistance in human breast cancer cells by combining sonodynamic therapy and chemotherapy. RSC Adv. 2016; 6: 100361–72.
    OpenUrl
  80. 80.↵
    2. Miyoshi N,
    3. Kundu SK,
    4. Tuziuti T,
    5. Yasui K,
    6. Shimada I,
    7. Ito Y.
    Combination of sonodynamic and photodynamic therapy against cancer would be effective through using a regulated size of nanoparticles. Nanosci Nanoeng. 2016; 4: 1–11.
    OpenUrl
  81. 81.↵
    2. Liu Z,
    3. Li J,
    4. Chen W,
    5. Liu L,
    6. Yu F.
    Light and sound to trigger the Pandora’s box against breast cancer: a combination strategy of sonodynamic, photodynamic and photothermal therapies. Biomaterials. 2020; 232: 119685.
  82. 82.↵
    2. Julian Norman K,
    3. Richard James F,
    4. Thomas Joseph L.
    Activated cancer therapy using light and ultrasound – a case series of sonodynamic photodynamic therapy in 115 patients over a 4 year period. Curr Drug Ther. 2009; 4: 179–93.
    OpenUrlCrossRef
  83. 83.
    2. Tserkovsky DA,
    3. Alexandrova EN,
    4. Chalau VN,
    5. Istomin YP.
    Effects of combined sonodynamic and photodynamic therapies with photolon on a glioma C6 tumor model. Exp Oncol. 2012; 34: 332–5.
    OpenUrlPubMed
  84. 84.
    2. Wang XJ,
    3. Mitchell D,
    4. Lewis TJ.
    Primary clinical use of sonodynamic therapy (SDT) for advanced breast cancer. J Clin Oncol. 2008; 26: 12029.
  85. 85.↵
    2. Wang X,
    3. Zhang W,
    4. Xu Z,
    5. Luo Y,
    6. Mitchell D,
    7. Moss RW.
    Sonodynamic and photodynamic therapy in advanced breast carcinoma: a report of 3 cases. Integr Cancer Ther. 2009; 8: 283–7.
    OpenUrlCrossRefPubMed
  86. 86.↵
    2. Lin L,
    3. Wang X,
    4. Guo Y,
    5. Ren K,
    6. Li X,
    7. Jing L, et al.
    Hybrid bicelles as a PH-sensitive nanocarrier for hydrophobic drug delivery. RSC Adv. 2016; 6: 79811–21.
    OpenUrl
  87. 87.↵
    2. Zhang W,
    3. Shen J,
    4. Su H,
    5. Mu G,
    6. Sun J-H,
    7. Tan C-P, et al.
    Co-delivery of cisplatin prodrug and chlorin e6 by mesoporous silica nanoparticles for chemo-photodynamic combination therapy to combat drug resistance. ACS Appl Mater Interfaces. 2016; 8: 13332–40.
    OpenUrl
  88. 88.↵
    2. Li H,
    3. Liu C,
    4. Zeng Y-P,
    5. Hao Y-H,
    6. Huang J-W,
    7. Yang Z-Y, et al.
    Nanoceria-mediated drug delivery for targeted photodynamic therapy on drug-resistant breast cancer. ACS Appl Mater Interfaces. 2016; 8: 31510–23.
    OpenUrlCrossRef
  89. 89.
    2. Feng X,
    3. Jiang D,
    4. Kang T,
    5. Yao J,
    6. Jing Y,
    7. Jiang T, et al.
    Tumor-homing and penetrating peptide-functionalized photosensitizer-conjugated PEG-PLA nanoparticles for chemo-photodynamic combination therapy of drug-resistant cancer. ACS Appl Mater Interfaces. 2016; 8: 17817–32.
    OpenUrl
  90. 90.↵
    2. Kato T,
    3. Jin CS,
    4. Ujiie H,
    5. Lee D,
    6. Fujino K,
    7. Wada H, et al.
    Nanoparticle targeted folate receptor 1-enhanced photodynamic therapy for lung cancer. Lung Cancer. 2017; 113: 59–68.
    OpenUrl
  91. 91.↵
    2. Yu G,
    3. Yu S,
    4. Saha ML,
    5. Zhou J,
    6. Cook TR,
    7. Yung BC, et al.
    A discrete organoplatinum(II) metallacage as a multimodality theranostic platform for cancer photochemotherapy. Nat Commun. 2018; 9: 4335.
    OpenUrl
  92. 92.↵
    2. Wang D,
    3. Li X,
    4. Li X,
    5. Kang A,
    6. Sun L,
    7. Sun M, et al.
    Magnetic and PH dual-responsive nanoparticles for synergistic drug-resistant breast cancer chemo/photodynamic therapy. Int J Nanomedicine. 2019; 14: 7665–79.
    OpenUrl
  93. 93.↵
    2. Yu H,
    3. Cui Z,
    4. Yu P,
    5. Guo C,
    6. Feng B,
    7. Jiang T, et al.
    PH- and NIR light-responsive micelles with hyperthermia-triggered tumor penetration and cytoplasm drug release to reverse doxorubicin resistance in breast cancer. Adv Funct Mater. 2015; 25: 2489–500.
    OpenUrl
  94. 94.↵
    2. Cheng L,
    3. Zhang F,
    4. Wang S,
    5. Pan X,
    6. Han S,
    7. Liu S, et al.
    Activation of prodrugs by NIR-triggered release of exogenous enzymes for locoregional chemo-photothermal therapy. Angew Chem Int Ed Engl. 2019; 58: 7728–32.
    OpenUrl
  95. 95.↵
    2. Overchuk M,
    3. Zheng G.
    Overcoming obstacles in the tumor microenvironment: recent advancements in nanoparticle delivery for cancer theranostics. Biomaterials. 2018; 156: 217–37.
    OpenUrl
  96. 96.↵
    2. Li L,
    3. Chen C,
    4. Liu H,
    5. Fu C,
    6. Tan L,
    7. Wang S, et al.
    Multifunctional carbon–silica nanocapsules with gold core for synergistic photothermal and chemo-cancer therapy under the guidance of bimodal imaging. Adv Funct Mater. 2016; 26: 4252–61.
    OpenUrl
  97. 97.↵
    2. Feng C,
    3. Rui M,
    4. Shen H,
    5. Xin Y,
    6. Zhang J,
    7. Li J, et al.
    Tumor-specific delivery of doxorubicin through conjugation of PH-responsive peptide for overcoming drug resistance in cancer. Int J Pharmaceut. 2017; 528: 322–33.
    OpenUrl
  98. 98.↵
    2. Sun W,
    3. Li S,
    4. Häupler B,
    5. Liu J,
    6. Jin S,
    7. Steffen W, et al.
    An amphiphilic ruthenium polymetallodrug for combined photodynamic therapy and photochemotherapy in vivo. Adv Mater. 2017; 29: 1603702.
  99. 99.↵
    2. Duan L,
    3. Yang L,
    4. Jin J,
    5. Yang F,
    6. Liu D,
    7. Hu K, et al.
    Micro/nano-bubble-assisted ultrasound to enhance the EPR effect and potential theranostic applications. Theranostics. 2020; 10: 462–83.
    OpenUrl
  100. 100.↵
    2. Shi J,
    3. Liu W,
    4. Fu Y,
    5. Yin N,
    6. Zhang H,
    7. Chang J, et al.
    “US-detonated nano bombs” facilitate targeting treatment of resistant breast cancer. J Control Release. 2018; 274: 9–23.
    OpenUrl
  101. 101.↵
    2. Li J,
    3. Sun C,
    4. Tao W,
    5. Cao Z,
    6. Qian H,
    7. Yang X, et al.
    Photoinduced PEG deshielding from ROS-sensitive linkage-bridged block copolymer-based nanocarriers for on-demand drug delivery. Biomaterials. 2018; 170: 147–55.
    OpenUrl
  102. 102.↵
    2. Pei P,
    3. Sun C,
    4. Tao W,
    5. Li J,
    6. Yang X,
    7. Wang J.
    ROS-sensitive thioketal-linked polyphosphoester-doxorubicin conjugate for precise phototriggered locoregional chemotherapy. Biomaterials. 2019; 188: 74–82.
    OpenUrl
  103. 103.↵
    2. Cao Z,
    3. Ma Y,
    4. Sun C,
    5. Lu Z,
    6. Yao Z,
    7. Wang J, et al.
    ROS-sensitive polymeric nanocarriers with red light-activated size shrinkage for remotely controlled drug release. Chem Mater. 2018; 30: 517–25.
    OpenUrl
  104. 104.↵
    2. Wang T,
    3. Wang D,
    4. Yu H,
    5. Wang M,
    6. Liu J,
    7. Feng B, et al.
    Intracellularly acid-switchable multifunctional micelles for combinational photo/chemotherapy of the drug-resistant tumor. ACS Nano. 2016; 10: 3496–508.
    OpenUrl
  105. 105.↵
    2. Wei X,
    3. Liu L,
    4. Guo X,
    5. Wang Y,
    6. Zhao J,
    7. Zhou S.
    Light-activated ROS-responsive nanoplatform codelivering apatinib and doxorubicin for enhanced chemo-photodynamic therapy of multidrug-resistant tumors. ACS Appl Mater Interfaces. 2018; 10: 17672–84.
    OpenUrlCrossRef
  106. 106.↵
    2. Das S,
    3. Mukherjee P,
    4. Chatterjee R,
    5. Jamal Z,
    6. Chatterji U.
    Enhancing chemosensitivity of breast cancer stem cells by downregulating SOX2 and ABCG2 using wedelolactone-encapsulated nanoparticles. Mol Cancer Ther. 2019; 18: 680.
    OpenUrlAbstract/FREE Full Text
  107. 107.
    2. Bhattarai P,
    3. Hameed S,
    4. Dai Z.
    Recent advances in anti-angiogenic nanomedicines for cancer therapy. Nanoscale. 2018; 10: 5393–423.
    OpenUrl
  108. 108.↵
    2. Gao C,
    3. Liang X,
    4. Mo S,
    5. Zhang N,
    6. Sun D,
    7. Dai Z.
    Near-infrared cyanine-loaded liposome-like nanocapsules of camptothecin-floxuridine conjugate for enhanced chemophotothermal combination cancer therapy. ACS Appl Mater Interfaces. 2018; 10: 3219–28.
    OpenUrl
  109. 109.↵
    2. Zhen S,
    3. Yi X,
    4. Zhao Z,
    5. Lou X,
    6. Xia F,
    7. Tang BZ.
    Drug delivery micelles with efficient near-infrared photosensitizer for combined image-guided photodynamic therapy and chemotherapy of drug-resistant cancer. Biomaterials. 2019; 218: 119330.
  110. 110.↵
    2. Wang M,
    3. Xiao Y,
    4. Li Y,
    5. Wu J,
    6. Li F,
    7. Ling D, et al.
    Reactive oxygen species and near-infrared light dual-responsive indocyanine green-loaded nanohybrids for overcoming tumour multidrug resistance. Eur J Pharm Sci. 2019; 134: 185–93.
    OpenUrl
  111. 111.↵
    2. Jackson J,
    3. Leung D,
    4. Burt H.
    The use of ultrasound to increase the uptake and cytotoxicity of dual taxane and P-glycoprotein inhibitor loaded, solid core nanoparticles in drug resistant cells. Ultrasonics. 2020; 101: 106033.
  112. 112.↵
    2. Luo Z,
    3. Tian H,
    4. Liu L,
    5. Chen Z,
    6. Liang R,
    7. Chen Z, et al.
    Tumor-targeted hybrid protein oxygen carrier to simultaneously enhance hypoxia-dampened chemotherapy and photodynamic therapy at a single dose. Theranostics. 2018; 8: 3584–96.
    OpenUrl
  113. 113.↵
    2. Yang G,
    3. Tian J,
    4. Chen C,
    5. Jiang D,
    6. Xue Y,
    7. Wang C, et al.
    An oxygen self-sufficient NIR-responsive nanosystem for enhanced PDT and chemotherapy against hypoxic tumors. Chem Sci. 2019; 10: 5766–72.
    OpenUrl
  114. 114.↵
    2. McEwan C,
    3. Kamila S,
    4. Owen J,
    5. Nesbitt H,
    6. Callan B,
    7. Borden M, et al.
    Combined sonodynamic and antimetabolite therapy for the improved treatment of pancreatic cancer using oxygen loaded microbubbles as a delivery vehicle. Biomaterials. 2016; 80: 20–32.
    OpenUrl
  115. 115.↵
    2. Guo Z,
    3. Li W,
    4. Yuan Y,
    5. Zheng K,
    6. Tang Y,
    7. Ma K, et al.
    Improvement of chemosensitivity and inhibition of migration via targeting tumor epithelial-to-mesenchymal transition cells by ADH-1-modified liposomes. Drug Deliv. 2018; 25: 112–21.
    OpenUrl
  116. 116.↵
    2. Balakrishnan S,
    3. Bhat FA,
    4. Raja Singh P,
    5. Mukherjee S,
    6. Elumalai P,
    7. Das S, et al.
    Gold nanoparticle–conjugated quercetin inhibits epithelial–mesenchymal transition, angiogenesis and invasiveness via EGFR/VEGFR-2-mediated pathway in breast cancer. Cell Prolif. 2016; 49: 678–97.
    OpenUrl
  117. 117.↵
    2. Geng Y,
    3. Goel HL,
    4. Le NB,
    5. Yoshii T,
    6. Mout R,
    7. Tonga GY, et al.
    Rapid phenotyping of cancer stem cells using multichannel nanosensor arrays. Nanomedicine. 2018; 14: 1931–9.
    OpenUrl
  118. 118.↵
    2. Spring BQ,
    3. Bryan Sears R,
    4. Zheng LZ,
    5. Mai Z,
    6. Watanabe R,
    7. Sherwood ME, et al.
    A photoactivable multi-inhibitor nanoliposome for tumour control and simultaneous inhibition of treatment escape pathways. Nat Nanotechnol. 2016; 11: 378–87.
    OpenUrl
  119. 119.↵
    2. Liu Y,
    3. Wan G,
    4. Guo H,
    5. Liu Y,
    6. Zhou P,
    7. Wang H, et al.
    A multifunctional nanoparticle system combines sonodynamic therapy and chemotherapy to treat hepatocellular carcinoma. Nano Res. 2017; 10: 834–55.
    OpenUrl
  120. 120.↵
    2. Friedrich M,
    3. Jasinski-Bergner S,
    4. Lazaridou M-F,
    5. Subbarayan K,
    6. Massa C,
    7. Tretbar S, et al.
    Tumor-induced escape mechanisms and their association with resistance to checkpoint inhibitor therapy. Cancer Immunol Immunother. 2019; 68: 1689–700.
    OpenUrlPubMed
  121. 121.↵
    2. Hu L,
    3. Cao Z,
    4. Ma L,
    5. Liu Z,
    6. Liao G,
    7. Wang J, et al.
    The potentiated checkpoint blockade immunotherapy by ROS-responsive nanocarrier-mediated cascade chemo-photodynamic therapy. Biomaterials. 2019; 223: 119469.
  122. 122.↵
    2. Im S,
    3. Lee J,
    4. Park D,
    5. Park A,
    6. Kim Y-M,
    7. Kim WJ.
    Hypoxia-triggered transforming immunomodulator for cancer immunotherapy via photodynamically enhanced antigen presentation of dendritic cell. ACS Nano. 2019; 13: 476–88.
    OpenUrl
  123. 123.↵
    2. He C,
    3. Duan X,
    4. Guo N,
    5. Chan C,
    6. Poon C,
    7. Weichselbaum RR, et al.
    Core-shell nanoscale coordination polymers combine chemotherapy and photodynamic therapy to potentiate checkpoint blockade cancer immunotherapy. Nat Commun. 2016; 7: 12499.
Back to top

In this issue

Print
Download PDF
Email Article
Citation Tools

Jump to section

Keywords