Commentary on: An improved nanoparticle-based combinatorial

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Commentary on: An improved nanoparticlebased combinatorial approach to fight cancer Channakeshava Umeshappa, and Kun Shao ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b11346 • Publication Date (Web): 15 Oct 2018 Downloaded from http://pubs.acs.org on October 16, 2018

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ACS Applied Materials & Interfaces

Comment on: An improved nanoparticle-based combinatorial approach to fight cancer Channakeshava Sokke Umeshappa1* and Kun Shao2

1 Department

of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming

School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.

2 State

Key Laboratory of Fine Chemicals, Dalian University of Technology, No 2 Linggong Road,

Dalian, 116024, China *Correspondence to: [email protected]

Key words: iRGD, photothermal therapy, combinatorial therapy, immunotherapy, primary and metastatic tumors.

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Abstract

Nanomedicine is at the forefront of targeted drug delivery for cancer therapy. An improved combinatorial approach is highlighted for breast cancer treatment by Hu et al. in this issue of ACS: Applied Materials and Interfaces. The authors demonstrated that by combining multistage-responsive nanoparticles carrying a therapeutic drug, doxorubicin, a photothermal agent, indocyanine green, and a nitric oxide donor with photothermal therapy and intravenous injection of a tumor-homing iRGD peptide, one could achieve efficient therapeutics distribution deep inside the tumor and nearly eradicate primary tumor growth. An in-depth understanding of this approach in combination with other strategies such as the use of immunomodulators would facilitate metastatic tumors treatment in distant organs and clinical translation of this platform, benefiting cancer patients by providing long-lasting efficacy.


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Nanomedicines are considerably impacting the current state of the cancer therapy. Nanomedicines possess several advantages, including prolonged circulation, tunable size, active targetability and intracellular drug release, which make them suitable candidates for cancer therapy, particularly in combinatorial approaches. Additionally, due to abnormal tumor vasculature, nanoparticles (NPs) get passively diffused and sequestered into a tumor called “enhanced permeability and retention” (EPR) effect. EPR facilitates NPs to deliver therapeutic moiety effectively into tumors;1 2

however, NPs reach only to the margin and fail to penetrate into the center of the tumor. Hence, they

achieve limited therapeutic effects. Besides, due to fast intravascular flow, small-sized particles stay in the tumor for a transient period, which further limits the therapeutic impact of nanomedicines. In this issue, Hu et al.,3 showed that the combinatorial approach, which consists use of advanced, enzymesensitive, size-changeable and laser-enhanced-nitric oxide(NO)-release NPs (IDDHN NPs), intravenous injection of a tumor-homing iRGD peptide, and photothermal therapy (PTT), could help to distribute therapeutic targets across the tumor, thereby suppressing tumor growth with minimal side effects. The authors' strategy is quite creative, which addresses many limitations associated with current cancer therapies. First, iRGD used in the therapy binds specifically to the αvβ3-integrin-receptorsexpressing neovascular endothelial cells and enhances tumors’ vascular and tissue permeability,4 thereby aiding extravasation and deep penetration of the NPs or any other therapeutic moieties, including antitumor drugs, imaging agents, immune modulators, or biological products that are coadministered.5 It also binds to αvβ3-integrin-receptors-expressing tumor cells and facilitates smaller drugs or NPs entry into tumor cells by the active process, thus aiding cytotoxic effects.6 Second, the engineered NPs contain indocyanine green (ICG), which increases the tumor temperature upon 808 nm near-infrared (NIR) laser irradiation. Thirdly, NPs comprise NO-donor-modified hyaluronic acid shell (HN), which under increased temperature, gets digested by hyaluronidase, which in turn facilitates the conversion of large NPs into a smaller-sized NPs and NO release. Together, iRGD, NO, and tumor ACS Paragon Plus Environment


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hyperthermia promote deep penetration of the designed NPs and their extravasation inside the tumor. Finally, once distributed evenly across the tumor mass, the doxorubicin (DOX) that is tethered to the dendrimer effectively kills tumor cells. Thus, these smartly engineered NPs protect the host from tumor establishment and subsequent metastasis. Further, this combinatorial approach appears to be safe to use as no cytotoxic effects were observed in healthy tissues such as the liver and kidneys despite iRGD facilitated IDDHN NPs accumulation in these organs. The Triad Approach to kill tumor One of the prerequisites of the authors’ approach is the laser irradiation of the primary tumor that facilitates size shrinkage of NPs and NO release. Here, authors observed a near eradication of the primary breast tumor when compared to their previous reports, where they followed the similar approach but without photothermal therapy7 or iRGD treatment8, suggesting the requirement of both iRGD and PTT to synergize the effects of IDDHN NPs. However, this Triad Approach is restricted to treat primary tumors and is of value in the early diagnosis of cancer when there is no metastasis due to a limited penetration depth of the NIR irradiation in deep tissues. Although metastasis is the prime cause of treatment failure and most cancer-related deaths, it is not addressed in the current work. As the primary goal of any cancer therapy is to treat metastatic cancer, the future work should be directed towards how this combinatorial approach is being used to treat metastatic cancer in the distant organs in the body. Although iRGD tumor-targeting effects were originally observed in mice xenografted with human breast or prostate by Sugahara et al.,6 in the case of prostate cancer, other researchers failed to see similar beneficial effects of iRGD.9 However, Gao groups clearly showed synergistic effects of iRGD when treating mouse 4T1 breast tumor.7-8 The expression of key receptors necessary for iRGD functions such as αvβ3 integrin and neuropilin-1 appears to play a crucial role in this combinatorial approach. Although tumor angiogenesis is prerequisite for all the tumors establishment and hence most tumors’ vasculature expresses a high level of αvβ3 integrin, to what extent this receptor expression by ACS Paragon Plus Environment

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tumor cells per se is required for iRGD effects need further investigation. Since iRGD facilitates drug entry into tumor cells actively in a receptor- and energy-dependent manner,6 this study is important as iRGD’s beneficial effects is maximally achieved if the therapeutic drug enters tumor cells rather than entering newly formed endothelial cells or mere extravasation in tumors. Consequently, as αvβ3 integrin expression level varies from tumor to tumor, and during tumor progression,10-11 this combinatorial approach may not be effective against all types and or different stages of tumors. Hence, iRGD use in the cancer therapy should be validated for each solid tumor before considering this combinatorial approach for clinical trial. Recently, Zhu et al., constructed bispecific tumor-penetrating protein, antiepidermal growth factors receptor (EGFR)-iRGD, using the heavy chain variable region of anti-EGFR antibody and a tumor-penetrating peptide iRGD and used this protein to increase the efficacy of paclitaxel and T cells response against clinically relevant xenograft mouse model of EBV-associated gastric cancer.12-13 It will be interesting to see whether combining iRGD with additional tumor-specific protein(s) such as EGFR will enhance therapeutic benefits of this approach in situations where iRGD use alone not effective. To our knowledge, only one clinical study (Phase I trial) has been conducted to see the effects of iRGD in patients with metastatic pancreatic adenocarcinoma (CEND1-001, Clinical trial reference NCT03517176). Although the effects of iRGD have been extensively studied in murine models, its clinical use in human is yet to be proved. Photothermal therapy is a minimally invasive technique that uses laser energy from photothermal agents to generate hyperthermia and kill cancer cells. So far upon combining with other therapies, PTT has achieved some success in treating local metastasized lymph node, bone, and even lung14, but not in large surface tumors and primary tumors and metastasis of deep organs, such as liver, ovaries, and kidneys. Clinically, it has been applied to treat tumors of epidermal tissues and few organs 15-16.

Although there is limited clinical study available on using PTT and nanotherapy combination in

humans, numerous preclinical studies in murine models suggest the potential of translating this therapy 17-18.

One study used a clinically relevant model, mice with triple negative breast cancer xenografts, and ACS Paragon Plus Environment


studied the effectiveness of sub-100 nm gold nanomatryoshkas in combination with PTT 19. One clinical trial also used AuroShell particles and NIR laser irradiation to treat refractory and recurrent head and neck cancers 20 suggesting PTT could be used in human in the near future. Owing to its smart designing and the use of iRGD and PTT, whether the Triad Approach effectively eradicates metastasis in local metastasized lymph node, bone and lung needs further investigation. It is possible this approach is useful in early stages of metastasis wherein PTT in combination with iRGD and DOX suppresses primary tumor growth while the iRGD- and or EPRmediated delivery of DOX could prevent and even inhibit small metastatic tumors in the distant organs without the aid of PTT. Recently, several researchers have investigated the use of a novel stimulated intracellular light therapy to overcome the deep-penetration limitations of traditional light-based treatments.21-23 This therapy uses radionuclides that trigger tumor-localized photosensitizing nanoparticles to generate cherenkov luminescence to kill tumor cells. Progress in imaging-guided PTT is also gaining momentum to treat metastatic cancer.14 In the near future, these advancements could be of use in this combinatorial approach for treating distant metastatic tumors. Immunotherapy to boost the efficacy of nanotherapeutics Despite the strategies mentioned above, eradicating a late stage metastatic cancer could remain a significant challenge in this combinatorial approach. Given the fact that this approach nearly eradicated primary tumor, it is possible that it contributes to anti-tumor immunity development in the host. Authors concluded that the maximal apoptosis, mediated by both DOX and PTT,24 can be achieved with the use of iRGD. Tumor apoptosis is known to promote a robust antitumor cellular immunity development compared to necrotic cells. Apoptotic tumor cells release tumor-associated antigens in a way that promotes robust cross-presentation of these antigens by antigen presenting cells (APCs) to CD8+ T cells, which contributes to protective adaptive immune response against not only primary tumors but also against subsequent metastasis (Figure 1).25 This antitumor response can be potentiated several folds by treating hosts additionally with immune adjuvants to inhibit the ongoing ACS Paragon Plus Environment

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anti-tumor immune suppressive mechanisms. The selection of adjuvants in this combinatorial approach should be aimed at APCs to facilitate robust T cells stimulation, to dampen suppressive effects of regulatory T cells, and or at effector T cells to reverse the ongoing exhausted status. Indeed, the use of an APCs stimulant, N-dihydro-galacto-chitosan (GC), a semi-synthetic functionalized glucosamine polymer, facilitated uptake of tumor antigens and presentation, leading to suppression of metastatic tumors growth.26-27 Similarly, the blockade of checkpoints, such as PD-1 and or CTLA-4, in melanoma and other tumor types such as non–small cell lung cancer reversed T cell exhaustion and enhanced antitumor immune response.28-30 Although holding enormous future promise, immunotherapy, as observed in the on-going clinical trials, is associated with lethal on-target and off-tumor toxicities 31. These side effects can be circumvented by systemic therapeutic approaches, such as combining both combinatorial Triad Approach and immunotherapy, which ensures both tumor-targeting and killing and, subsequent generation of anti-tumor immunity. To sum, the authors-described combinatorial approach can overcome many limitations of the current tumor therapy. A near-complete eradication of primary breast tumor by this approach is quite exciting and holds future promise. Future studies should focus on whether this approach, perhaps in conjunction with immunotherapy, is effective against metastasis, and in different types of primary tumors. Elucidation of the critical antitumor immunological events that occur consequent to this therapy is also paramount essential. Ultimately, these studies would help us to improve this combinatorial approach further for generating efficient and prolonged antitumor immune responses not only against primary tumors but also against distant metastatic tumors. AUTHOR INFORMATION Corresponding Author * E-mail: [email protected]



Present Address 1 Department

of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming

School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada. Author Contributions C.S.U. conceived the work, and wrote the paper with supports from K.S. Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT C.S.U. was supported by CIHR, Alberta Innovates–Health Solutions (#20140079) and Banting-CIHR (#BPF134464) fellowships from Canadian funding agencies. K.S is supported by The Thousand Talents Plan for Young Professionals (#2100-874D01) from the government of China.

ABBREVIATIONS NPs, Nanoparticles; EPR, enhanced permeability and retention; NO, nitric oxide; PTT, photothermal therapy; NIR, near-infrared; DOX, doxorubicin; EGFR, epidermal growth factors receptor; APCs, antigen presenting cells.

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Legend: Figure 1. Promoting anti-tumor immunity development in the combinatorial approach to suppress metastatic tumors. In nanoparticles-based combinatorial strategy, NO release, and NPs down-sizing occurs under the influence of iRGD and photothermal therapy. Smaller NPs then penetrate the center of the primary tumor and release DOX, which in turn induce immunogenic cell death, apoptosis, and tumor antigens shedding. Immature APCs (iAPCs) pick up the released tumor antigens and, under the influence of immune adjuvants, undergo maturation (mAPCs), inhibit regulatory T cells’ (Tregs) suppressive activity, and cross-present tumor antigens efficiently to naive T cells, leading to the generation of cytotoxic effector T cells and killing of both primary and metastasized tumor cells. When there is immune exhaustion, checkpoints blockade rescues and converts the exhausted effector T cells into functional potent cytotoxic T cells, which in turn kill tumor cells.


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NIR DOX

iRGD


Immunogentic cell death & Tumor antigen release

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Boosting Immunity

Adjuvants

Tumor draining lymph node mAPCs

ICG

iAPCs Naive T cells

Primary solid tumor

Tregs

Apoptotic cells

Effector T cells Checkpoints blockade

Metastatic tumor


Commentary on: An improved nanoparticle-based combinatorial

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