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Recent Studies and Progress in the Intratumoral Administration of Nano-Sized Drug Delivery Systems

Yun, Wan Su, Kim, Jeongrae, Lim, Dong-Kwon, Kim, Dong-Hwee, Jeon, Seong Ik, Kim, Kwangmeyung·2023·Nanomaterials
DOI 10.3390/nano13152225PMC PMC10421122
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Abstract

Over the last 30 years, diverse types of nano-sized drug delivery systems (nanoDDSs) have been intensively explored for cancer therapy, exploiting their passive tumor targetability with an enhanced permeability and retention effect. However, their systemic administration has aroused some unavoidable complications, including insufficient tumor-targeting efficiency, side effects due to their undesirable biodistribution, and carrier-associated toxicity. In this review, the recent studies and advancements in intratumoral nanoDDS administration are generally summarized. After identifying the factors to be considered to enhance the therapeutic efficacy of intratumoral nanoDDS administration, the experimental results on the application of intratumoral nanoDDS administration to various types of cancer therapies are discussed. Subsequently, the reports on clinical studies of intratumoral nanoDDS administration are addressed in short. Intratumoral nanoDDS administration is proven with its versatility to enhance the tumor-specific accumulation and retention of therapeutic agents for various therapeutic modalities. Specifically, it can improve the efficacy of therapeutic agents with poor bioavailability by increasing their intratumoral concentration, while minimizing the side effect of highly toxic agents by restricting their delivery to normal tissues. Intratumoral administration of nanoDDS is considered to expand its application area due to its potent ability to improve therapeutic effects and relieve the systemic toxicities of nanoDDSs.

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Scheme 1 Schematic illustration of intratumoral nanoDDS administration. Various types of nanoDDSs can be administered intratumorally for different therapeutic approaches, enhancing their tumor-specific accumulation and diminishing off-target delivery.
Scheme 1 Schematic illustration of intratumoral nanoDDS administration. Various types of nanoDDSs can be administered intratumorally for different therapeutic approaches, enhancing their tumor-specific accumulation and diminishing off-target delivery.CC BY · PubMed Central
Scheme 2 External factors affecting the intratumoral distribution of intratumorally administered nanoDDSs. To achieve maximal therapeutic outcomes, intratumorally administered nanoDDSs should be uniformly distributed throughout the tumor tissue without any intravasation or washout. Therefore, external factors affecting the intratumoral distribution of nanoDDSs, such as particle size, surface charge and functionalization, and injection site and rate, should be precisely regulated.
Scheme 2 External factors affecting the intratumoral distribution of intratumorally administered nanoDDSs. To achieve maximal therapeutic outcomes, intratumorally administered nanoDDSs should be uniformly distributed throughout the tumor tissue without any intravasation or washout. Therefore, external factors affecting the intratumoral distribution of nanoDDSs, such as particle size, surface charge and functionalization, and injection site and rate, should be precisely regulated.CC BY · PubMed Central
Figure 1 Intratumoral-nanoDDS-administration-mediated chemotherapy. (A) Thermosensitive polymeric micelles loaded with both cisplatin and paclitaxel were prepared for intratumorally administered chemotherapy. (B) Thermosensitive polymeric micelles underwent a phase transition to a gel state. (C) The cumulative release profiles of cisplatin and paclitaxel were observed. (D) The tumor size changes after intratumoral administration of polymeric micelles were measured over time. Reproduced with permission [104]. Copyright 2017, ACS Publications. (E) The microneedle-mediated intratumoral administration of cisplatin-encapsulated nanoparticles was proposed. (F) The sizes and (G) weights of tumors with microneedle-mediated administration were significantly regressed compared to those with intravenous and instant intratumoral administrations. *** p < 0.05. Reproduced with permission [106]. Copyright 2018, ACS Publications.
Figure 1 Intratumoral-nanoDDS-administration-mediated chemotherapy. (A) Thermosensitive polymeric micelles loaded with both cisplatin and paclitaxel were prepared for intratumorally administered chemotherapy. (B) Thermosensitive polymeric micelles underwent a phase transition to a gel state. (C) The cumulative release profiles of cisplatin and paclitaxel were observed. (D) The tumor size changes after intratumoral administration of polymeric micelles were measured over time. Reproduced with permission [104]. Copyright 2017, ACS Publications. (E) The microneedle-mediated intratumoral administration of cisplatin-encapsulated nanoparticles was proposed. (F) The sizes and (G) weights of tumors with microneedle-mediated administration were significantly regressed compared to those with intravenous and instant intratumoral administrations. *** p < 0.05. Reproduced with permission [106]. Copyright 2018, ACS Publications.CC BY · PubMed Central
Figure 2 Immune activation by PTT with intratumorally administered nanoDDSs. (A) The intratumoral administration of Au@Se NPs and NIR irradiation simultaneously induced the ICD by PTT and dendritic cell activation, enhancing antitumor immunity. (B) The maturation of dendritic cells and activation of CD8+ and CD4+ T cells were demonstrated after PTT with intratumorally administered Au@Se NPs. ** p < 0.01, *** p < 0.001. (C) The treatment with Au@Se NPs successfully inhibited the growth of both primary and distant tumors. Reproduced with permission [109]. Copyright 2020, Elsevier.
Figure 2 Immune activation by PTT with intratumorally administered nanoDDSs. (A) The intratumoral administration of Au@Se NPs and NIR irradiation simultaneously induced the ICD by PTT and dendritic cell activation, enhancing antitumor immunity. (B) The maturation of dendritic cells and activation of CD8+ and CD4+ T cells were demonstrated after PTT with intratumorally administered Au@Se NPs. ** p < 0.01, *** p < 0.001. (C) The treatment with Au@Se NPs successfully inhibited the growth of both primary and distant tumors. Reproduced with permission [109]. Copyright 2020, Elsevier.CC BY · PubMed Central
Figure 3 PDT with intratumorally administered Mal-PEG-TiO2-UCN nanoparticles. (A) A TEM image of synthesized Mal-PEG-TiO2-UCNs was obtained. (B) The UCNs shifted the wavelength of irradiated light to 450~475 nm, and the TiO2 shell absorbed the shifted light to produce ROSs. (C) The Mal-PEG-TiO2-UCNs effectively generated ROSs even inside the deep tissue phantoms. * p < 0.05. (D) The intratumoral administration of Mal-PEG-TiO2-UCN with 980 nm light irradiation significantly suppressed tumor growth (E) without causing any notable side effects. Reproduced with permission [110]. Copyright 2015, ACS Publications.
Figure 3 PDT with intratumorally administered Mal-PEG-TiO2-UCN nanoparticles. (A) A TEM image of synthesized Mal-PEG-TiO2-UCNs was obtained. (B) The UCNs shifted the wavelength of irradiated light to 450~475 nm, and the TiO2 shell absorbed the shifted light to produce ROSs. (C) The Mal-PEG-TiO2-UCNs effectively generated ROSs even inside the deep tissue phantoms. * p < 0.05. (D) The intratumoral administration of Mal-PEG-TiO2-UCN with 980 nm light irradiation significantly suppressed tumor growth (E) without causing any notable side effects. Reproduced with permission [110]. Copyright 2015, ACS Publications.CC BY · PubMed Central
Figure 4 Hypoxia alleviation and PDT by PCM-224-Pt. (A) PCM-224-Pt was synthesized via the in situ growth of Pt nanozymes on the PCN-224 MOFs. (B) Pt nanozyme produced oxygen from H2O2, and the oxygen was converted into ROSs by PCN-224 inside cancer cells. (C) The synthesized PCM-224-Pt was observed with TEM. (D) PCM-224-Pt exhibited high toxicity in both hypoxic and normoxic conditions, whereas the cytotoxicity of PCN-224 was diminished in hypoxia. (E) When PCN-224-Pt was intratumorally administered, it greatly promoted tumor regression by alleviating tumor hypoxia and enhancing the effect of PDT. ** p < 0.01. Reproduced with permission [112]. Copyright 2018, ACS Publications.
Figure 4 Hypoxia alleviation and PDT by PCM-224-Pt. (A) PCM-224-Pt was synthesized via the in situ growth of Pt nanozymes on the PCN-224 MOFs. (B) Pt nanozyme produced oxygen from H2O2, and the oxygen was converted into ROSs by PCN-224 inside cancer cells. (C) The synthesized PCM-224-Pt was observed with TEM. (D) PCM-224-Pt exhibited high toxicity in both hypoxic and normoxic conditions, whereas the cytotoxicity of PCN-224 was diminished in hypoxia. (E) When PCN-224-Pt was intratumorally administered, it greatly promoted tumor regression by alleviating tumor hypoxia and enhancing the effect of PDT. ** p < 0.01. Reproduced with permission [112]. Copyright 2018, ACS Publications.CC BY · PubMed Central
Figure 5 Intratumoral-administration-mediated combined cancer immunotherapy. (A) The intratumorally administered ZGd-NRs for combination therapy were supposed to release Zol and Gd3+, which depletes TAMs and induces RT-based ICD, respectively, leading to antitumor immunity activation. ZGd-NRs exhibited significant toxicity to both (B) cancer cells and (C) TAMs. (D) The intratumorally administered ZGd-NRs remained inside tumor tissues for a much longer time than the free ICGs (red dot circle and D: distant tumors, P: primary tumors). (E) The intratumoral administration of ZGd-NRs showed higher anticancer efficacy compared to the administration of Zol or Gd3+ alone, demonstrating the effectiveness of combination therapy. N.S. not significant, * p < 0.05, *** p < 0.001. Reproduced with permission [115]. Copyright 2017, ACS Publications.
Figure 5 Intratumoral-administration-mediated combined cancer immunotherapy. (A) The intratumorally administered ZGd-NRs for combination therapy were supposed to release Zol and Gd3+, which depletes TAMs and induces RT-based ICD, respectively, leading to antitumor immunity activation. ZGd-NRs exhibited significant toxicity to both (B) cancer cells and (C) TAMs. (D) The intratumorally administered ZGd-NRs remained inside tumor tissues for a much longer time than the free ICGs (red dot circle and D: distant tumors, P: primary tumors). (E) The intratumoral administration of ZGd-NRs showed higher anticancer efficacy compared to the administration of Zol or Gd3+ alone, demonstrating the effectiveness of combination therapy. N.S. not significant, * p < 0.05, *** p < 0.001. Reproduced with permission [115]. Copyright 2017, ACS Publications.CC BY · PubMed Central

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Cited by

Sorted by citations

Metadata

Authors
Yun, W. S., Kim, J., Lim, D.-K., Kim, D.-H., Jeon, S. I., & Kim, K.
Venue
Nanomaterials
Publisher
MDPI AG
Published
2023-07-31
Volume
13
Issue
15
Pages
2225
ISSN
2079-4991
DOI
10.3390/nano13152225
PMC
PMC10421122
Cited by
76
References
14
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
National Research Foundation (NRF) of Korea (NRF-2022M3H4A1A03067401)

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