Transport-driven engineering of liposomes for delivery of α-particle radiotherapy to solid tumors: effect on inhibition of tumor progression and onset delay of spontaneous metastases

Prasad, Aprameya; Nair, Rajiv; Bhatavdekar, Omkar; Howe, Alaina; Salerno, Dominick; Sempkowski, Michelle; Josefsson, Anders; Pacheco-Torres, Jesús; Bhujwalla, Zaver M.; Gabrielson, Kathleen L.; Sgouros, George; Sofou, Stavroula

doi:10.1007/s00259-021-05406-z

Cited by 17 publications

(46 citation statements)

References 29 publications

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“…Spheroids, which were formed by each of the cell lines, developed interstitial pH profiles that ranged from 6.5 at the spheroid center to around 7.4 at the spheroid periphery (Supplemental Figure S11). These values were comparable to the tumor extracellular pH values that were measured in vivo [10,16] and were within the range of pH values that activated the properties of binding/adhesion and release on responsive NP (Tables 1 and 2).…”

Section: Spheroid Characterization and Treatmentsupporting

confidence: 81%

“…The pK a of DAP is approximately 6.58-6.81 [21]; therefore, during circulation in the blood, the surface of these NP maintained electrostatic neutrality with the NP exhibiting identical pharmacokinetics to conventionally PEGylated NP, and when in the tumor interstitium, protonation of DAP resulted in a measurable increase in zeta potential. We demonstrated that the presentation of a cationic charge on an undulating PEG chain significantly reduced the NP interactions with cancer cells, limiting their cell internalization, but it retained measurable adhesion to the tumors' ECM [16,17].…”

Section: Figurementioning

confidence: 98%

“…Herein, spheroids, which were utilized as surrogates of the tumor avascular regions, were designed-as we have previously demonstrated-to capture the critical diffusionlimited transport of therapeutics within solid tumors: the trends in efficacy, among various treatments, to inhibit spheroid growth are directly translated on inhibiting tumor growth (and/or delaying metastatic onset) in mouse models bearing the same cancers, as long as the duration times of incubation of spheroids with each of the agents (or formulations thereof) are scaled to their corresponding blood clearance times in vivo [16,17]. In this study, we compared the efficacy to inhibit spheroid growth to the corresponding spatiotemporal microdistributions of each of the agents, in all delivery forms, alone and in combination.…”

Section: Figurementioning

confidence: 99%

“…Spheroids were used as surrogates of the avascular regions of solid tumors [16,17,24]. Spheroids, which were formed by each of the cell lines, developed interstitial pH profiles that ranged from 6.5 at the spheroid center to around 7.4 at the spheroid periphery (Supplemental Figure S11).…”

Section: Spheroid Characterization and Treatmentmentioning

confidence: 99%

“…NP for both DXR [14] and CDDP [15] were designed to release their therapeutic contents directly in the tumor interstitium in an effort to improve the uniformity of the spatiotemporal profiles of the therapeutic agents within solid tumors. We have previously demonstrated that release in the tumor interstitium of molecularsized therapeutics, which have significantly higher diffusivities than their nanometer-sized carriers, enabled their deeper penetration in solid tumors, reaching more cancer cells and improving efficacy [16,17]. On both types of responsive NP, the release mechanism was enabled by the formation of phase-separated lipid domains on the membrane comprising the NP.…”

Section: Introductionmentioning

confidence: 99%

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Growth Inhibition of Triple-Negative Breast Cancer: The Role of Spatiotemporal Delivery of Neoadjuvant Doxorubicin and Cisplatin

Salerno¹,

Sofou

2021

Pharmaceuticals

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Combinations of platinum-based compounds with doxorubicin in free and/or in liposomal form for improved safety are currently being evaluated in the neoadjuvant setting on patients with advanced triple-negative breast cancer (TNBC). However, TNBC may likely be driven by chemotherapy-resistant cells. Additionally, established TNBC tumors may also exhibit diffusion-limited transport, resulting in heterogeneous intratumoral delivery of the administered therapeutics; this limits therapeutic efficacy in vivo. We studied TNBC cells with variable chemosensitivities, in the absence (on monolayers) and presence (in 3D multicellular spheroids) of transport barriers; we compared the combined killing effect of free doxorubicin and free cisplatin to the killing effect (1) of conventional liposomal forms of the two chemotherapeutics, and (2) of tumor-responsive lipid nanoparticles (NP), specifically engineered to result in more uniform spatiotemporal microdistributions of the agents within solid tumors. This was enabled by the NP properties of interstitial release, cell binding/internalization, and/or adhesion to the tumors’ extracellular matrix. The synergistic cell kill by combinations of the agents (in all forms), compared to the killing effect of each agent alone, was validated on monolayers of cells. Especially for spheroids formed by cells exhibiting resistance to doxorubicin combination treatments with both agents in free and/or in tumor-responsive NP-forms were comparably effective; we not only observed greater inhibition of outgrowth compared to the single agent(s) but also compared to the conventional liposome forms of the combined agents. We correlated this finding to more uniform spatiotemporal microdistributions of agents by the tumor-responsive NP. Our study shows that combinations of NP with properties specifically optimized to improve the spatiotemporal uniformity of the delivery of their corresponding therapeutic cargo can improve treatment efficacy while keeping favorable safety profiles.

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Section: Spheroid Characterization and Treatmentsupporting

confidence: 81%

Section: Figurementioning

confidence: 98%

Section: Figurementioning

confidence: 99%

Section: Spheroid Characterization and Treatmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Growth Inhibition of Triple-Negative Breast Cancer: The Role of Spatiotemporal Delivery of Neoadjuvant Doxorubicin and Cisplatin

Salerno¹,

Sofou

2021

Pharmaceuticals

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Two diverse carriers are better than one: A case study in α‐particle therapy for prostate specific membrane antigen‐expressing prostate cancers

Salerno

Howe

Bhatavdekar

et al. 2021

Bioengineering & Transla Med

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Partial and/or heterogeneous irradiation of established (i.e., large, vascularized) tumors by α‐particles that exhibit only a 4–5 cell‐diameter range in tissue, limits the therapeutic effect, since regions not being hit by the high energy α‐particles are likely not to be killed. This study aims to mechanistically understand a delivery strategy to uniformly distribute α‐particles within established solid tumors by simultaneously delivering the same α‐particle emitter by two diverse carriers, each killing a different region of the tumor: (1) the cancer‐agnostic, but also tumor‐responsive, liposomes engineered to best irradiate tumor regions far from the vasculature, and (2) a separately administered, antibody, targeting any cancer‐cell's surface marker, to best irradiate the tumor perivascular regions. We demonstrate that on a prostate specific membrane antigen (PSMA)‐expressing prostate cancer xenograft mouse model, for the same total injected radioactivity of the α‐particle emitter Actinium‐225, any radioactivity split ratio between the two carriers resulted in better tumor growth inhibition compared to the tumor inhibition when the total radioactivity was delivered by any of the two carriers alone. This finding was due to more uniform tumor irradiation for the same total injected radioactivity. The killing efficacy was improved even though the tumor‐absorbed dose delivered by the combined carriers was lower than the tumor‐absorbed dose delivered by the antibody alone. Studies on spheroids with different receptor‐expression, used as surrogates of the tumors' avascular regions, demonstrated that our delivery strategy is valid even for as low as 1+ (ImmunoHistoChemistry score) PSMA‐levels. The findings presented herein may hold clinical promise for those established tumors not being effectively eradicated by current α‐particle radiotherapies.

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Nanobiotechnology‐mediated radioimmunotherapy treatment for triple‐negative breast cancer

Zhu

Yang

You

et al. 2023

MedComm – Biomaterials and Applications

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Breast cancer has become the most common and greatest threat to women's health in the world. As the most dangerous subtype of breast cancer, triplenegative breast cancer (TNBC) can lead develop drug resistance, resulting in poor therapeutic effects. The synergistic effect of radiotherapy and immunotherapy can not only improve the therapeutic effect of in situ TNBC but also MedComm -Biomaterials and Applications.

show abstract

Transport-driven engineering of liposomes for delivery of α-particle radiotherapy to solid tumors: effect on inhibition of tumor progression and onset delay of spontaneous metastases

Cited by 17 publications

References 29 publications

Growth Inhibition of Triple-Negative Breast Cancer: The Role of Spatiotemporal Delivery of Neoadjuvant Doxorubicin and Cisplatin

Growth Inhibition of Triple-Negative Breast Cancer: The Role of Spatiotemporal Delivery of Neoadjuvant Doxorubicin and Cisplatin

Two diverse carriers are better than one: A case study in α‐particle therapy for prostate specific membrane antigen‐expressing prostate cancers

Nanobiotechnology‐mediated radioimmunotherapy treatment for triple‐negative breast cancer

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