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Reappraisal of anticancer nanomedicine design criteria in three types of preclinical cancer models for better clinical translation.

ABSTRACT: Anticancer nanomedicines are designed to improve anticancer efficacy by increasing drug accumulation in tumors through enhanced permeability retention (EPR) effect, and to reduce toxicity by decreasing drug accumulation in normal organs through long systemic circulation. However, the inconsistent efficacy/safety of nanomedicines in cancer patients versus preclinical cancer models have provoked debate for nanomedicine design criteria. In this study, we investigate nanomedicine design criteria in three types of preclinical cancer models using five clinically used nanomedicines, which identifies the factors for better clinical translations of their observed clinical efficacy/safety compared to free drug or clinical micelle formulation. When those nanomedicines were compared with drug solution or clinical micelle formulation in breast tumors, long and short-circulating nanomedicines did not enhance tumor accumulation by EPR effect in transgenic spontaneous breast cancer model regardless of their size or composition, although they improved tumor accumulations in subcutaneous and orthotopic breast cancer models. However, when tumors were compared to normal breast tissue, nanomedicines, drug solution and clinical micelle formulation showed enhanced tumor accumulation regardless of the breast cancer models. In addition, long-circulating nanomedicines did not further increase tumor accumulation in transgenic mouse spontaneous breast cancer nor universally decrease drug accumulations in normal organs; they decreased or increased accumulation in different organs, potentially changing the clinical efficacy/safety. In contrast, short-circulating nanomedicines decreased blood concentration and altered drug distribution in normal organs, which are correlated with their clinical efficacy/safety. A reappraisal of current nanomedicine design criteria is needed to ensure consistent clinical translation for improvement of their clinical efficacy/safety in cancer patients.

SUBMITTER: Luan X

PROVIDER: S-EPMC8883361 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Reappraisal of anticancer nanomedicine design criteria in three types of preclinical cancer models for better clinical translation.

Luan Xin X Yuan Hebao H Song Yudong Y Hu Hongxiang H Wen Bo B He Miao M Zhang Huixia H Li Yan Y Li Feng F Shu Pan P Burnett Joseph P JP Truchan Nathan N Palmisano Maria M Pai Manjunath P MP Zhou Simon S Gao Wei W Sun Duxin D

Biomaterials 20210603

Anticancer nanomedicines are designed to improve anticancer efficacy by increasing drug accumulation in tumors through enhanced permeability retention (EPR) effect, and to reduce toxicity by decreasing drug accumulation in normal organs through long systemic circulation. However, the inconsistent efficacy/safety of nanomedicines in cancer patients versus preclinical cancer models have provoked debate for nanomedicine design criteria. In this study, we investigate nanomedicine design criteria in ...[more]

PMID: 34144373

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Project description:Mixed-species forest plantation is a sound option to facilitate ecological restoration, plant diversity and ecosystem functions. Compatible species combinations are conducive to reconstruct plant communities that can persist at a low cost without further management and even develop into natural forest communities. However, our understanding of how the compatibility of mycorrhizal types mediates species coexistence is still limited, especially in a novel agroforestry system. Here, we assessed the effects of mycorrhizal association type on the survival and growth of native woody species in mixed-species Eucalyptus plantations. To uncover how mycorrhizal type regulates plant-soil feedbacks, we first conducted a pot experiments by treating distinct mycorrhizal plants with soil microbes from their own or other mycorrhizal types. We then compared the growth response of arbuscular mycorrhizal plants and ectomycorrhizal plants to different soil microbial compositions associated with Eucalyptus plants. We found that the type of mycorrhizal association had a significant impact on the survival and growth of native tree species in the Eucalyptus plantations. The strength and direction of the plant-soil feedbacks of focal tree species depended on mycorrhizal type. Non-mycorrhizal plants had consistent negative feedbacks with the highest survival in the Eucalyptus plantations, whereas nitrogen-fixing plants had consistent positive feedbacks and the lowest survival. Arbuscular mycorrhizal and ectomycorrhizal plants performed varied feedback responses to soil microbes from distinct mycorrhizal plant species. Non-mycorrhizal plants grew better with Eucalyptus soil microbes while nitrogen-fixing plants grew worse with their own conspecific soil microbes. Different soil microbial compositions of Eucalyptus consistently increased the aboveground growth of arbuscular mycorrhizal plants, but the non-mycorrhizal microbial composition of the Eucalyptus soil resulted in greater belowground growth of ectomycorrhizal plants. Overall, Eucalyptus plants induced an unfavorable soil community, impeding coexistence with other mycorrhizal plants. Our study provides consistent observational and experimental evidence that mycorrhizal-mediated plant-microbial feedback on species coexistence among woody species. These findings are with important implications to optimize the species combinations for better design of mixed forest plantations.

Project description:BACKGROUND: Microarray comparative genomic hybridization (CGH) is currently one of the most powerful techniques to measure DNA copy number in large genomes. In humans, microarray CGH is widely used to assess copy number variants in healthy individuals and copy number aberrations associated with various diseases, syndromes and disease susceptibility. In model organisms such as Caenorhabditis elegans (C. elegans) the technique has been applied to detect mutations, primarily deletions, in strains of interest. Although various constraints on oligonucleotide properties have been suggested to minimize non-specific hybridization and improve the data quality, there have been few experimental validations for CGH experiments. For genomic regions where strict design filters would limit the coverage it would also be useful to quantify the expected loss in data quality associated with relaxed design criteria. RESULTS: We have quantified the effects of filtering various oligonucleotide properties by measuring the resolving power for detecting deletions in the human and C. elegans genomes using NimbleGen microarrays. Approximately twice as many oligonucleotides are typically required to be affected by a deletion in human DNA samples in order to achieve the same statistical confidence as one would observe for a deletion in C. elegans. Surprisingly, the ability to detect deletions strongly depends on the oligonucleotide 15-mer count, which is defined as the sum of the genomic frequency of all the constituent 15-mers within the oligonucleotide. A similarity level above 80% to non-target sequences over the length of the probe produces significant cross-hybridization. We recommend the use of a fairly large melting temperature window of up to 10 C, the elimination of repeat sequences, the elimination of homopolymers longer than 5 nucleotides, and a threshold of -1 kcal/mol on the oligonucleotide self-folding energy. We observed very little difference in data quality when varying the oligonucleotide length between 50 and 70, and even when using an isothermal design strategy. CONCLUSIONS: We have determined experimentally the effects of varying several key oligonucleotide microarray design criteria for detection of deletions in C. elegans and humans with NimbleGen's CGH technology. Our oligonucleotide design recommendations should be applicable for CGH analysis in most species.

Dataset Information

Reappraisal of anticancer nanomedicine design criteria in three types of preclinical cancer models for better clinical translation.

Publications

Reappraisal of anticancer nanomedicine design criteria in three types of preclinical cancer models for better clinical translation.

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