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Camouflaging Nanoparticles for Ratiometric Delivery of Therapeutic Combinations.

ABSTRACT: Combination therapy is a common clinical practice in the management of malignancies. Synergistic therapeutic outcomes are achieved only when tumor cells are exposed to drugs in an optimal ratio and sequence; therefore, carriers coencapsulating multiple drugs are widely pursued for their coordinated delivery. However, it is challenging to coload drugs with different physicochemical properties in a single carrier with specific ratios. It is not even beneficial to load them in one carrier if they need to be released at different times. We propose to load drugs into chemically compatible carriers separately, equalize different carriers by a simple, rapid, and versatile camouflage technique based on natural polyphenol tannic acid (TA), and administer them in desirable ratios and sequences. To demonstrate this potential, different nanoparticles (NPs) with different charges and material basis, such as polymeric (carboxyl-terminated or amine-terminated cationic polystyrene NPs or poly(lactic- co-glycolic acid (PLGA) NPs), inorganic (mesoporous silica NPs (MSNs)), and liposomal NPs, are camouflaged with TA layers and further modified with folate-conjugated polyethylene glycol to aid in the delivery to tumors. The camouflaged NPs show similar physicochemical properties and interactions with KB cells despite the difference in core platforms, and their mixtures interact with common cell targets in a ratiometric manner. In KB-tumor-bearing mice, the camouflaged PLGA NPs and MSNs show near-perfect colocalization in tumors. These results support that TA helps equalize different NPs with high versatility and enables their ratiometric delivery to common targets. This approach can relieve technical challenges in ratiometric codelivery or sequential delivery of therapeutic agents with distinct physicochemical properties.

SUBMITTER: Meng F

PROVIDER: S-EPMC6417971 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Camouflaging Nanoparticles for Ratiometric Delivery of Therapeutic Combinations.

Meng Fanfei F Wang Jianping J Ping Qineng Q Yeo Yoon Y

Nano letters 20190207 3

Combination therapy is a common clinical practice in the management of malignancies. Synergistic therapeutic outcomes are achieved only when tumor cells are exposed to drugs in an optimal ratio and sequence; therefore, carriers coencapsulating multiple drugs are widely pursued for their coordinated delivery. However, it is challenging to coload drugs with different physicochemical properties in a single carrier with specific ratios. It is not even beneficial to load them in one carrier if they n ...[more]

PMID: 30707035

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Project description:Attaching affinity ligands to nanoparticles (NPs) increases selectivity for targeting cells and tissues, and can result in improved sensitivity and reduced off-target toxicity in diagnostic and therapeutic systems. The decision over key features - NP size, shape, coating strategies and targeting ligands for clinical translation is often hampered by a lack of quantitative in vivo NP homing assays. Sensitive, internally controlled assays are needed which allow for quantitative comparisons (auditions) among various formulations of targeted NPs. We recently reported the development of peptide-functionalized, isotopically-barcoded silver NPs (AgNPs) for ultrasensitive studies centered on measuring relative ratios of NP internalization into cultured cells. Here we evaluated the application of this technology for NP homing studies in live mice using peptides with previously described tissue tropism; one peptide that favors vascular beds of the normal lungs (RPARPAR; receptor neuropilin-1, or NRP-1) and another that is selective for central nervous system vessels (CAGALCY). Equimolar mixtures of the peptide-targeted Ag107-NPs and Ag109 control particles were mixed and injected intravenously. Distribution profiles of Ag107 and Ag109 in tissue extracts were determined simultaneously through inductively coupled plasma mass spectrometry (ICP-MS). Compared to non-targeted particles up to ?9-fold increased lung accumulation was seen for RPARPAR-OH AgNPs (but not for AgNPs functionalized with RPARPAR-NH2, which does not bind to NRP-1). Similarly, AgNPs functionalized with the brain-homing CAGALCY peptide were overrepresented in brain extracts. Spatial distribution (mapping) analysis by laser ablation ICP-MS (LA-ICP-MS) was used to determine the ratio Ag107/Ag109 in tissue cryosections. The mapping demonstrated preferential accumulation of the RPARPAR-AgNPs in the perivascular areas around pulmonary veins, and CAGALCY AgNPs accumulated in discrete areas of the brain (e.g. in the vessels of cerebellar fibrillary tracts). Based on these results, the internally controlled ratiometric AgNP system is suitable for quantitative studies of the effect of targeting ligands on NP biodistribution, at average tissue concentration and distribution at the microscopic level. The platform might be particularly relevant for target sites with high local variability in uptake, such as tumors.

Dataset Information

Camouflaging Nanoparticles for Ratiometric Delivery of Therapeutic Combinations.

Publications

Camouflaging Nanoparticles for Ratiometric Delivery of Therapeutic Combinations.

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