Multifunctional nanoparticle-mediated combining therapy for human diseases

Abstract

Combining existing drug therapy is essential in developing new therapeutic agents in disease prevention and treatment. In preclinical investigations, combined effect of certain known drugs has been well established in treating extensive human diseases. Attributed to synergistic effects by targeting various disease pathways and advantages, such as reduced administration dose, decreased toxicity, and alleviated drug resistance, combinatorial treatment is now being pursued by delivering therapeutic agents to combat major clinical illnesses, such as cancer, atherosclerosis, pulmonary hypertension, myocarditis, rheumatoid arthritis, inflammatory bowel disease, metabolic disorders and neurodegenerative diseases. Combinatorial therapy involves combining or co-delivering two or more drugs for treating a specific disease. Nanoparticle (NP)-mediated drug delivery systems, i.e., liposomal NPs, polymeric NPs and nanocrystals, are of great interest in combinatorial therapy for a wide range of disorders due to targeted drug delivery, extended drug release, and higher drug stability to avoid rapid clearance at infected areas. This review summarizes various targets of diseases, preclinical or clinically approved drug combinations and the development of multifunctional NPs for combining therapy and emphasizes combinatorial therapeutic strategies based on drug delivery for treating severe clinical diseases. Ultimately, we discuss the challenging of developing NP-codelivery and translation and provide potential approaches to address the limitations. This review offers a comprehensive overview for recent cutting-edge and challenging in developing NP-mediated combination therapy for human diseases.

Fig. 1

Timeline mapping the historical development and advancement of combinatorial therapies. Parts of the figure were drawn using Servier Medical Art licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/)

Fig. 2

Combinatorial therapy and NP-codelivery therapy strategies for human diseases. Parts of the figure were drawn using Servier Medical Art licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/)

Fig. 3

Timeline mapping the historical development and advancement of multifunction NPs. Parts of the figure were drawn using Servier Medical Art licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/)

Fig. 4

Schematic diagram of the models for evaluating combination effects. Effect-based models: a Highest Single Agent model : CI = max (EA, EB)/EAB, the significance of a positive combination is given by the P value of the statistical test compared to the HSA. b Response Additivity model : CI = (EA + EB)/EA, the drug combination is positive when EAB is greater than the sum of the individual effects EA and EB. c Bliss Independence model: CI = (EA + EB – EAEB)/EAB, the drug combinations based on the assumption that drugs act independently on distinct action sites. d Concentration-based model: d Loewe Additivity model : CI= a/A + b/B, this flexible model provides isobol representation in addition to the algebraic analysis

Fig. 5

Schematic illustration of pathological features of tumor and therapeutic approaches against cancer. a Hyperproliferation. Compared with normal cells, the proliferation rate of tumor cells is greatly increased. b Anti-apoptosis. The cell cycle of normal cells includes an apoptotic phase, whereas the anti-apoptotic ability of tumor cells promotes their unlimited proliferation. c Multidrug resistance. Tumor cells achieve multidrug resistance by increasing drug efflux, mutating drug targets, and disordering intracellular genes. d Tumor-specific microenvironment includes enhanced permeability and retention effect, acidic environment, immunosuppressive microenvironment, high blood flow and thick extracellular matrix. e Metastasis. Tumor cells can migrate to distant tissues through systemic circulation, leading to cancer metastasis. Parts of the figure were drawn using Servier Medical Art licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/)

Fig. 6

Liposome-based co-delivery. a Typical liposome co-delivery loading drugs in cores or lipid membranes. b Liposome co-delivery based on core-encapsulation and membrane anchoring. One drug is loaded in the aqueous cores, while other active compounds, e.g., prodrug and photothermal agents, could be anchored on the liposomes through various interaction forces, such as H-bonding, hydrophobic force and π-π stacking. Parts of the figure were drawn using Servier Medical Art licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/)

Fig. 7

a The therapy strategies for AS include reducing lipid deposition, dissolving platelet thrombus and reducing inflammation. b The structure of rHDL. rHDL mainly comprises phospholipids and apoAI; the structure includes a hydrophobic core and a hydrophilic shell. c RCT process of HDL. Pre-HDL turns into HDL by combining cholesterol, promotes the transformation of foam cells into normal cells, and transports cholesterol to the liver for elimination. Parts of the figure were drawn using Servier Medical Art licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/)

Fig. 8

Targets and combining strategies for PAH, MCD, RA, IBD, hyperthyroidism, diabetes and NDs therapy. PAH, MCD, RA, and IBD are inflammation-associated diseases. For treating PAH and RA, fasudil- and MTX-based NP codelivery is the most frequently reported, respectively. For the MCD treatment, the combination of glucocorticoids and immunotherapy is often used. For IBD therapy, NP-codelivery is developed to target the inflammatory sites and increase drug availability and therapeutic efficacy, aiming to reduce the administration frequency and adverse side effects. For diabetes treatment, the typical case is the co-delivery of GLP-1 and DPP4 inhibitors. A combination of tripterygium glycosides and chemical compounds is promising to combat hyperthyroidism. For ND therapy, NP codelivery primarily aims to overcome the BBB barrier, i.e., mesoporous silica NPs for co-delivering leptin and pioglitazone. Parts of the figure were drawn using Servier Medical Art licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/)