Delivering more for less: nanosized, minimal-carrier and pharmacoactive drug delivery systems

https://doi.org/10.1016/j.addr.2021.113994Get rights and content

Highlights

  • Minimal-carrier and pharmacoactive nano-drug delivery systems are an emerging trend.

  • Balance-designed, minimal-carrier nanoparticle systems are summarized and discussed.

  • Bioactive carrier materials improve specificity, efficacy, and safety.

Abstract

Traditional nanoparticle carriers such as liposomes, micelles, and polymeric vehicles improve drug delivery by protecting, stabilizing, and increasing the circulatory half-life of the encapsulated drugs. However, traditional drug delivery systems frequently suffer from poor drug loading and require an excess of carrier materials. This carrier material excess poses an additional systemic burden through accumulation, if not degradable the need for metabolism, and potential toxicity. To address these shortcomings, minimal-carrier nanoparticle systems and pharmacoactive carrier materials have been developed. Both solutions provide drug delivery systems in which the majority of the nanoparticle is pharmacologically active. While minimal-carrier and pharmacoactive drug delivery systems can improve drug loading, they can also suffer from poor stability. Here, we review minimal-carrier and pharmacoactive delivery systems, discuss ongoing challenges and outline opportunities to translate minimal-carrier and pharmacoactive drug delivery systems into the clinic.

Section snippets

Minimal-carrier drug delivery systems and pharmacoactive drug carriers

The delivery of small molecule drugs, proteins, and nucleic acids is often hampered by their poor pharmacokinetics and insufficient stability in the presence of degradative enzymes [1], [2]. In the case of small molecules, a lack of specific disease targeting can cause non-specific interactions and systemic off-target adverse effects in healthy tissues [3]. Proteins and nucleic acids often require a delivery vehicle to maintain their structure long enough to reach their target cells and site of

Improved therapeutic efficacy with high drug-loading minimal-carrier delivery systems

MCDDS are therapeutics that use minimal drug carrier materials and where most constituents are the drug (Fig. 1, Table 1). MCDDS could have a maximum loading capacity of up to 100% where no or minimal amounts of carriers are used for the formation of nanoparticles, microparticles, fibers, or other delivery systems. In these formulations, drugs self-assemble into nanoparticles or microparticles by precipitation, solvent exchange, or self-assembly (Fig. 2A) [44], [45], [46], [47].

The first

Triggerable MCDDS improve therapeutic specificity and efficacy

Drug release from MCDDS could also be triggerable and react to changes in the environment, such as the pH or redox state inside diseased tissues (Fig. 2C) [48], [50], [52], [53]. To accomplish this, Hou et al. conjugated methotrexate (MTX), a hydrophilic drug, to the hydrophobic drugs DOX and CPT using pH-sensitive hydrazone bond and disulfide bond linkers, respectively, resulting in self-assembling amphiphilic nanoparticles [52]. MTX was used as both an anticancer drug and a targeting agent

Stability considerations with minimal-carrier drug delivery systems

Since MCDDS might not always contain a stable carrier shell, they could suffer from undesired stability and premature disassembly before reaching the disease site. One common method employed to improve stability is adding PEG to the nanoparticle to provide steric shielding and to increase circulatory half-life [61]. For example, Yu et al. added PEGylation to pure DOX nanoparticles and, in doing so, increased the circulatory half-life 18-fold compared to pure DOX drugs [44]. Li et al. used PEG

Enhancing drug efficacy through pharmacoactive or bioactive carrier materials

Pharmacoactive or bioactive drug carriers (PBACS) are drug carriers with inherent pharmacological or biological activity (Table 2). PBACS could significantly improve the therapeutic efficacy of the drug cargo by acting on the system in combination with the active drug without the need for excessive, inactive carrier materials. Emerging PBACS can be roughly organized into the following categories: i) biological materials only, ii) small molecule (drug) scaffolded biological materials, iii)

Discussion and future perspectives

The emerging field of MCDDS and PBACS is promising. In the majority of cases, MCDDS show substantially higher drug loading (40–90%) than current clinically approved nano-therapeutics (Fig. 4 and Table 3) and display enhanced therapeutic efficacy compared to free drugs. The majority of FDA-approved nano-therapeutics have a drug loading of < 20% except for Onivyde® (liposomal irinotecan), which has a drug loading of 37.1% w/w. This is mostly limited to the drug loading/encapsulation strategies

Declaration of Competing Interest

JN is an inventor on the patent applications for the EXO-Code technology that have been licensed to Exopharm and has received royalties. These relationships have been disclosed to and are under management by UNC-Chapel Hill.

Acknowledgments

This review is dedicated to Professor Frank Szoka in honor of his lifetime achievements and significant contributions to the field of drug delivery. This work is supported through funding by the NIH (R01EB023262, R01CA241679 and R21GM135853) and the National Science Foundation DMR2000256. Parts of figures 1, 2, and 3 were created with BioRender.

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    Given her role as Theme Editor, Dr. Yu-Kyoung Oh had no involvement in the peer-review of this article and has no access to information regarding its peer-review. Full responsibility for the editorial process for this article was delegated to Dr. Tamara Minko.

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