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Review
. 2012 Apr 7;41(7):2971-3010.
doi: 10.1039/c2cs15344k. Epub 2012 Mar 5.

Targeted polymeric therapeutic nanoparticles: design, development and clinical translation

Nazila Kamaly  1 , Zeyu Xiao, Pedro M Valencia, Aleksandar F Radovic-Moreno, Omid C Farokhzad
Affiliations
Review

Targeted polymeric therapeutic nanoparticles: design, development and clinical translation

Nazila Kamaly et al. Chem Soc Rev. .

Abstract

Polymeric materials have been used in a range of pharmaceutical and biotechnology products for more than 40 years. These materials have evolved from their earlier use as biodegradable products such as resorbable sutures, orthopaedic implants, macroscale and microscale drug delivery systems such as microparticles and wafers used as controlled drug release depots, to multifunctional nanoparticles (NPs) capable of targeting, and controlled release of therapeutic and diagnostic agents. These newer generations of targeted and controlled release polymeric NPs are now engineered to navigate the complex in vivo environment, and incorporate functionalities for achieving target specificity, control of drug concentration and exposure kinetics at the tissue, cell, and subcellular levels. Indeed this optimization of drug pharmacology as aided by careful design of multifunctional NPs can lead to improved drug safety and efficacy, and may be complimentary to drug enhancements that are traditionally achieved by medicinal chemistry. In this regard, polymeric NPs have the potential to result in a highly differentiated new class of therapeutics, distinct from the original active drugs used in their composition, and distinct from first generation NPs that largely facilitated drug formulation. A greater flexibility in the design of drug molecules themselves may also be facilitated following their incorporation into NPs, as drug properties (solubility, metabolism, plasma binding, biodistribution, target tissue accumulation) will no longer be constrained to the same extent by drug chemical composition, but also become in-part the function of the physicochemical properties of the NP. The combination of optimally designed drugs with optimally engineered polymeric NPs opens up the possibility of improved clinical outcomes that may not be achievable with the administration of drugs in their conventional form. In this critical review, we aim to provide insights into the design and development of targeted polymeric NPs and to highlight the challenges associated with the engineering of this novel class of therapeutics, including considerations of NP design optimization, development and biophysicochemical properties. Additionally, we highlight some recent examples from the literature, which demonstrate current trends and novel concepts in both the design and utility of targeted polymeric NPs (444 references).

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Conflict of interest statement

The rest of the authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Time line of clinical stage nanomedicine firsts. Liposomes, controlled release polymeric systems for macromolecules, dendrimers, targeted-PEGylated liposomes, first FDA approved liposome (DOXIL), long circulating poly(lactic-co-glycolic acid)-polyethyleneglycol (PLGA-PEG) NPs, iron oxide MRI contrast agent NP (Ferumoxide), protein based drug delivery system (Abraxane; nab technologyt), polymeric micelle NP (Genexol-PM), targeted cyclodextrin-polymer hybrid NP (CALAA-01), targeted polymeric NP (BIND-014; Accurint™ Technology), fully integrated polymeric nanoparticle vaccines (SEL-068, t SVPt™ Technology).
Fig. 2
Fig. 2
Common biodegradable polymers utilized in controlled-release drug delivery applications. Poly(lactic acid) (PLA), poly(glutamic acid) (PGA), poly(d,l-lactic-co-glycolide) (PLGA), poly(caprolactone) (PCL).
Fig. 3
Fig. 3
Components of CALAA-01 (Calando Pharmaceuticals-01) – a targeted NP for siRNA delivery: (a) CDP: water-soluble, linear cyclodextrin-containing polymer, AD: adamantane (AD)-PEG conjugate (PEG MW of 5000) (AD-PEG), and Tf-PEG-AD: an adamantane conjugate of PEG (PEGMWof 5000) conjugated with human transferrin (Tf) ligand. (b) CALAA-01 is formulated via a single self-assembly process of four individual components. Figure taken from Davis, M et al.
Fig. 4
Fig. 4
(a) Microfluidic synthesis of polymeric nanoparticles prepared under rapid mixing conditions in 2D flow focusing. (b) 3D flow focusing. Figure adapted from Karnik et al. and Rhee et al.,
Fig. 5
Fig. 5
Drug release mechanisms from polymeric NPs: (a) diffusion from polymer matrix with time varying diffusivity, (b) surface erosion/degradation of polymer matrix, and (c) biodegradation of polymer matrix due to hydrolytic degradation leading to drug release.
Fig. 6
Fig. 6
Self-assembly of triblock PLGA-b-PEG copolymers in aqueous solution: (a) Polymeric NP formation via nanoprecipitation, FG = functional group (b) Conjugation of targeting ligand to the surface of pre-formed polymeric NPs (c) Pre-functionalized diblock polymer with hydrophilic targeting ligand.
Fig. 7
Fig. 7
Self-assembling targeted polymeric NPs. A-B: Synthesis and characterization of PLGA-PEG-Apt triblock polymers. C: Nanoprecipitation leading to the self-assembly of PLGA-PEG-Apt NPs. Aptamer surface density is precisely controlled using distinct ratios of PLGA-PEG-Apt and PLGA- PEG. Figure taken from Gu et al.
Fig. 8
Fig. 8
PLGA-PEG-RGD and PLGA-PEG-folate triblock polymers used to prepare targeted NPs with different surface ligand densities. Figure taken from Valencia et al.
Fig. 9
Fig. 9
Polymer-lipid hybrid ‘Nanoburr’ particles. A: Polymer-drug conjugate synthesis (Ptxl-PLA), B: HPLC characterization of Ptxl and Ptxl-PLA polymer, C: Nanoburr synthesis via polymer lipid, and lipid-PEG self-assembly, D: TEM image of Nanoburrs (stained with 3% uranyl acetate), E: Dynamic light scattering measurements (DLS) pre and post peptide conjugation, F: Zeta potential measurements pre and post peptide onjugation, and G: in vitro drug release profile of Ptxl from Nanoburr NPs. Figure taken from Chan et al.
Fig. 10
Fig. 10
Schematic protocol of cell-uptake selection for evolving cancer cell-specific internalizing Apts. Figure taken from Xiao et al.
Fig. 11
Fig. 11
NPs and their biophysicochemical characteristics which affect their performance both in vitro and in vivo.
Fig. 12
Fig. 12
Development of an array of nano and microparticles with variable shapes and aspect ratios using the PRINT technique by Desimone et al. Figure taken from Wang et al.
Fig. 13
Fig. 13
Different strategies for multi-ligand targeting of NPs: A: Various modes of targeting using single or multi-ligands (Figure taken from Ruoslahti et al.), B: Dual-targeting where one NP has two different ligands that target receptors on the same cell (Figure adapted from Li et al.), C: example of cellular and sub-cellular targeting (Figure taken from Ashley et al.), and D: dual targeting of one peptide to two different receptors on the same cell (Figure adapted from K. Sugahara et al.).
Fig. 14
Fig. 14
Screening targeted NPs from a derived NP library: (a–b) Laser light scattering and atomic force microscopy of NPs. (c) Model of the crosslinked dextran coating NPs modified with small molecules. (d) Water solubility, as well as fluorescent and magnetic properties of NPs. (e) Different classes of small molecules with amino, sulfhydryl, carboxyl or anhydride functionalities anchored onto the NPs. (f) Hemotoxylin eosin–stained sections of the tumours targeting with NPs. (g) Tumour cross-sections observed using the Cy5.5 fluorescence channel indicate marked fluorescence of one identified NP; CLIO-isatoic within tumour cells. (h) Biodistribution study with 111In-labelled NPs confirmed tumoural targeting of CLIO-isatoic NPs. Figure adapted from Weissleder et al.
Fig. 15
Fig. 15
Strategy for co-encapsulating hydrophobic Dtxl and more hydrophilic Pt(IV)-monosuccinate prodrug on a single nanoparticle. Figure taken from Kolishetti et al.
Fig. 16
Fig. 16
Biodegradable and biocompatible polymers and lipids forming hybrid core/shell nanoparticles for siRNA delivery. The unique lipid–polymer–lipid nanostructure is demonstrated by TEM (top right) and fluorescence microscopy (bottom right) with microsized particles. Figure taken from Shi et al.
Fig. 17
Fig. 17
Design of fluorescent-labelled DACHPt/m (F-DACHPt/m) for visualization of localization and drug release in cancer cells: (A) F-DACHPt/m self-assembled through polymer-metal complex formation between DACHPt and boron dipyrromethene (BODIPY) FL–poly(ethylene glycol)-b-poly(glutamic acid)–BODIPY TR in distilled water. (B) Schematic representation of hypothetical subcellular pathways and action of DACHPt/m. Figure taken from Murakami et al.
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