Theranostic immunoliposomes for osteoarthritis

doi:10.1016/j.nano.2013.09.004

Nanomedicine: Nanotechnology, Biology and Medicine

Volume 10, Issue 3, April 2014, Pages 619-627

https://doi.org/10.1016/j.nano.2013.09.004 Get rights and content

Abstract

Although there have been substantial advancements in the treatment of inflammatory arthritis, treatments for osteoarthritis (OA) have lagged and currently are primarily palliative until joints become totally dysfunctional and prosthetic replacement is needed. One obstacle for developing a preventive therapy for OA is the lack of good tools for efficiently diagnosing the disease and monitoring its progression during the early stages when the effect of therapeutic drugs or biologics is most likely to be effective. We have developed near infrared immunoliposomes conjugated with type II collagen antibody for diagnosis and treatment of early OA. These immunoliposomes bind to damaged but not normal cartilage. Utilizing these reagents, we can quantitate exposure of type II collagen during cartilage degradation in individual joints in vivo in a guinea pig. Immunoliposomes could be used to determine the effectiveness of therapeutic interventions in small animals as well as vehicles for localized drug delivery to OA chondrocytes.

From the Clinical Editor

This team of authors have developed near infrared immunoliposomes conjugated with type II collagen antibody for diagnosis and treatment of early OA, with promising results demonstrated in a guinea pig model.

Graphical Abstract

Schematic diagram of antibody targeted immunoliposomes binding onto damaged cartilage. Antibodies to type II collagen are normally blocked from binding to the surface of the articular cartilage. Proteolytic enzymes secreted by resident chondrocytes, synoviocytes or infiltrating leukocytes degrade the surface proteins and allow access of the antibodies to the type II collagen fibrillar network within.

Section snippets

Animal and in vivo test

Two different age groups (3-5 month and 1-2 years old) of Dunkin-Hartley (DH, osteoarthritic) guinea pigs (n = 12 for each age group) were used in these experiments. The spontaneous model of OA in DH-guinea pigs shares many features of human OA including correlation with obesity, aging and increased severity in weight bearing areas of the articular cartilage.⁸ 100 μl of immunoliposomes that contains near infrared-emitting dye, Xenofluor 750 (0.38 μmol, Caliper Life Science, Hopkinton, MA) and

Characterization of immunoliposomes

After preparation, the size distribution and sample consistency were verified using transmission electron microscopy (TEM; JEM1200EX II, JEOL USA Inc, MA) (Figure 1, C) and dynamic light scattering (DLS) (Figure 1, B). To determine size distribution using TEM, the liposomes were negatively stained by phosphotungstic acid (PTA). In the DLS (Malvern, UK) analysis, the extrusion of multilamellar vesicles through polycarbonate track etched filters with uniform cylindrical 200 nm pores results in

Discussion

In this study, we used the 200 nm size of pendant-type PEG immunoliposomes carrying CII antibodies at the distal ends of the PEG-maleimide chains. This type of liposome has been shown to exhibit higher binding efficiency to target tissues, and this is the type of liposome that this study has employed.20., 21. In addition to the chemical composition, the physical size of the liposome is also a contributory factor to its circulation time.32., 33., 34. Smaller liposomes, nanosomes, ranging in size

References (48)

K.A. Elsaid et al.
Collagen markers in early arthritic diseases
Clin Chim Acta
(2006)
F. Leblond et al.
Pre-clinical whole-body fluorescence imaging: Review of instruments, methods and applications
J Photochem Photobiol B
(2010)
J.L. Huebner et al.
A comparative analysis of bone and cartilage metabolism in two strains of guinea-pig with varying degrees of naturally occurring osteoarthritis
Osteoarthr Cartil
(2002)
T. Ishida et al.
A combinatorial approach to producing sterically stabilized (stealth) Immunoliposomal drugs
FEBS Lett
(1999)
K. Maruyama et al.
Targeting efficiency of PEG-Immunoliposome-conjugated antibodies at PEG terminals
Adv Drug Deliv Rev
(1997)
F. Olson et al.
Preparation of liposomes of defined size distribution by extrusion through polycarbonate membranes
Biochim Biophys Acta
(1979)
H.A.H. Rongen et al.
Liposomes and immunoassays
J Immunol Methods
(1997)
F. Szoka et al.
Preparation of unilamellar liposomes of intermediate size (0.1-0.2 um) by a combination of reverse phase evaporation and extrusion through polycarbonate membranes
Biochim Biophys Acta
(1980)
S.M. Moghimi et al.
Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties
Prog Lipid Res
(2003)
D. Liu et al.
Large liposomes containing ganglioside GM1 accumulate effectively in spleen
Biochem Biophys Acta
(1991)

D. Liu et al.

Role of liposome size and RES blockade in controlling biodistribution and tumor uptake of GM-1 containing liposomes

Biochem Biophys Acta

(1992)

V.P. Torchilin

Multifunctional and stimuli-sensitive pharmaceutical nanocarriers

Eur J Pharm Biopharm

(2009)

A. Vojta et al.

Determination of liposome size: A tool for protein reconstitution

Anal Biochem

(2005)

A. Vanniasinghe et al.

The potential of liposomal drug delivery for the treatment of inflammatory arthritis

J Semin Arthritis Rheum

(2009)

R.M. Aspden

Osteoarthritis: a problem of growth not decay?

Rheumatology

(2008)

R. Bitton

The economic burden of Osteoarthritis

Am J Manag Care

(2009)

H.A. Wieland et al.

Osteoarthritis; an untreatable disease?

Nat Rev

(2005)

H.E. Jasin et al.

Characteristics of anti-type II collagen antibody binding to articular cartilage

Arthritis Rheum

(1993)

C.E. Quatman et al.

The Clinical Utility and Diagnostic Performance of Magnetic Resonance Imaging for Identification of Early and Advanced Knee Osteoarthritis: A Systematic Review

Am J Sports Med

(2011)

L.G. Ameye et al.

Animal models of osteoarthritis: lessons learned while seeking the “Holy Grail”

Curr Opin Rheumatol

(2006)

A.M. Bendele

Animal models of osteoarthritis

J Musculoskelet Neuronal Interact

(2001)

A.M. Bendele

Animal models of osteoarthritis in an era of molecular biology

J Musculoskelet Neuronal Interact

(2002)

A.P. Hollander et al.

Increased damage to type II collagen in osteoarthritic articular cartilage detected by a new immunoassay

J Clin Invest

(1994)

S. Hovinga et al.

Addition of low-dose tumor necrosis factor-a to systemic treatment with STEALTH liposomal doxorubicin (Doxil) improved anti-tumor activity in osteosarcoma-bearing rats

Anti-Cancer Drugs

(2005)

Cited by (32)

Rational engineering of ferritin nanocages for targeted therapy of osteoarthritis
2020, Nanomedicine: Nanotechnology, Biology, and Medicine
Citation Excerpt :
Intra-articular (IA) drug delivery is a valid treatment for OA through direct targeting of OA joints.4 Various delivery systems in the application of IA-injections have been reported, such as liposomes,5 microparticles,6 nanoparticles,7 and hydrogels.8 However, the efficacy of drug delivery is limited, which disfavors the therapy of OA.9
Intra-articular (IA) drug delivery to treat osteoarthritis (OA) is limited by the short retention time of drugs in the joints due to poor specific targeting and non-responsiveness under acidic environment. A cartilage-targeting peptide was engineered to the surface of ferritin nanocages (CT-Fn) and loaded with an anti-inflammatory drug, metformin (Met), via the self-assembling nature of Fn nanocages. It demonstrated that the CT-Fn/Met could specifically bind to type II collagen, leading to the downregulation of catabolic markers of OA and promotion of cartilage-specific makers in IL-1β-induced chondrocytes. IA delivery of CT-Fn/Met prolonged the retention time for 3 weeks and remarkably reduced inflammation. Moreover, better release under acidic conditions which enabling longer retention time of Met after IA delivery in OA joints for one more week. CT-Fn/Met could target and efficiently enter chondrocytes, further inducing prolonged IA accumulation and achieving enhanced therapeutic efficacy for OA treatment.
Effects of cartilage-targeting moieties on nanoparticle biodistribution in healthy and osteoarthritic joints
2020, Acta Biomaterialia
Understanding intra-articular biodistribution is imperative as candidate osteoarthritis (OA) drugs become increasingly site-specific. Cartilage has been identified as opportunistic for therapeutic intervention, but poses numerous barriers to drug delivery. To facilitate drug delivery to cartilage, nanoscale vehicles have been designed with different features that target the tissue's matrix. However, it is unclear if these targeting strategies are influenced by OA and the associated structural changes that occur in cartilage. The goal of this work was to study the effectiveness of different cartilage-targeting nanomaterials with respect to cartilage localization and retention, and to determine how these outcomes change in OA. To address these questions, a nanoparticle (NP) system was developed, and the formulation was tuned to possess three distinct cartilage-targeting strategies: (1) passive targeting cationic NPs for electrostatic attraction to cartilage, (2) active targeting NPs with binding peptides for collagen type II, and (3) untargeted neutrally-charged NPs. Ex vivo analyses with bovine cartilage explants demonstrated that targeting strategies significantly improved NP associations with both healthy and OA-like cartilage. In vivo studies with collagenase-induced OA in rats revealed that disease state influenced joint biodistribution for all three NP formulations. Importantly, the extent of cartilage accumulation for each NP system was affected by disease differently; with active NPs, but not passive NPs, cartilage accumulation was increased in OA relative to healthy knees. Together, this work suggests that NPs can be strategically designed for site-specific OA drug delivery, but the biodistribution of the NPs are influenced by the disease conditions into which they are delivered.
As emerging drugs for osteoarthritis are becoming increasingly site-specific, the need for targeted intra-articular drug delivery has evolved. To improve drug delivery to cartilage, targeting strategies for nanomaterials have been developed, but the manner in which these targeted systems accumulate at different sites within the joint remains poorly understood. Moreover, it is unclear how nanomaterial-tissue interactions change in osteoarthritic conditions, as tissue structure and composition change after disease onset. By understanding how nanomaterials distribute within healthy and disease joints, we can advance targeted drug delivery strategies and improve therapeutic outcomes for emerging drugs.
Intra-articular targeting of nanomaterials for the treatment of osteoarthritis
2019, Acta Biomaterialia
Citation Excerpt :
For example, a 150–200 nm fluorescent liposome decorated with collagen type II antibodies were formulated for theranostic applications in OA. After intravenous injection, these particles migrate into the joint but do not bind to cartilage unless the collagen II network is exposed, namely in conditions of tissue degradation [90]. Additionally, similar particles were shown via fluorescence to accumulate in the knee in a manner proportional to OA severity in vivo [91].
Osteoarthritis is a prevalent and debilitating disease that involves pathological contributions from numerous joint tissues and cells. The joint is a challenging arena for drug delivery, since the joint has poor bioavailability for systemically administered drugs and experiences rapid clearance of therapeutics after intra-articular injection. Moreover, each tissue within the joint presents unique barriers to drug localization. In this review, the various applications of nanotechnology to overcome these drug delivery limitations are investigated. Nanomaterials have reliably shown improvements to retention profiles of drugs within the joint space relative to injected free drugs. Additionally, nanomaterials have been modified through active and passive targeting strategies to facilitate interactions with and localization within specific joint tissues such as cartilage and synovium. Last, the limitations of drawing cross-study comparisons, the implications of synovial fluid, and the potential importance of multi-modal therapeutic strategies are discussed. As emerging, cell-specific disease modifying osteoarthritis drugs continue to be developed, the need for targeted nanomaterial delivery will likely become critical for effective clinical translation of therapeutics for osteoarthritis.
Improving drug delivery to the joint is a pressing clinical need. Over 27 million Americans live with osteoarthritis, and this figure is continuously expanding. Numerous drugs have been investigated but have failed in clinical trials, likely related to poor bioavailability to target cells. This article comprehensively reviews the advances in nano-scale delivery vehicles designed to overcome the delivery barriers in the joint. This is the first review to analyze active and passive targeting strategies systematically for different target sites while also delineating between tissue homing and whole joint retention. By bringing together the lessons learned across numerous nano-scale platforms, researchers may be able to hone future nanomaterial designs, allowing emerging therapeutics to perform with clinically relevant efficacy and disease modifying potential.
Emerging vistas in theranostic medicine
2019, International Journal of Pharmaceutics
Citation Excerpt :
Uptake studies after intravenous injection in guinea pig model of arthritis which bears close resemblance to human osteoarthritis demonstrated that binding of the immunoliposomes was directly related to extent of cartilage damage in the joint. The study provided a valuable theranostic tool for osteoarthritis overcoming the need for costly imaging modalities and also achieving targeted delivery of therapeutics to the inflamed tissue (Cho et al., 2014). The treatment of inflammatory bowel disease involves use of corticosteroids like dexamethasone which have poor bioavailability and target specificity issues.
Recent years have witnessed a paradigm shift in the focus of healthcare towards development of customized therapies which cater to the unmet needs in a myriad of disease areas such as cancer, infections, cardiovascular diseases, neurodegenerative disorders and inflammatory disorders. The term ‘theranostic’ refers to such multifunctional systems which combine the features of diagnosis and treatment in a single platform for superior control of the disease. Theranostic systems enable detection of disease, treatment and real time monitoring of the diseased tissue. Theranostic nanocarriers endowed with multiple features of imaging, targeting, and providing on-demand delivery of therapeutic agents have been designed for enhancement of therapeutic outcomes. Fabrication of theranostics involves utilization of materials having distinct properties for imaging, targeting, and programming drug release spatially and temporally. Although the field of theranostics has been widely researched and explored so far for treatment of different types of cancer, there have been considerable efforts in the past few years to extend its scope to other areas such as infections, neurodegenerative disorders and cardiovascular diseases. This review showcases the potential applications of theranostics in disease areas other than cancer. It also highlights the cardinal issues which need to be addressed for successful clinical translation of these theranostic tools.
Towards the antioxidant therapy in Osteoarthritis: Contribution of nanotechnology
2017, Journal of Drug Delivery Science and Technology
Osteoarthritis (OA) is a common joint disorder with an increased prevalence. Despite its frequency, there are few therapies (disease modifying osteoarthritic drugs, DMOAD) to slow the progression of the disease. Its multifactorial etiology includes oxidative stress.
The current progress in the use of lipid nanocarriers to deliver DMOAD and antioxidant agents to the synovial space will be the topic of this review article.
We will first discuss the pathophysiological aspects of OA, focusing on the role of oxidative stress in the course of this disease. The following is a description of the conventional treatments used and their drawbacks for patient quality and efficacy. We then review the advances in DMOAD and antioxidant therapy, and how the nanotechnology could improve some of the limitations of these therapies.
A classification of lipid nanocarriers used in OA regarding their structure and composition has been proposed. Some studies are detailed in order to give the reader a better understanding of the functionality of these nanosystems.
Finally, we consider the recent trends in targeting of antioxidant-loaded lipid nanosystems towards activated macrophages as the main source of reactive oxygen species and reactive nitrogen species in OA. The relevance of macrophages for theranostic purposes is also highlighted.
Immunoliposomes: A review on functionalization strategies and targets for drug delivery
2017, Colloids and Surfaces B: Biointerfaces
Citation Excerpt :
For the purpose of arthritis treatment and diagnosis, near infrared immunoliposomes conjugated with CII antibody were developed. Researchers demonstrated selective binding and quantified cartilage degradation in vivo in guinea pigs [136]. Lupus nephritis is a serious consequence of systemic lupus erythematous, an autoimmune disease that also affects other organs, including the skin, pericardium, lungs, and nervous system.
Nanoparticles, especially liposomes, have gained prominence in the field of drug delivery for the treatment of human diseases, particularly cancer; they provide several advantages, including controlled drug release, protection of the drug against degradation, improved pharmacokinetics, long circulation, and passive targeting to tumors and inflammatory sites due to the enhanced permeability and retention effect. The functionalization of liposomes with monoclonal antibodies or antibody fragments to generate immunoliposomes has emerged as a promising strategy for targeted delivery to and uptake by cells overexpressing the antigens to these antibodies, with a consequent reduction in side effects. In this review, we address functionalization strategies for the non-covalent and covalent attachment of monoclonal antibodies and their fragments to liposomal surfaces. The main reaction occurs between the sulfhydryl groups of thiolated antibodies and maleimide-containing liposomes. Furthermore, we explore the main targeting possibilities with these ligands for the treatment of a variety of pathologies, including HER2- and EGFR-positive cancers, inflammatory and cardiovascular diseases, infectious diseases, and autoimmune and neurodegenerative diseases, which have not previously been reviewed together. Overall, many studies have shown selective delivery of immunoliposomes to target cells, with promising in vivo results, particularly for cancer treatment. Although clinical trials have been conducted, immunoliposomes have not yet received clinical approval. However, immunoliposomes are promising formulations that are expected to become available for therapeutic use after clinical trials prove their safety and efficacy, and after scaling issues are resolved.

View all citing articles on Scopus

: This work supported with resources and the use facilities at the Veterans Affairs Medical Center (VAMC) at Memphis TN USA. This research was supported by a VA Merit Review award from Department of Veterans Affairs, R21from National Institutes of Health (AR060408) and CTSI from the UTHSC (Karen A. Hasty) and also the Arthritis Foundation Fellowship Award (H. Cho) and the National Science Foundation (CHE-1316680) award (E. Pinkhassik).

View full text

Published by Elsevier Ltd.

Original ArticleTheranostic immunoliposomes for osteoarthritis

Abstract

From the Clinical Editor

Graphical Abstract

Section snippets

Animal and in vivo test

Characterization of immunoliposomes

Discussion

Clin Chim Acta

J Photochem Photobiol B

Osteoarthr Cartil

FEBS Lett

Adv Drug Deliv Rev

Biochim Biophys Acta

J Immunol Methods

Biochim Biophys Acta

Prog Lipid Res

Biochem Biophys Acta

Biochem Biophys Acta

Eur J Pharm Biopharm

Anal Biochem

J Semin Arthritis Rheum

Osteoarthritis: a problem of growth not decay?

Rheumatology

The economic burden of Osteoarthritis

Am J Manag Care

Osteoarthritis; an untreatable disease?

Nat Rev

Characteristics of anti-type II collagen antibody binding to articular cartilage

Arthritis Rheum

The Clinical Utility and Diagnostic Performance of Magnetic Resonance Imaging for Identification of Early and Advanced Knee Osteoarthritis: A Systematic Review

Am J Sports Med

Animal models of osteoarthritis: lessons learned while seeking the “Holy Grail”

Curr Opin Rheumatol

Animal models of osteoarthritis

J Musculoskelet Neuronal Interact

Animal models of osteoarthritis in an era of molecular biology

J Musculoskelet Neuronal Interact

Increased damage to type II collagen in osteoarthritic articular cartilage detected by a new immunoassay

J Clin Invest

Addition of low-dose tumor necrosis factor-a to systemic treatment with STEALTH liposomal doxorubicin (Doxil) improved anti-tumor activity in osteosarcoma-bearing rats

Anti-Cancer Drugs

Original Article
Theranostic immunoliposomes for osteoarthritis