Pharmaceutical nanocarrier association with chondrocytes and cartilage explants: influence of surface modification and extracellular matrix depletion

Abstract

Objective To evaluate cartilage diffusion and isolated chondrocyte association of micelles and liposomes and to determine the effect of cell-penetrating peptide (CPP) surface functionalization and extracellular matrix depletion on chondrocyte association and cartilage diffusion, respectively. Methods Rhodamine-labeled micelles and liposomes were incubated with bovine chondrocytes and cell-associated fluorescence was quantified using flow cytometry. Rhodamine-labeled CPP-modified micelles and liposomes were incubated with chondrocytes and cell-associated fluorescence was compared to unmodified nanocarriers. Rhodamine-labeled micelles and liposomes were incubated with bovine cartilage explants for 1, 2 and 4 hours and cartilage-associated fluorescence was compared across groups. Cartilage explants were treated with interleukin-1 alpha (IL-1α) or with 0.25% trypsin. Rhodamine-labeled micelles and liposomes were incubated with control, IL-1 and trypsin-treated explants and cartilage-associated fluorescence was compared across groups. Results Chondrocyte-associated fluorescence following treatment with micelles was significantly higher (P<0.001) than fluorescence in the cells treated with liposomes while there was no difference between cell-associated fluorescence in the liposomes-treated and untreated controls. CPP-modified nanocarriers exhibited a significant increase in chondrocyte association compared to unmodified nanocarriers (P<0.001). Micelles exhibited a time and concentration-dependent diffusion in cartilage explants while liposomes showed no diffusion. Following IL-1 and trypsin treatments, micelle diffusion in articular cartilage was significantly higher (P<0.001) than their diffusion in untreated explants. Conclusion Micelles exhibit superior association with isolated chondrocytes compared to liposomes. Surface modification with a CPP enhances chondrocyte association of both nanocarriers. 15 nm diameter Micelles are better than 138 nm diameter liposomes in penetrating articular cartilage and extracellular matrix depletion enhances micelle penetration.

Cartilage penetrating cationic peptide carriers for applications in drug delivery to avascular negatively charged tissues

“…It is, therefore, critical to develop cartilage penetrating materials that, following IA administration, can enable rapid uptake of drugs through the full thickness of cartilage to reach a therapeutic level before being cleared out and bind within to increase joint residence time. Drug delivery systems under investigation include micron sized polymeric particles [17, 18], micelles [19, 20], liposomes [21, 22] and aggregating hydrogels [23–25] but none of them have been shown to penetrate the cartilage and thus remain ineffective in eliciting a disease modifying biological response. Gene transfer vectors can only penetrate through the intact superficial zone of tissues [26] and suffer from concerns of immunogenicity and safety that make their clinical translation difficult [6, 27].…”

Avidin as a model for charge driven transport into cartilage and drug delivery for treating early stage post-traumatic osteoarthritis

“…A variety of particles have been explored in vitro and in vivo [19–23] but the effects of particle size and surface morphology on their penetration, binding and retention within cartilage are less well understood [24]. The relative utility of 15 nm micelles vs. 138 nm liposomes was recently reported, showing the need to further differentiate between size and structure [25]. …”

Poly-beta-amino-esters nano-vehicles based drug delivery system for cartilage

“…The size of the drug carrier directly impacts its cartilage penetration ability41, 42; it has been shown that the exclusion size for avidin in cartilage is about 10 nm, 7 analogously Elsaid et al (2013) 40 gave evidence that 10 nm liposome were more effective than 100 nm micelle in delivery drugs into cartilage. The remarkable cartilage penetration ability exhibited by PBAE is despite their relative large size, that is in the order of hundreds of nanometers (Figure A6, Table 1); only few successful delivery systems for cartilage have sizes comparable to PBAE 12, 13.…”