HPMA copolymer-collagen hybridizing peptide conjugates targeted to breast tumor extracellular matrix

Subrahmanyam, Nithya; Yathavan, Bhuvanesh; Kessler, Julian; Yu, S. Michael; Ghandehari, Hamidreza

doi:10.1016/j.jconrel.2022.10.017

Cited by 4 publications

(8 citation statements)

References 64 publications

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“…Selective binding of HPMA–CHP to denatured collagen was verified previously . Although the conjugation efficiency was lower for targeted peptides than scrambled peptides, collagen binding experiments demonstrated significantly more collagen binding for HPMA–CHP conjugates than for HPMA– S CHP conjugates …”

Section: Resultsmentioning

confidence: 99%

“…While changes in vasculature and fenestrations due to tumor growth likely played a substantial role in extravasation, the earlier t max for HPMA–CHP (similar to CHP) compared to HPMA– S CHP suggests that binding to degraded collagen in the bone appears to have played a major role in retention. Previously, we administered these three compounds in breast tumor-bearing mice and found that both polymers, targeted and nontargeted, had similar t max values of ∼24 h while the peptide had a t max of ∼6 h, which may reflect a difference between the vasculature and extravasation at the bone versus the breast tumor tissue. In the OS tumors, the targeted polymer had a higher AUC than the nontargeted polymer (Figure B), indicating that targeting remodeling collagen may elicit a higher potential drug exposure if used as a drug delivery vehicle.…”

Section: Discussionmentioning

confidence: 96%

“…Collagen is remodeled as a part of normal tissue maintenance, and the higher level of binding of the targeted polymer may be due to a basal level of denatured collagen. The relative distribution of signal (which is semiquantitative given the differences in tissue penetration of signal) between organs is comparable to what has been seen in our previous work in a breast cancer model . While the signal at the heart is very low in all three, the higher level seen in the heart for HPMA–CHP compared to HPMA– S CHP may be due to a higher amount in circulation at the 168 h time point, which may have only been washed away from the tumor and other organs at a later time point and thus remains in the bloodstream at this time.…”

Section: Discussionmentioning

confidence: 99%

“…Copolymer conjugates were synthesized according to previously published procedures . Briefly, the comonomers N -(2-hydroxypropyl)methacrylamide (HPMA) and N -methacryloylglycylglycine (MA-GG-OH) were synthesized according to previously published methods and characterized by electrospray ionization mass spectrometry (ESI-MS) and/or nuclear magnetic resonance (NMR) spectroscopy.…”

Section: Methodsmentioning

confidence: 99%

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Targeting Intratibial Osteosarcoma Using Water-Soluble Copolymers Conjugated to Collagen Hybridizing Peptides

Subrahmanyam

Yathavan

et al. 2023

Mol. Pharmaceutics

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Osteosarcoma (OS) is the most common form of primary malignant bone cancer in adolescents. Over the years, OS prognosis has greatly improved due to adjuvant and neoadjuvant (preoperative) chemotherapeutic treatment, increasing the chances of successful surgery and reducing the need for limb amputation. However, chemotherapeutic treatment to treat OS is limited by off-target toxicities and requires improved localization at the tumor site. Collagen, the main constituent of bone tissue, is extensively degraded and remodeled in OS, leading to an increased availability of denatured (monomeric) collagen. Collagen hybridizing peptides (CHPs) comprise a class of peptides rationally designed to selectively bind to denatured collagen. In this work, we have conjugated CHPs as targeting moieties to water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers to target OS tumors. We demonstrated increased accumulation of collagen-targeted HPMA copolymer–CHP conjugates compared to nontargeted HPMA copolymers, as well as increased retention compared to both nontargeted copolymers and CHPs, in a murine intratibial OS tumor model. Furthermore, we used microcomputed tomography analysis to evaluate the bone microarchitecture and correlated bone morphometric parameters (porosity, bone volume, and surface area) with maximum accumulation (S max) and accumulation at 168 h postinjection (S 168) of the copolymers at the tumor. Our results provide the foundation for the use of HPMA copolymer–CHP conjugates as targeted drug delivery systems in OS tumors.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Targeting Intratibial Osteosarcoma Using Water-Soluble Copolymers Conjugated to Collagen Hybridizing Peptides

Subrahmanyam

Yathavan

et al. 2023

Mol. Pharmaceutics

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“…Since local injection is a better drug delivery route for managing OA, and fast clearance in the joint is a known problem for IA therapeutics used in OA treatment, we investigated CHP binding to joint tissues after IA injection for the first time. Since CHP can be readily conjugated to drug molecules 16 and drug delivery systems for enhanced accumulation in pathological sites with high collagen degradation, 31,32 extended retention of CHPs in the joint tissue could potentially be applied to extending the efficacy of IA OA drugs. CHP retention was tested by in vivo imaging of rat knees after IA injection of NIRF‐labeled CHPs (Figures 1–2).…”

Section: Discussionmentioning

confidence: 99%

Targeting damaged collagen for intra‐articular delivery of therapeutics using collagen hybridizing peptides

Luke

Bhuket

et al. 2023

Journal Orthopaedic Research

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The objective of this study was to investigate the potential of collagen hybridizing peptides (CHPs), which bind to denatured collagen, to extend the retention time of near‐infrared fluorophores (NIRF) following intra‐articular (IA) injection in rat knee joints. CHPs were synthesized with a NIRF conjugated to the N‐terminus. Male Sprague−Dawley rats were assigned to one of four experimental groups: healthy, CHP; osteoarthritis (OA), CHP; healthy, scrambled‐sequence CHP (sCHP), which has no collagen binding affinity; or OA, sCHP. Animals in the OA groups received an IA injection of monosodium iodoacetate to induce OA. All animals then received the corresponding CHP injection. Animals were imaged repeatedly over 2 weeks using an in vivo fluorescence imaging system. Joint components were isolated and imaged to determine CHP binding distribution. Safranin‐O and Fast Green histological staining was performed to confirm the development of OA. CHPs were found to be retained within the joint following IA injection in both healthy and OA animals for the full study period. In contrast, sCHP signal was negligible by 24−48 h. CHP signal was significantly greater (p < 0.05) in OA joints when compared to healthy joints. At the 2‐week end point, multiple joint components retained CHPs, including cartilage, meniscus, and synovium. CHPs dramatically extended the retention time of NIRFs following IA injection in healthy and OA knee joints by binding to multiple collagenous tissues in the joint. These results support the pursuit of further research to develop CHP based therapeutics for IA treatment of OA.

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From Collagen Mimetics to Collagen Hybridization and Back

Ratnatilaka Na Bhuket,

Li,

2024

Acc. Chem. Res.

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Conspectus Facilitated by the unique triple-helical protein structure, fibrous collagens, the principal proteins in animals, demonstrate a dual function of serving as building blocks for tissue scaffolds and as a bioactive material capable of swift renewal in response to environmental changes. While studies of triple-helical collagen mimetic peptides (CMPs) have been instrumental in understanding the molecular forces responsible for the folding and assembly of triple helices, as well as identifying bioactive regions of fibrous collagen molecules, single-strand CMPs that can specifically target and hybridize to denatured collagens (i.e., collagen hybridizing peptides, CHPs) have proven useful in identifying the remodeling activity of collagen-rich tissues related to development, homeostasis, and pathology. Efforts to improve the utility of CHPs have resulted in the development of new skeletal structures, such as dimeric and cyclic CHPs, as well as the incorporation of artificial amino acids, including fluorinated proline and N-substituted glycines (peptoid residues). In particular, dimeric CHPs were used to capture collagen fragments from biological fluid for biomarker study, and the introduction of peptoid-based collagen mimetics has sparked renewed interest in peptidomimetic research because peptoids enable a stable triple-helical structure and the presentation of an extensive array of side chain structures offering a versatile platform for the development of new collagen mimetics. This Account will cover the evolution of our research from CMPs as biomaterials to ongoing efforts in developing triple-helical peptides with practical theranostic potential in targeting denatured and damaged collagens. Our early efforts in functionalizing natural collagen scaffolds via noncovalent modifications led to the discovery of an entirely new use of CMPs. This discovery resulted in the development of CHPs that are now used by many different laboratories for the investigation of pathologies associated with changes in the structures of extracellular matrices including fibrosis, cancer, and mechanical damage to collagen-rich, load-bearing tissues. Here, we delve into the essential design features of CHPs contributing to their collagen binding properties and practical usage and explore the necessity for further mechanistic understanding of not only the binding processes (e.g., binding domain and stoichiometry of the hybridized complex) but also the biology of collagen degradation, from proteolytic digestion of fibrils to cellular processing of collagen fragments. We also discuss the strengths and weaknesses of peptoid-based triple-helical peptides as applied to collagen hybridization touching on thermodynamic and kinetic aspects of triple-helical folding. Finally, we highlight current limitations and future directions in the use of peptoid building blocks to develop bioactive collagen mimetics as new functional biomaterials.

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HPMA copolymer-collagen hybridizing peptide conjugates targeted to breast tumor extracellular matrix

Cited by 4 publications

References 64 publications

Targeting Intratibial Osteosarcoma Using Water-Soluble Copolymers Conjugated to Collagen Hybridizing Peptides

Targeting Intratibial Osteosarcoma Using Water-Soluble Copolymers Conjugated to Collagen Hybridizing Peptides

Targeting damaged collagen for intra‐articular delivery of therapeutics using collagen hybridizing peptides

From Collagen Mimetics to Collagen Hybridization and Back

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