Antiangiogenic Antitumor Activity of HPMA Copolymer–Paclitaxel–Alendronate Conjugate on Breast Cancer Bone Metastasis Mouse Model

Abstract

Polymer therapeutics have shown promise as tumor-targeted drug delivery systems in mice. The multivalency of polymers allows the attachment of different functional agents to a polymeric backbone, including chemotherapeutic and antiangiogenic drugs, as well as targeting moieties, such as the bone-targeting agent alendronate (ALN). We previously reported the conjugation of ALN and the chemotherapeutic drug paclitaxel (PTX) with N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer. The in vitro physicochemical properties, cancer cytotoxicity and antiangiogenic activity of HPMA copolymer-PTX-ALN conjugate were extensively characterized. The reported results warranted in vivo evaluations of the conjugate. In this manuscript, we evaluated the in vivo anticancer and antiangiogenic activity of HPMA copolymer-PTX-ALN conjugate. The conjugate exhibited an antiangiogenic effect by decreasing microvessel density (MVD), and inducing apoptotic circulating endothelial cells (CEC) following treatment of the mice. Using intravital imaging system and mCherry-labeled breast cancer cell lines, we were able to monitor noninvasively the progression of orthotopic metastatic tumors injected into the tibia of the mice. HPMA copolymer-PTX-ALN conjugate showed the greatest antitumor efficacy on mCherry-labeled 4T1 mammary adenocarcinoma inoculated into the tibia, as compared with PTX alone or in combination with ALN. Treatment with the bone-targeted polymeric conjugate demonstrated improved efficacy, was better tolerated, and was more easily administered intravenously than the clinically used PTX formulated in Cremophor/ethanol.

Polymeric nanotheranostics for real-time non-invasive optical imaging of breast cancer progression and drug release

“…The difference in IC 50 between the free drug and the conjugate can be attributed to the slow release kinetics of the drug from the carrier. These results are in accordance with previous reports showing the cytotoxic effect of an analogous HPMA copolymer-PTX conjugate on breast cancer cells [33,34].…”

“…This site-specific release mechanism should provide selective delivery to cathepsin B-overexpressing breast tumors. This assumption is based on previously published data from in vivo studies, demonstrating selective accumulation of the delivery system and drug release upon GFLG cleavage in breast cancer [33,34,39,40].…”

“…We have previously shown the anti-angiogenic effect of PTX on endothelial cells [33][34][35]. These studies have demonstrated inhibitory effect of PTX on different stages of the angiogenic cascadeproliferation, migration and formation of tube-like structures.…”

Novel Pullulan Bioconjugate for Selective Breast Cancer Bone Metastases Treatment

“…44 Stability studies showed that under physiological conditions at 37°C the bioconjugate is chemically and physically stable over more than 8 h, a prerequisite for EPR accumulation in the tumour size that takes place throughout a few hour circulation in the bloodstream. 45 h. The chemical stability can be ascribed to the -(GGPNle-ϕ-PTX) module localization in the core of the assembly that prevents the chemical hydrolysis observed in the case of dendrimeric bioconjugates 19,20 where this module is exposed on the surface. The drug was instead rapidly 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 The toxicity and biological activity of Pull-(GGPNle-ϕ-PTX)-(PEG-ALN) was assessed in vitro by using MDA-MB-231 human mammary adenocarcinoma cells that were in vivo inoculated in mice to isolate an aggressive bone metastases-derived cell population (MDA-MB-231 BM), which simulate the early invasive phase of breast cancer that forms bone metastases.…”

Dual-targeting delivery system for bone cancer: synthesis and preliminary biological evaluation

“…Such as the conjugation of ALN and the PTX with HPMA Copolymer was only based on alendronate for a bone targeting agent (Miller et al, 2011). However, there are few reports about dual-targeting drug delivery used in the treatment for bone tumors.…”