Characterization and validation of a bone metastatic castration-resistant prostate cancer model as a nanomedicine evaluation platform

Rationale: Bone metastases -common in metastatic castration-resistant prostate cancer (mCRPC) -lead to severe complications and currently suffer from limited therapeutic options.Poor solubility, systemic toxicity, and therapeutic resistance hamper conventional approaches, such as docetaxel (Dtx) treatment.Nanomedicine-based strategies -including polymer-drug conjugates -can help overcome said limitations through enhanced tumor targeting and reduced unwanted side effects in healthy tissues.Methods: An intratibial bone mCRPC mouse model -used to recapitulate tumor growth and microenvironmental dynamics -was developed and characterized.A poly-L-glutamic acid (PGA)-Dtx) conjugate synthesized to enhance Dtx delivery and efficacy was also characterized in terms of size, zeta potential, drug loading, and pH-dependent release.In vivo evaluations included tumor growth monitoring by bioluminescence imaging, cathepsin K activity from tumor by fluorescence imaging, bone damage evaluation by micro-computed tomography, tumor vasculature by light-sheet fluorescent microscopy, cell population at tumor site by histology, modulation of blood cell populations by tumor and treatment by hematology, and biodistribution of PGA-Dtx using fluorescent imaging and intravital microscopy.Results: Our intratibial bone mCRPC model supported reliable tumor establishment, progressive osteolytic damage and vascularization, and systemic inflammation.PGA-Dtx displayed optimal properties (6.6 nm size, -24.1 mV zeta potential, 3.3 mol % drug loading) and supported lower but sustained Dtx release at acidic pH.The enhanced tumor accumulation following PGA-Dtx administration significantly suppressed tumor growth in vivo, normalized cathepsin K activity levels, and reduced bone damage while avoiding the systemic toxicity associated with free Dtx.Conclusions: Our intratibial bone mCRPC mouse model provides a robust platform for studying PCa bone metastases and evaluating nanomedicine efficacy.PGA-Dtx displays promise as a safe and effective therapy for mCRPC, offering improved drug delivery and reduced systemic side effects, which supports the translational potential of polymer-drug conjugates in mCRPC management.