The transport and accumulation of anticancer nanodrugs in tumor tissues are affected by many factors including particle properties, vascular density and leakiness, and interstitial diffusivity. It is important to understand the effects of these factors on the detailed drug distribution in the entire tumor for an effective treatment. In this study, we developed a small-scale mathematical model to systematically study the spatiotemporal responses and accumulative exposures of macromolecular carriers in localized tumor tissues. We chose various dextrans as model carriers and studied the effects of vascular density, permeability, diffusivity, and half-life of dextrans on their spatiotemporal concentration responses and accumulative exposure distribution to tumor cells. The relevant biological parameters were obtained from experimental results previously reported by the Dreher group. The area under concentration-time response curve (AUC) quantified the extent of tissue exposure to a drug and therefore was considered more reliable in assessing the extent of the overall drug exposure than individual concentrations. The results showed that 1) a small macromolecule can penetrate deep into the tumor interstitium and produce a uniform but low spatial distribution of AUC; 2) large macromolecules produce high AUC in the perivascular region, but low AUC in the distal region away from vessels; 3) medium-sized macromolecules produce a relatively uniform and high AUC in the tumor interstitium between two vessels; 4) enhancement of permeability can elevate the level of AUC, but have little effect on its uniformity while enhancement of diffusivity is able to raise the level of AUC and improve its uniformity; 5) a longer half-life can produce a deeper penetration and a higher level of AUC distribution. The numerical results indicate that a long half-life carrier in plasma and a high interstitial diffusivity are the key factors to produce a high and relatively uniform spatial AUC distribution in the interstitium.

Objective: Haematological toxicity (HT) is common in patients with oesophageal cancer (EC) treated with chemoradiotherapy (CRT). The Quantitative Analysis of Normal Tissue Effects in the Clinic guidelines provide no dose constraints for the bone marrow (BM) to avoid HT. We aimed to determine dosimetric factors associated with HT during CRT for EC. Methods: 41 patients with EC treated with neoadjuvant cisplatin and 5-fluorouracil-based CRT were retrospectively reviewed. Associations between the dose-volume histogram parameters of thoracic bones and blood cell count changes during CRT were assessed using logistic regression analyses. Receiver-operating characteristic curves were used to derive optimal dosimetric planning constraints. V x indicates the total organ volume percentage exceeding a radiation dose of x (Gy). Results: Greater thoracic vertebrae and rib irradiation doses, including mean vertebral dose (MVD), thoracic vertebrae V 5-30 (TVV 5-30 ), mean rib dose and rib V 5-20 , were associated with increased leukopenia (grade $ 3) risk. Additional BM sites (sternum, scapulae and clavicles) did not influence HT. White blood cell and absolute neutrophil count nadirs were associated with increased irradiation doses to the thoracic vertebrae, ribs and sternum. Chemotherapy cycle number was not significantly associated with severe neutropenia or leukopenia. Cut-off values with the highest likelihood of avoiding leukopenia were MVD , 25.9 Gy, TVV 20 , 70% and TVV 10 , 77%. Conclusion: Thoracic bone irradiation dose was significantly associated with HT after adjusting for chemotherapy effects. Efforts to maintain MVD , 25.9 Gy, TVV 10 , 77% and TVV 20 , 70% could reduce HT. Advances in knowledge: This is the first study addressing issues concerning HT in patients with neoadjuvant CRTtreated EC.

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