Development of a Selective Tumor-Targeted Drug Delivery System: Hydroxypropyl-Acrylamide Polymer-Conjugated Pirarubicin (P-THP) for Pediatric Solid Tumors


Abstract

Most pediatric cancers are highly chemo-sensitive, and cytotoxic chemotherapy has always been the mainstay of treatment. Anthracyclines are highly effective against most types of childhood cancer, such as neuroblastoma, hepatoblastoma, nephroblastoma, rhabdomyosarcoma, Ewing sarcoma, and so forth. However, acute and chronic cardiotoxicity, one of the major disadvantages of anthracycline use, limits their utility and effectiveness. Hydroxypropyl acrylamide polymer-conjugated pirarubicin (P-THP), which targets tumor tissue highly selectively via the enhanced permeability and retention (EPR) effect, and secondarily releases active pirarubicin molecules quickly into the acidic environment surrounding the tumor. Although, the latter rarely occurs in the non-acidic environment surrounding normal tissue. This mechanism has the potential to minimize acute and chronic toxicities, including cardiotoxicity, as well as maximize the efficacy of chemotherapy through synergy with tumor-targeting accumulation of the active molecules and possible dose-escalation. Simply replacing doxorubicin with P-THP in a given regimen can improve outcomes in anthracycline-sensitive pediatric cancers with little risk of adverse effects, such as cardiotoxicity. As cancer is a dynamic disease showing intra-tumoral heterogeneity during its course, continued parallel development of cytotoxic agents and molecular targeting agents is necessary to find potentially more effective treatments.

Keywords: DDS; EPR effect; P-THP; anthracyclines; drug delivery system; enhanced permeability and retention effect; hydroxypropyl acrylamide polymer-conjugated pirarubicin; nanomedicine; pediatric cancers; targeted drug delivery.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Comparison of scanning electron microscopy (SEM) images of blood vessels in normal, healthy tissues (A–D) and tumor tissues (E–H). Blood vessels in healthy tissue in (A–C) show clear, smooth, regular features and no leakage of polymeric resin. In contrast, the tumor vessels show leakage of polymeric resin at the capillary level (E). Although normal colonic tissue consists of organized vascular casts (C), colon tumor tissue shows a disorganized, irregular vascular network (G). The luminal surface of normal blood vessels (D) shows tight cell-cell junctions in the endothelium whereas blood vessels in the tumor (H) have large gaps (OP in H) among the endothelial cells. Adapted from reference [14] with permission. Images (C,D,E,H) are courtesy of Professor Moritz Anton Konerding in Mainz, Germany.
Figure 2
Figure 2
The enhanced permeability and retention (EPR) effect in tumor vasculature. The mechanism of this tumor-selective macromolecular drug targeting depends on various effectors affecting vascular tone as shown here. Aprotinin is an inhibitor of kallikrein; HOE-140 is a peptide antagonist of kinin. SBTI, soybean trypsin inhibitor; NO, nitric oxide; eNOS, endothelial nitric oxide synthase; iNOS, inducible form of nitric oxide synthase; COXs, cyclooxygenases; PGs, prostaglandins; MMP, metalloproteinase; ONOO-, peroxynitrite; O2?, superoxide anion radical; MF, macrophage; VEGF, vascular endothelial growth factor; VPF, vascular permeability factor; uPA, urokinase plasminogen activator; IL, interleukin; TNF, tumor necrosis factor; B2 receptor, bradykinin B2 receptor. Adapted from ref. [3].
Figure 3
Figure 3
Multiple barriers and necessary conditions for overcoming them in nanomedicine targeting tumors. To maximize the effectiveness of nanomedicine, the following three conditions must be met: (1) Selective accumulation of the macromolecule in the tumor; (2) release of the active pharmaceutical ingredients (API) into the tumor tissue; and (3) active cellular uptake of the API into the tumor cells. Adapted from reference [29].
Figure 4
Figure 4
Chemical structure of hydroxypropyl-acrylamide polymer-conjugated pirarubicin (P-THP). Pirarubicin, the active pharmaceutical ingredient (API), is connected to hydroxypropyl-acrylamide (HPMA) polymer by the hydrazone bond, an acid-cleavable linkage. The structure demonstrates the enhanced permeability and retention (EPR) effect targeting the tumor and the secondary release of the API there exerting the antitumor effect.
Figure 5
Figure 5
Release profile of free pirarubicin (THP) from the polymer conjugate (P-THP) at 37 °C. P-THP was dissolved in buffer solutions with different pH. The release of THP was determined by HPLC. Adapted from reference [51].
Figure 6
Figure 6
Body distribution of P-THP. (A) Free pirarubicin (THP) was administered at 10 mg of THP per kg equivalent. (B) and (C) Profile of P-THP administered at 10 mg of THP per kg equivalent into S-180 tumor-bearing mice. At the indicated time periods, mice were anesthetized and tissues were collected. (B) Total THP content and (C) released free THP content in each tissue sample were measured using HPLC. Values are expressed as the mean ± S.E. (n = 3). (D) Ratio of free THP to total THP in each tissue. The fluorescence intensity of the free THP was divided by the fluorescence intensity of the total THP. Adapted from ref. [4].
Figure 7
Figure 7
Antitumor activity of P-THP in vivo. (A,B) P-THP or free pirarubicin (THP) was injected once at 5 mg/kg (A) or 15 mg/kg (B) of THP per kg equivalent into S-180 tumor-bearing mice. (C) Body weight change and (D) survival rate after administration of 15 mg/kg of THP per kg equivalent to S-180 tumor-bearing mice. Values are expressed as the mean ± S.E. (n = 5–6). * One of the five mice with the largest tumor died; the tumors in the remaining mice continued to grow. Adapted from reference [4].
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