HPMA Copolymer-Conjugated Pirarubicin in Multimodal Treatment of a Patient with Stage IV Prostate Cancer and Extensive Lung and Bone Metastases

Abstract

Nanomedicine allows achievement of tumor-selective drug delivery because of the enhanced permeability and retention (EPR) effect of solid tumors. We report here the first clinical application of a new agent-HPMA copolymer-conjugated pirarubicin (P-THP)-with a molecular size of about 8 nm, or 38.5 kDa. A patient had advanced prostate cancer with multiple metastases in the lung, pelvis, femur, and perhaps the sacrum. In April 2013, this 60-year-old patient started treatment with leuprorelin and estradiol, which continued until July 2014, but the patient became refractory to this treatment. So the patient underwent proton beam radiotherapy targeted to the primary prostate cancer, and P-THP was administered for numerous metastatic tumor nodules concomitantly with radiotherapy. This combination therapy had remarkable results, with complete remission of multiple metastases in the lung and bone. The prostate-specific antigen (PSA) value was decreased from about 1000 ng/mL on April 30, 2013, to about 100 ng/mL on June 24, 2013, with hormone therapy, but rose again to 964.2 ng/mL and then to 1472 ng/mL in July 2013, during leuprorelin administration. P-THP treatment administered concomitantly with proton beam irradiation was started in August 2013. The PSA value was decreased to 102 ng/mL on August 26, 2013, and then to 0.971 ng/mL on October 8, 2013, and 0.277 ng/mL on January 15, 2015. The P-THP doses ranged from 30 to 75 mg of free THP equivalent/patient every 2-3 weeks without signs of serious toxicity, such as cardiovascular side effects or a reduction in quality of life. No evidence of relapse was found more than 20 months after P-THP administration. This case demonstrates the value of hydrazone-bonded polymeric drugs in multimodal therapy.

The light at the end of the tunnel—second generation HPMA conjugates for cancer treatment

“…In this case, the activity of cathepsin B is not essential for biological activity of the conjugate. One such conjugate consisting of hydrazone linker and drug pirarubicin (P-THP) has been applied together with proton beam radiation to a patient with stage IV prostate cancer and extensive metastases, resulting in complete remission and no evidence of relapse was observed after 20 months [36]. …”

Polymer-drug conjugates as inhalable drug delivery systems: A review

“…Other polymer such as HPMA [N-(2-hydroxypropyl)methacrylamide] conjugated to pirarubicin via hydrazone bonds showed high therapeutic potential against lung cancers [109]. This conjugate was found to improve the treatment of metastases in patient suffering from stage IV lung cancer.…”

Development of octreotide-conjugated polymeric prodrug of bufalin for targeted delivery to somatostatin receptor 2 overexpressing breast cancer in vitro and in vivo

“…Polymeric micelles constructed from polymeric prodrug of hydrophobic small molecular drugs have emerged as a very promising choice considering its good water solubility, easy to further modification, enhanced permeability and retention (EPR) effect, and tunable drug content. [18][19][20][21][22][23][24][25][26][27] Moreover, it was reported that the introduction of tumor-targeting moieties onto polymeric prodrugs can effectively enhance the accumulation in tumor tissues and therapeutic efficacy of drugs. 28 In this context, somatostatin receptors (SSTRs) were explored as potential targets because they are overexpressed in a variety of tumors and cancer cell lines, including breast cancer.…”

“…36 It is worthy of noting that in addition to physically encapsulating drugs by nanoparticles, polymeric prodrug is another promising strategy owing to its intrinsic advantages such as passive targeting via the EPR effect, increased circulation time, improved water solubility, and tunable and well-defined drug content. [18][19][20][21][22][23][39][40][41][42][43][44] Besides, premature/burst drug release, which is one of the most common shortcomings of encapsulating method, can be effectively addressed. By using responsive chemical bonds to link drugs and polymers, polymeric prodrug can effectively release drugs under specific stimuli when reached into tumor tissues or cancer cells but released little drug in the circulation period.…”

“…× circulation time and more accumulation in tumor tissues than their small molecular counterparts based on EPR effects. [18][19][20][21][22][23] Besides, in vitro cell cytotoxicity also demonstrated improved anticancer efficacy of P(OEGMA-co-BUF), possibly due to its nanostructure and prodrug design. The two factors might together lead to the improved tumor inhibition effect in in vivo experiment.…”