HPMA copolymers: Origins, early developments, present, and future☆

Kopeček, Jindřich; Kopečková, Pavla

doi:10.1016/j.addr.2009.10.004

Cited by 535 publications

(449 citation statements)

References 194 publications

(260 reference statements)

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“…N-(2-hydroxypropyl)methacrylamide (HPMA)-doxorubicin conjugate was the first synthetic polymer-drug conjugate to enter clinical trials in 1994 [169][170][171][172][173]. Since then, other polymerdrug conjugates, based on synthetic polymers like HPMA, polyglutamic acid (PGA) or PEG, have been submitted to clinical trials [93,125,129,[172][173][174][175].…”

Section: Polymer Therapeuticsmentioning

confidence: 99%

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

Pérez-Herrero

Fernández‐Medarde

2015

European Journal of Pharmaceutics and Biopharmaceutics

1,460

754

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Cancer is the second worldwide cause of death, exceeded only by cardiovascular diseases. It is characterized by uncontrolled cell proliferation and an absence of cell death that, except for hematological cancers, generates an abnormal cell mass or tumor. This primary tumor grows thanks to new vasculatization and, in time, adquires metastatic potential and spreads to other body sites, which causes metastasis and finally death. Cancer is caused by damage or mutations in the genetic material of the cells due to environmental or inherited factors. While surgery and radiotherapy are the primary treatment used for local and non-metastatic cancers, anti-cancer drugs (chemotherapy, hormone and biological therapies) are the choice currently used in metastasic cancers. Chemotherapy is based on the inhibition of the division of rapidly growing cells, which is a characteristic of the cancerous cells, but unfortunately, it also affects normal cells with fast proliferation rates, like the hair follicles, bone marrow and gastrointestinal tract cells, generating the characteristic side effects of chemotherapy. The indiscriminate destruction of normal cells, the toxicity of conventional chemotherapeutic Código de campo cambiado

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Section: Polymer Therapeuticsmentioning

confidence: 99%

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

Pérez-Herrero

Fernández‐Medarde

2015

European Journal of Pharmaceutics and Biopharmaceutics

1,460

754

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“…the relative vascular volume of tumors) correlates with the degree of EPR-mediated passive drug targeting, no experimental evidence for this has thus far been provided. Here, we therefore set out to visualize and quantify the tumor accumulation of near-infrared-fluorophore (NIRF) labeled polymeric drug carriers based on N-(2-hydroxypropyl)-methacrylamide HPMA copolymers are prototypic and routinely used macromolecular drug carriers, which have been extensively employed for EPR-mediated passive drug targeting [15][16][17]. As for other long-circulating nanocarriers, however, such as for liposomes, the tumor accumulation of HPMA copolymers varies quite considerably, both in animal models and in patients, from barely detectable, to up to 5% of the injected dose [18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

“…HPMA copolymers are prototypic and routinely used macromolecular drug carriers, which have been extensively employed for EPR-mediated passive drug targeting [15][16][17]. As for other long-circulating nanocarriers, however, such as for liposomes, the tumor accumulation of HPMA copolymers varies quite considerably, both in animal models and in patients, from barely detectable, to up to 5% of the injected dose [18][19][20][21].…”

Section: : Introductionmentioning

confidence: 99%

Section: : Introductionmentioning

confidence: 99%

“…In spite of this conceptual shortcoming, HPMA copolymers have been extensively used over the years, to improve the tumor-directed delivery of many different low-molecular-weight drugs, including e.g. anthracyclines, antimetabolites, taxanes and platinates [15,16,22,23], and their biodistribution and target site accumulation have been detailedly documented upon labeling them with radionuclides, magnetic resonance contrast agents and fluorophores [24][25][26][27][28].Preclinically, drug delivery systems generally work very well, with significant improvements in both target site accumulation and therapeutic efficacy. Clinically, however, due to the abovementioned large inter-and intraindividual variability in EPR, the efficacy of passively tumor-targeted nanomedicines is compromised, with often significant improvements in tolerability, but hardly any increases in efficacy [9,10,14].…”

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confidence: 99%

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Characterizing EPR-mediated passive drug targeting using contrast-enhanced functional ultrasound imaging

Theek

Gremse

Kunjachan

et al. 2014

Journal of Controlled Release

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The Enhanced Permeability and Retention (EPR) effect is extensively used in drug delivery research. Taking into account that EPR is a highly variable phenomenon, we have here set out to evaluate if contrast-enhanced functional ultrasound (ceUS) imaging can be employed to characterize EPR-mediated passive drug targeting to tumors. Using standard fluorescence molecular tomography (FMT) and two different protocols for hybrid computed tomographyfluorescence molecular tomography (CT-FMT), the tumor accumulation of a ~10 nm-sized nearinfrared-fluorophore-labeled polymeric drug carrier (pHPMA-Dy750) was evaluated in CT26 tumor-bearing mice. In the same set of animals, two different ceUS techniques (2D MIOT and 3D B-mode imaging) were employed to assess tumor vascularization. Subsequently, the degree of tumor vascularization was correlated with the degree of EPR-mediated drug targeting. Depending on the optical imaging protocol used, the tumor accumulation of the polymeric drug carrier ranged from 5-12% of the injected dose. The degree of tumor vascularization, determined using ceUS, varied from 4-11%. For both hybrid CT-FMT protocols, a good correlation between the degree of tumor vascularization and the degree of tumor accumulation was observed, with in the case of reconstructed CT-FMT, correlation coefficients of ~0.8 and p-values of <0.02. These findings indicate that ceUS can be used to characterize and predict EPR, and potentially also to preselecting patients likely to respond to passively tumor-targeted nanomedicine treatments. KeywordsDrug targeting; Nanomedicine; Theranostics; Cancer; EPR; HPMA; US; FMT; CT The biodistribution of nanomedicine formulations is very different from that of lowmolecular-weight drugs. As the size of nanocarrier materials generally is above the kidney clearance threshold (~5 nm), they tend to circulate for prolonged periods of time, and they are consequently able to exploit the fact that tumor blood vessels are more leaky that healthy blood vessels, resulting in passive, progressive and relatively selective accumulation at the pathological site over time. This phenomenon is known as the Enhanced Permeability and Retention (EPR) effect [7,8], and it is extensively used in drug delivery research. It is increasingly recognized, however, that EPR is a highly variably phenomenon, presenting not only with large differences between different animal models and patient tumors, but also with large inter-and intraindividual differences between tumors of the same sub-type. And even within a single tumor, certain vessels are significantly more leaky than others. Several recent reviews critically describe and comprehensively discuss the validity and the variability of the EPR effect [9][10][11][12][13][14]. To better understand EPR, to predict which animal models or patient tumors are likely to benefit from EPR-mediated passive drug targeting, and to thereby individualize and improve nano-chemotherapeutic treatments, it therefore seems highly important to identify imageable parameters to c...

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