Photo/radiosensitizers, such as octahedral molybdenum clusters (Mo6), have been intensively studied for photodynamic applications to treat various diseases. However, their delivery to the desired target can be hampered by its limited solubility, low stability in physiological conditions, and inappropriate biodistribution, thus limiting the therapeutic effect and increasing the side effects of the therapy. To overcome such obstacles and to prepare photofunctional nanomaterials, we employed biocompatible and water-soluble copolymers based on N-(2-hydroxypropyl)methacrylamide (pHPMA) as carriers of Mo6 clusters. Several strategies based on electrostatic, hydrophobic, or covalent interactions were employed for the formation of polymer-cluster constructs. Importantly, the luminescent properties of the Mo6 clusters were preserved upon association with the polymers: all polymer-cluster constructs exhibited an effective quenching of their excited states, suggesting a production of singlet oxygen (O2(1Δg)) species which is a major factor for a successful photodynamic treatment. Even though the colloidal stability of all polymer-cluster constructs was satisfactory in deionized water, the complexes prepared by electrostatic and hydrophobic interactions underwent severe aggregation in phosphate buffer saline (PBS) accompanied by the disruption of the cohesive forces between the cluster and polymer molecules. On the contrary, the conjugates prepared by covalent interactions notably displayed colloidal stability in PBS in addition to high luminescence quantum yields, suggesting that pHPMA is a suitable nanocarrier for molybdenum cluster-based photosensitizers intended for photodynamic applications.

• Keywords
• octahedral molybdenum clusters, photodynamic therapy, polymer carrier,
• Publication type
• Journal Article MeSH

Recently, numerous polymer materials have been employed as drug carrier systems in medicinal research, and their detailed properties have been thoroughly evaluated. Water-soluble polymer carriers play a significant role between these studied polymer systems as they are advantageously applied as carriers of low-molecular-weight drugs and compounds, e.g., cytostatic agents, anti-inflammatory drugs, antimicrobial molecules, or multidrug resistance inhibitors. Covalent attachment of carried molecules using a biodegradable spacer is strongly preferred, as such design ensures the controlled release of the drug in the place of a desired pharmacological effect in a reasonable time-dependent manner. Importantly, the synthetic polymer biomaterials based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers are recognized drug carriers with unique properties that nominate them among the most serious nanomedicines candidates for human clinical trials. This review focuses on advances in the development of HPMA copolymer-based nanomedicines within the passive and active targeting into the place of desired pharmacological effect, tumors, inflammation or bacterial infection sites. Specifically, this review highlights the safety issues of HPMA polymer-based drug carriers concerning the structure of nanomedicines. The main impact consists of the improvement of targeting ability, especially concerning the enhanced and permeability retention (EPR) effect.

• Keywords
• EPR effect, HPMA copolymers, controlled release, drug delivery, nanomedicines,
• Publication type
• Journal Article MeSH
• Review MeSH

The study describes the synthesis, physicochemical properties, and biological evaluation of polymer therapeutics based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers intended for a tumor-targeted immuno-oncotherapy. Water-soluble linear and cholesterol-containing HPMA precursors were synthesized using controlled reversible addition-fragmentation chain transfer polymerization to reach molecular weight Mn about 2 × 104 g·mol-1 and low dispersity. These linear or self-assembled micellar conjugates, containing immunomodulatory agent cucurbitacin-D (CuD) or the anticancer drug doxorubicin (Dox) covalently bound by the hydrolytically degradable hydrazone bond, showed a hydrodynamic size of 10-30 nm in aqueous solutions. The CuD-containing conjugates were stable in conditions mimicking blood. Importantly, a massive release of active CuD in buffer mimicking the acidic tumor environment was observed. In vitro, both the linear (LP-CuD) and the micellar (MP-CuD) conjugates carrying CuD showed cytostatic/cytotoxic activity against several cancer cell lines. In a murine metastatic and difficult-to-treat 4T1 mammary carcinoma, only LP-CuD showed an anticancer effect. Indeed, the co-treatment with Dox-containing micellar polymer conjugate and LP-CuD showed potentiation of the anticancer effect. The results indicate that the binding of CuD, characterized by prominent hydrophobic nature and low bioavailability, to the polymer carrier allows a safe and effective delivery. Therefore, the conjugate could serve as a potential component of immuno-oncotherapy schemes within the next preclinical evaluation.

• Keywords
• N-(2-hydroxypropyl) methacrylamide (HPMA), cucurbitacin-D, immuno-oncotherapy, pH-controlled release, signal transducer and activator of transcription 3 (STAT3) inhibition,
• Publication type
• Journal Article MeSH

Patients with inadequate anti-cancer T cell responses experience limited benefit from immune checkpoint inhibitors and other immunotherapies that require T cells. Therefore, treatments that induce de novo anti-cancer T cell immunity are needed. One strategy - referred to as in situ vaccination - is to deliver chemotherapeutic or immunostimulatory drugs into tumors to promote cancer cell death and provide a stimulatory environment for priming T cells against antigens already present in the tumor. However, achieving sufficient drug concentrations in tumors without causing dose-limiting toxicities remains a major challenge. To address this challenge, nanomedicines based on nano-sized carriers ('nanocarriers') of chemotherapeutics and immunostimulants are being developed to improve drug accumulation in tumors following systemic (intravenous) administration. Herein, we present the rationale for using systemically administrable nanomedicines to induce anti-cancer T cell immunity via in situ vaccination and provide an overview of synthetic nanomedicines currently used clinically. We also describe general strategies for improving nanomedicine design to increase tumor uptake, including use of micelle- and star polymer-based nanocarriers. We conclude with perspectives for how nanomedicine properties, host factors and treatment combinations can be leveraged to maximize efficacy.

• Keywords
• Chemotherapeutic and immunostimulant, Immunogenic cell death, Nanomedicine and biomaterials, Nanoparticle and microparticle, Pattern recognition receptor,
• MeSH
• Adjuvants, Immunologic administration & dosage   MeSH
• Immunotherapy methods   MeSH
• Humans MeSH
• Neoplasms drug therapy   immunology   therapy   MeSH
• Nanomedicine methods   MeSH
• Cancer Vaccines administration & dosage   immunology   MeSH
• T-Lymphocytes drug effects   immunology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Names of Substances
• Adjuvants, Immunologic MeSH
• Cancer Vaccines MeSH